A Phase III Randomized, Open-Label, Multi-Center Study of Durvalumab (MEDI4736) Versus Standard of Care (SoC) Platinum-Based Chemotherapy as First Line Treatment in Patients With PD-L1-High Expression Advanced Non Small-Cell Lung Cancer
Phase: PHASE3
Conditions: Non Small Cell Lung Carcinoma NSCLC
Sponsor: AstraZeneca

Clinical Study Protocol 
Drug Substance
Durvalumab (MEDI4736) 
Study Code
D419AC00002
Version
9
Date
18 Jun 2021
A Phase III Randomized, Open-Label, Multi-Center Study of Durvalumab 
Versus Standard of Care Platinum-Based Chemotherapy as First Line 
Treatment in Patients with PD-L1-High Expression Advanced Non Small-
Cell Lung Cancer (NSCLC)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736)
Study Code D419AC00002
Version 9
Date 18 Jun 2021
2 (183)
VERSION HISTORY
Version 9, 18 Jun 2021
Section 1.1 Background and rationale for conducting this study and 1.1.1 Immunotherapies
Reference to <<FDA>> <<US>> approval for use of durvalumab in urothelial cancer has been 
deleted following the voluntarily withdrawal of this conditionally approved indication by 
AstraZeneca, in consultation and with guidance provided by the FDA.
Section 1.4.1 Study Conduct Mitigation During Study Disruptions Due to Cases of Civil Crisis, 
Natural Disaster, or Public Health Crisis and Appendix F
Inserted language describing the study conduct mitigations during study disruptions due to a health 
crisis.
Section 1.3.2.1 Durvalumab
Added risks for Durvalumab rash/dermatitis (pemphigoid) and immune thrombocytopenia.
Section 6.9.1 Specific toxicity management and dose modification information – Durvalumab
TMG portal was decommissioned.
Section 8 Statistical analyses by AstraZeneca
Additional analyses assessing the impact of COVID-19 may be included in the SAP.
Definition of PD-L1 TC ≥50% analysis set in Section 8.3.3 and OS analyses of considering the 
impact of switching to other immunotherapies in Section 8.5.1 were clarified. 
Sentence of “All data collected will be listed.” in Section 8.5 was removed. Details will be specified 
in SAP. 
Minor changes to correct typographical errors.
Version 8, 26 Feb 2020
Change the sole primary objective to dual primary objectives to compare durvalumab 
monotherapy versus standard of care (SoC) in terms of overall survival (OS) in all randomised 
patients (PD-L1 TC ≥25%) and in patients who are at low risk of early mortality (EM) based 
on baseline laboratory values according to a specific prognostic model.
The primary objective of the study has been changed from the sole primary objective of durvalumab 
monotherapy versus SoC in all randomized patients (PD-L1 TC ≥25%) to the dual primary 
objectives of durvalumab monotherapy versus SoC in all randomised patients (PD-L1 TC ≥25%) 
and in patients who are at low risk of early mortality (hereafter referred to as "population at low risk 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736)
Study Code D419AC00002
Version 9
Date 18 Jun 2021
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of early mortality") in terms of OS. The population at low risk of early mortality consists of patients 
identified by a prognostic model developed by AstraZeneca as having low risk of early mortality. 
The multiple testing procedure (MTP) has been updated accordingly to reflect this change. 
In line with the changes to the primary objective, the analysis of interim OS will be performed when 
approximately 85% of final target OS events (approximately 68% maturity) in PD-L1 TC ≥25% 
population, approximately 85% of final target OS events (approximately 64% maturity) in the PD-
L1 TC ≥25% and low risk of early mortality population, and a minimum 12 months follow-up from 
last patient randomized to the study (whichever occurs last). The analysis of final OS will be 
performed when approximately 521 death events (approximately 80% maturity) have occurred in 
PD-L1 TC ≥25% population and approximately 414 death events (approximately 76% maturity) in 
the PD-L1 TC ≥25% and low risk of early mortality population across the durvalumab monotherapy 
and SoC treatment groups (whichever occurs last). 
All relevant sections throughout the protocol have been updated to reflect these changes. This 
includes the Synopsis, Section 1.2 (Rationale for study design, doses and control groups), Section 
1.2.1 (Study population rationale), Section 1.2.4 (Rationale for endpoints), Section 2.1 (Primary 
objectives), Section 2.2 (Secondary objectives), Section 8.2 (Sample size estimate), Section 8.3 
(Definitions of analysis sets) and Section 8.5 (Methods for statistical analyses).
This change has been made based on emerging data that are external to the PEARL study. Immune 
checkpoint inhibitors (ICIs) are profoundly changing the treatment of many types of cancer, 
including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), squamous 
cell carcinoma of the head and neck (SCCHN), urothelial carcinoma (UC), and Hodgkin’s 
lymphoma, and have been associated with long-lasting tumor responses. However, an early 
mortality (EM) phenomenon has been observed in many randomized clinical trials comparing ICIs 
with active comparator arms in advanced or metastatic cancer patients, even with overall benefit 
ultimately favoring ICI therapy (Champiat et al 2018). While the precise etiology of this 
phenomenon is not clearly established, it is characterized by what seems to be disproportionately 
higher mortality in the early treatment period favoring the active control arm, followed by 
subsequent benefit in OS favoring the ICI treatment arm. This is often reflected in the clinical data 
by the “crossing of the Kaplan-Meier curves” suggesting a subpopulation of patients at a higher risk 
of EM whose advanced rate of tumor growth may initially benefit more with chemotherapy. 
Accordingly, it is of great therapeutic interest to better predict the risk of EM for a given patient to 
better choose the appropriate treatment for their individual clinical state. To aid in this objective, 
AstraZeneca has developed and implemented a model that predicts a patient’s risk of EM to 
optimize the benefit: risk profile for treatment of patients with ICIs.
Changes not related to the analysis of the primary endpoint include the following:
Synopsis: Study site(s) and number of subjects planned
Slightly update the description for “global sites include China and other countries”.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736)
Study Code D419AC00002
Version 9
Date 18 Jun 2021
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Remove the sensitivity analysis of PFS based on RECIST 1.1 modified for confirmation of 
progression using Investigator assessments in the footnote.  
Section 1.1 Background and rationale for conducting this study.
A discussion added on the role of ICI in NSCLC and in 1st line setting, to reflect the evolving 
treatment algorithm up to date.
Section 1.3.2.1 Durvalumab
Updated the potential risk of durvalumab based on pooled safety data across the durvalumab 
monotherapy programme.
Section 2.2 Secondary objectives
Add PFS, ORR, DoR, APF12, PFS2 in patients with PD-L1 TC ≥50% as secondary endpoints, add 
OS, PFS, ORR, DoR, APF12, PFS2 in patients with PD-L1 TC ≥50% and low risk of early
mortality as secondary endpoints. Remove the sensitivity analysis of PFS based on RECIST 1.1 
modified for confirmation of progression using Investigator assessments in the footnote.  
Section 4.1 Enrolment/screening period
Add the statement to clarify the requirement of the laboratory and imaging procedures performed 
prior to signing consent.
Section 6.5 Regulatory reporting requirements for SAEs 
Added a new section of “Regulatory reporting requirements for SAEs” to appropriately describe the 
process and sponsor responsibilities for SAE and SUSAR reporting in AZ studies. 
Section 6.9.2 Adverse events of special interest
Updated AESI list based on pooled safety data across the durvalumab monotherapy programme. 
Added more content in “Other inflammatory events”.
Section 6.10 Study governance and oversight
Updated for IDMC frequency and unblinded IDMC review on interim analysis summaries of 
efficacy date. 
Section 7.7.1 Other concomitant treatment
Emphasis that steroids and other immunosuppressant rescue medication has to be made available to 
this patient population.
Section 8 Statistical analyses by AstraZeneca

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736)
Study Code D419AC00002
Version 9
Date 18 Jun 2021
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Sample size estimate, definitions of analysis sets and multiple testing procedures for controlling the 
type I error rate were updated in alignment with revised objectives in Section 2. The sensitivity
analysis of PFS based on RECIST 1.1 modified for confirmation of progression using Investigator 
assessments was removed in alignment with Section 2.
Additional changes are:  
1.
Max-combo test was added as sensitivity analysis for OS. OS subgroup analyses were 
modified.
2.
Wording in Section 8.4.1.1 Time from randomization to second progression (PFS2) 
modified to clarify the timing of assessments for a second progression event, to align with 
the durvalumab project level CSP standard template: Actual timing of assessments for a 
second progression event will be according to local standard practice. 
3.
Wording in Section 8.4.1.1 Best objective response modified to consider 1 week assessment 
window instead of 3 days.
4.
Wording in Sections 8.4.1.1 and 8.5 Objective response rate (ORR), duration of response 
(DOR) and best objective response (BOR) modified to add the analyses based on confirmed 
response. 
5.
The analysis of time to deterioration for EORTC QLQ-C30 scales/items was modified in 
Section 8.4.3.1. Wording in Section 8.4.3.2 Lung cancer module (EORTC QLQ-LC13) 
modified to consider a minimum clinical meaningful change of 10 instead of 5.
6.
The analysis of expected duration of response (EDoR) was removed to be consistent with 
other durvalumab studies in Section 8.5. 
7.
The analysis of comparison of APF12, OS12, OS18 were removed to be consistent with 
other durvalumab studies in Section 8.5. Kaplan Meier estimates of APF12, OS12 and OS18 
will still be provided for each treatment arm.  
Minor changes to correct typographical errors.
Version 7, 22 May 2019
Section 4 Study plan and timing of procedures 
In Tables 4, a text added to clarify that immunogenicity assessment (ADA sampling) is applicable 
for patients in the durvalumab group only.
Section 8 Statistical analyses by AstraZeneca
Minor changes to correct typographical errors.
Version 6, 09 Apr 2019
Synopsis was modified to reflect the changes in Section 2 (Study objectives), Section 7.2.2 
(Duration of treatment), Section 8 (Statistical analyses by AstraZeneca) and Section 9.3 (Study 
timetable and end of study). 

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Study Code D419AC00002
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Date 18 Jun 2021
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Section 1.2.4 Rationale for endpoints
OS18 and OS24 were added as secondary endpoints, based on emerging data external to this study 
suggesting the clinical importance in the immunotherapy setting. 
Section 1.3 Benefit/risk and ethical assessment
Updated information from the PACIFIC study was added. 
Additional information on the potential risks that based on the mechanism of action of PD-1/PD-
L1/CTLA-4 anti-bodies were added.
Section 2 Study objectives
Explicitly stated that the primary endpoint for this study is the OS in PD-L1 TC ≥ 25% population 
for the sake of clarity. 
OS18 and OS24 were added as secondary endpoints, based on emerging data external to this study 
suggesting the clinical importance in the immunotherapy setting. 
Section 3.9 Discontinuation of investigational product
The procedures for patients who permanently discontinue drug for reasons other than objective 
RECIST disease progression and discontinued for unconfirmed progression was introduced in this 
section to align with the durvalumab project level CSP standard template and to maintain 
consistency across the durvalumab program. 
Clarified the survival follow-up procedure for patients who decline to return to the site.
Section 3.10.2 Withdrawal of the informed consent
Specified in more detail on the different scenarios of withdrawn consent. 
Specified the survival follow-up procedure for withdrawn consent and lost to follow-up patients.
Section 4 Study plan and timing of procedures 
Added clarifications to the schedules for regular study assessment and in the event of dose delay.
Section 4.2 Treatment period
The recommended assessment order for vital signs, electrocardiograms (ECGs), and blood draws 
scheduled for the same nominal time were added, to be in line with the follow-up period.
Section 5.1 Efficacy assessments
Modified the criteria for confirmed radiologic progression to align with the durvalumab project level 
CSP standard template which is consistent with previous version but has wording modified.

Clinical Study Protocol
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Study Code D419AC00002
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Date 18 Jun 2021
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Section 5.2.1 Laboratory safety assessments
Clarified the requirement of ‘All patients should have further chemistry profiles performed at 30 
days (±3 days), 2 months (±1 week) and 3 months (±1 week) after permanent discontinuation of IP 
(see Table 4).
Section 5.2.4 Vital signs
Modified the vital sign assessment guidance to align with the durvalumab project level CSP 
standard template to maintain consistency across the durvalumab program.
Section 6.1.8 Death
Added the instruction to remind that all death cases with causality assessment should be documented 
in the ‘Statement of Death page’ in the eCRF.
Section 6.7 Medication Error
Section 6.7 was added to outline the medication error reporting procedure.
6.8.1 Specific toxicity management and dose modification information – Durvalumab
Slightly revised the session to indicate that the TMGs is now a standalone clinical document as 
annex to the protocol.
Section 6.8.2 Adverse events of special interest
Modified the AESI category and instruction on Toxicity Management Guidelines to align with the 
durvalumab project level CSP standard template to maintain consistency across the durvalumab 
program.
Updated terminology from immune-related Adverse Event (irAE) to immune-mediated Adverse 
Event (imAE).
Section 7.1.1 Durvalumab (MEDI4736)
The section for durvalumab was updated with the current recommendations for preparation and dose 
calculations.
Section 7.2.2 Duration of treatment
Wordings modified on ‘Progression during treatment’ based on durvalumab project level CSP 
standard template to be consistent across program.
Updated text to clarify the data collection options for long-term overall survival after Final analysis.
Section 7.3 Labeling 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736)
Study Code D419AC00002
Version 9
Date 18 Jun 2021
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Added the wording of ‘Label text prepared for durvalumab (MEDI4736) 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.’
Section 7.4 Storage 
Updated the instruction for storage, the requirement of temperature log, and the report of 
temperature excursions outside the permissible range.
Section 7.7 Concomitant and other treatments
Added the remind of reporting duration on concomitant medicines which should be ‘from the time 
of screening until the end of the clinical treatment phase of the study, including the 90 days follow-
up period following the last dose of study drug’, to be aligned with Table 4.
Added ‘For agents in the SoC arm, please refer to the local prescribing information with regards to 
warnings, precautions, and contraindications.’
Section 8 Statistical analyses by AstraZeneca
Updated to be consistent with the change in Section 2 with the following other changes.
Update of interim analysis plan to remove one of two planned IA's and conduct the only IA at 85% 
of target OS events at final and a minimum 12 months follow-up since last patient randomized in the 
study (whichever occurs later) in sections 8.2, 8.4 and 8.5. Emerging data external to this study 
suggests that longer follow-up is needed for an IA. 
Removal of disease control rate in sections 8.4.1.1 and 8.5.3. Emerging understanding of 
immunotherapy suggests that the existing efficacy endpoints in Section 2 are sufficient to 
characterize the clinical benefit. 
Minor changes to correct typographical errors.
Section 9.3 Study timetable and end of study
Updated the end of study date as per the latest prediction.
Dosing Modifications and Toxicity Management
Previous Appendix F (Dose Modification and Toxicity Management Guidelines for Immune-
mediated, Infusion related, and Non Immune-mediated Reactions) was removed from study protocol 
and became a standalone clinical document.
Version 5, 13 Mar 2018

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736)
Study Code D419AC00002
Version 9
Date 18 Jun 2021
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Synopsis was modified to reflect the changes in Section 1.4 (Study design), Section 2 (Study 
objectives) and Section 8 (Statistical analyses by AstraZeneca). 
Section 1.2.4 (Rationale for endpoints)
The rationale was updated as OS will be the only primary endpoint.
Section 1.3 (Durvalumab)
Information on PACIFIC study was added.
Section 1.4 (Study Design)
Numbers of subjects randomized, and per treatment group were updated to 650 and 325, 
respectively. Figure 1 (overall study design) was updated accordingly. The sample size was updated 
based on changes of primary endpoints as well as changes of statistical assumptions.
Section 2 (Study objectives)
1.
Remove PFS from co-primary endpoint and make it a secondary endpoint. This change is 
based on emerging data suggesting OS might be a more meaningful endpoint to demonstrate 
efficacy in first line NSCLC patients treated with IO. 
2.
The RECIST based secondary endpoints including PFS, ORR, DoR, and APF12 will be 
based on Investigator assessments instead of BICR assessments. Sensitivity analysis based 
on irRECIST 1.1 is removed.  
3.
To assess the efficacy of durvalumab compared to SoC in terms of OS among subjects with 
PD-L1 ≥ 50% is added as one of the secondary objectives.  
Section 3.2 – Exclusion criteria
The following expression is added to Exclusion criterion #4 ‘Asymptomatic brain metastases 
discovered during screening period must confirm stability in no less than 2 weeks by imaging 
(intravenous contrast-enhanced MRI (preferred) or IV contrast-enhanced CT).’  Patients with brain 
metastases should not enter the study unless the brain metastases are asymptomatic and confirmed 
stable. 
Exclusion criterion #7 added ‘or haemoglobin ≥9.0 g/dL but with transfusion 4 weeks prior to the 
screening and randomization’.
Exclusion criterion #13 ‘Mean QT interval corrected for heart rate using Fridericia’s formula 
(QTcF) ≥470 ms’ has been deleted. Data from the ECG analysis in ATLANTIC suggest no effect 
of durvalumab on QT interval, and the durvalumab serum concentration versus change in QTcF 
analysis did not indicate a risk for clinically significant QT prolongation. Current data did not
indicate any QT liability or identify a risk for other adverse ECG or cardiovascular effects following 
exposure to durvalumab.

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Study Code D419AC00002
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Date 18 Jun 2021
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Section 3.3 – Patient enrolment and randomization
The requirement for EGFR and ALK status before sending PD-L1 sample is deleted. There are no 
medical or scientific concerns associated with running EGFR/ALK and PD-L1 test at the same time. 
Therefore, it is allowed to test EGFR/ALK/PD-L1 in parallel. 
Remove the procedure to record the pre-defined SOC in IVRS/IWRS system.
Section 4 (Study plan and timing of procedures)
In Tables 2 and 4, footnotes relating to ADA collection during/after retreatment were removed as 
retreatment is not applied for this study.
The title of Table 4 was revised properly.
Section 5.1 (Efficacy assessments)
The original plan of full BICR review is updated to be performed at the discretion of AstraZeneca as 
PFS changed to secondary endpoint. 
Section 5.2.3 – Electrocardiograms
Removed QTcF requirement to keep consistent with exclusion criteria.
Section 5.4.2 – Storage and destruction of ADA samples
Add the clarification for China.
Section 5.5-Biomarker analysis
Add the clarification for China.
Modify the wording on Chain of custody of biological samples based on practice.
Section 6.3.12 (Safety Data To Be Collected following the final DCO of the study)
This section was introduced to align with the durvalumab project level CSP standard template to 
maintain consistency across the durvalumab program.
Section 7.2.2 (Duration of treatment)
Post final Data Cut Off information was introduced in this section to align with the durvalumab 
project level CSP standard template to maintain consistency across the durvalumab program.
Section 8.2 (Sample size estimate) 
1.
PFS has been dropped from co-primary endpoints. Sample size is updated to power for 
primary OS analysis. The alpha previously assigned to PFS has been reassigned to OS.  

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736)
Study Code D419AC00002
Version 9
Date 18 Jun 2021
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2.
OS assumption is revised. As a result, the number of subjects randomized increase from 440 
to 650. The final OS analysis will occur after approximately 520 events have been observed. 
Two OS IAs are planned at approximately 60%, and 72% of target events.  
Section 8.3 (Definitions of analysis sets)
Table 9 is updated to reflect the changes in Section 2. 
PD-L1 TC ≥50% analysis set was added.
Section 8.4 (Outcome measures for analyses)
Updated to be consistent with changes in Section 2. The efficacy variables based on BICR 
assessments have been removed. 
Section 8.5 (Methods for statistical analyses)
Updated to be consistent with changes in Section 2 and Section 8.2 with following additional 
changes:
1.
Adding the subgroup analyses for OS endpoint (including but not limited to, sex, age at 
randomization, level of PD-L1 expression,  histology and smoking status, and region) and 
some supportive analyses (access the effect of covariates on HR, test the interaction 
between treatment and stratification factors).
3.
Test of secondary OS endpoint is included in the multiple testing procedure. 
Appendix D (Guidelines for Evaluation of Objective Tumor Response)
Central review section is removed.
Version 4, 15 December 2017
Section Protocol synopsis and 8.5.1.1 -Progression-free survival
Typo update: The HR will be estimated using a stratified Cox model.
Section Protocol synopsis 
Progression during treatment some wordings are updated to be in line with the new protocol 
template. 
Section 1.1.1 – Immunotherapies, 1.1.2 – Durvalumab, 1.2.2 – Durvalumab dose rationale and 
1.3.2.1 – Potential risks
CCI

Clinical Study Protocol
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Study Code D419AC00002
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Background information, durvalumab PK/PD data, clinical data and safety profile have been 
updated according to the new investigator’s brochure. 
Section 3.1 – Inclusion criteria
The performance status criteria used in criterion #6 has been updated as ‘World Health Organization 
(WHO)/Eastern Cooperative Oncology Group (ECOG)’ to ensure accuracy of expression.
Life expectancy of at least 12 weeks has been added as inclusion criterion #8.
Section 3.2 – Exclusion criteria
Some more exceptions are added to original exclusion criterion #14 regarding autoimmune and 
inflammatory disorders. 
Section 3.8 – Restrictions, section 3.9 – Discontinuation of investigational product
Some wordings are updated to be in line with the new protocol template. 
Section 5.3.3 – ECOG performance status
Added “5 = Dead”
Section 5.3.4 – Pneumonitis (ILD) investigation
The whole section has been added to instruct investigation of pneumonitis and to support the use of 
ILD module in eCRF. 
Section 6.1.8 – Deaths 
An instruction about the recording of deaths occurring after defined safety follow up period has 
been added. 
Section 6.3 – Recoding of adverse events, section 6.5 - overdose
The wordings have been updated based on Durvalumab project level CSP standard template to be 
consistent across program.
Section 6.7.1 - Specific toxicity management and dose modification information – Durvalumab
An overall irAE management and dose modification principles has been added. the etiology of 
adverse events should be carefully investigated and durvalumab Dosing Modification and Toxicity 
Management Guidelines should be referred to if AE is considered potentially immune related. Dose 
reductions of Durvalumab is not permitted.
Section 6.7.2 - Durvalumab adverse events of special interest 

Clinical Study Protocol
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Study Code D419AC00002
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AESI list has been updated. Myocarditis and myositis/polymyositis have been added to the list to 
reflect the update of durvalumab safety profile. Some minor changes of description have been made 
to other AESIs.
Section 6.7.3 - Standard of Care agents
The wordings have been updated based on Durvalumab project level CSP standard template to be 
consistent across program.
Section 7.2.1 – Treatment regimens
Clarified that durvalumab treatment should be given unless there is unacceptable toxicity, 
withdrawal of consent, or another discontinuation criterion is met. Clarified the standard infusion 
time is one hour. SoC regimen in CSP should be strictly followed once chosen unless local standard 
clinical practice guideline or local prescribing information states otherwise.
Section 7.2.2 – Duration of treatment
The definition of duration of treatment and progression during treatment is updated. Both arms will 
continue therapy until disease progression. Both arms with PD can receive treatment beyond PD if
they continue to receive benefit from their assigned treatment and meet the criteria for treatment in 
the setting of PD. Wordings have been updated based on Durvalumab project level CSP standard 
template to be consistent across program.
Section 7.7 – Concomitant and other treatments
Emphasised that patients should consult the investigator before taking any medications. 
Restricted, prohibited, and permitted concomitant medications list has been updated. The usage of 
immunosuppressive medications has been revised to give a more specific instruction. EGFR TKIs 
and herbal remedies have been added as prohibited medication. Inactivated viruses have been added 
as permitted medication. 
Section 7.7.2 – Durvalumab drug drug interactions
Standard wordings of drug interactions has been added based on Durvalumab project level CSP 
standard template to be consistent across program.
Appendix F - Dose Modification and Toxicity Management Guidelines for Immune-mediated, 
Infusion related, and Non Immune-mediated Reactions
The new version of Dose Modification and Toxicity Management Guidelines have been added to 
replace the old one.
Version 3, 19 September 2016

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Study Code D419AC00002
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Title pages and Section 7 – Investigational product and other treatments
MEDI4736 is replaced with its generic name “durvalumab” in the study title and throughout the 
document.
In Section 7, “durvalumab (MEDI4736)” is used to clarify that durvalumab and MEDI4736 are the 
same drug and the names may be used interchangeably in other study documents and drug labels.
“Asia Pacific” is removed due to the planned participation of other countries outside of Asia in order 
to recruit approximately 10% Caucasian patients. The inclusion of 10% Caucasian patients is to 
provide evidence for durvalumab monotherapy in support of the global program.
Synopsis, Section 1.2.4 – Rationale for Endpoints, Section 2 – Study Objectives, Section 5.1 –
Efficacy Assessments, Section 8.4 – Outcome Measures for Analysis, Section 8.5 – Methods for 
Statistical Analysis
The primary and secondary objective endpoints have been updated to reflect changes to endpoint 
measures - Blinded Independent Central Review (BICR) tumor assessments rather than Investigator 
assessments. Investigator assessments will be used for sensitivity analysis. This change was made in 
order to comply with China regulatory requirement for assessments to be based on BICR if PFS will 
be used for registration.
Synopsis, Section 1 – Introduction, Section 1.4 – Study design, Section 2, and Section 3 – Study 
objectives, Section 3 – Patient selection, section 7-IP and other treatment and Section 8 –
Statistical Analyses
The overall study design was revised from a 3-arm study of combination therapy of durvalumab +
tremelimumab vs durvalumab vs SoC to 2-arm study of durvalumab monotherapy vs SoC.
The assessment of progression-free survival (PFS) and overall survival (OS) were nominated as 
co-primary objectives.  Primary and secondary objectives, endpoints and rational for endpoints were 
modified accordingly.
Study population was updated to include only PD-L1-high patients (as PD-L1 expression ≥25% 
who shall be randomized on a 1:1 ratio into 2 treatment groups: durvalumab and SOC. 
The sponsor decided to amend the clinical development strategy of durvalumab to: a) allow 
evaluating the efficacy of durvalumab monotherapy comparing with SoC with sufficient power in a 
2-arm study; b)refine the target patient population from PD-L1 unselected to PD-L1 high expression 
that has greater possibility to respond to durvalumab in order to improve the benefit risk profile of 
the study; c) accommodate the emerging data from other immuno-oncology studies, which suggest 
that the treatment benefit of immunotherapies can more strongly manifest in OS compared to PFS, 
this enables to increase the possibility of success of the study and also in line with the consultation 
with Chinese Health Authority. 

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Study Code D419AC00002
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Introduction was updated to remove irrelevant references to the combination treatment or 
tremelimumab.
Stratification factors were amended to include level of PD-L1 expression and histology + smoking 
status. Smoking status was added based on results in CD-ON-MEDI4736-1108 study showing 
difference response rates based on smoking status. Level of PD-L1 expression was added to ensure 
the uniform distribution of PD-L1 intensity which correlates with the magnitude of response in each 
treatment group.
Inclusion and exclusion criteria were updated to add patient must have tumor cell PD-L1-high 
expression status, prior to randomization, defined as ≥25% PD-L1–membrane expression in 
tumoral tissue. The requirement for patients to use effective birth control for up to 180 days after 
last dose of IP was also removed since only up to 90 days is required for durvalumab.
Statistical analysis plan was updated accordingly based on study design change.
Synopsis, Section 1.4 – Study design and Section 8.2 – Sample size estimate 
Numbers of subjects enrolled, randomized, and per treatment group were updated to 1760, 440, and 
220, respectively.  Figure 1 (overall study design) and Figure 2 (study flow chart) were updated 
accordingly. The sample size was updated based on statistical assumptions related to change in 
primary endpoints and target population.
Synopsis, Section 7.2.2 - Duration of treatment 
All references to retreatment were removed since retreatment was only applicable to the durvalumab 
+ tremelimumab treatment group in the previous CSP version. Figure 2 (study flow chart) was also 
updated accordingly.
Section 3 - Patient Selection, enrolment, and randomization
The following statement was deleted: “If a patient has squamous histology or is known to have a 
tumor with a KRAS mutation, then EGFR and ALK testing is not required” The prevalence rate of 
KRAS mutation is relatively rare in Asian population, nevertheless, EGFR mutation rate in Asia in 
squamous NSCLC is around 14% which is much higher than in Caucasians, permission of skipping 
EGFR/ALK testing in squamous patients will increase the false negative rate of EGFR/ALK testing 
and make the target population less homogenous. 
Section 3.3- Patient Enrolment and Randomization, Section 4 – Study Plan and Timing of 
Procedures
In order to manage high screen failure rate due to PD-L1 expression < 25%, guidance was added to 
consent patient and test for PD-L1 status and EGFR and ALK status, if unknown, if clinically 
feasible before proceeding with the rest of the screening procedures.
Section 7.7 – Concomitant and other treatments

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736)
Study Code D419AC00002
Version 9
Date 18 Jun 2021
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Updates were made including the deletion of drugs with laxative properties, herbal or natural 
remedies, and sunitinib from the prohibited medication table. The restrictions on these drugs are 
related only to tremelimumab.
Prohibiting the use mAbs against CTLA-4, PD-1, or PD-L1 within 90 days of last dose of IP was 
also deleted. This is in accordance with the Sponsor’s new standard template for durvalumab studies 
since physicians and patients are at liberty to select any treatment after they discontinue the IP.
Section 3.8 Restrictions
Spermicide was removed from Table 1. Highly effective methods of contraception, it is not solely a 
highly effective method of contraception.
Section 6 – Safety reporting and medical management and Appendix F.
Updated toxicity management guidelines were incorporated.
Section 5.1 – Efficacy assessments, Section 7.2 – Duration of treatment, Table 4, and Appendix 
D.
Specified additional criteria for confirmed radiologic progression in section 5.1 and Appendix D. 
The CSP was also revised to clarify that confirmatory scan is required in both treatment arms 
provided the patient is clinically stable.
Table 4 was updated to add footnote “If the patient continues to derive benefit from study treatment, 
then scans should continue to be collected following the original schedule and analysed by 
RECIST1.1, even after confirmed radiographic progression.”
Clarified criteria for treatment in setting of PD in section 7.2.2. 
Section 5.5.2 –
 
Version 2, 20 April 2016
Title pages
MEDI4736 is identified as durvalumab in Drug substance in the header box, and referred to as 
MEDI4736 thereafter.
Title updated to specify patients from Asia Pacific rather than “Asian” patients, in anticipation that 
Australia may be selected to participate in the study.
Protocol Synopsis
Updated to add the information on International Coordinating Investigator Professor Yilong Wu.
CCI
CCI

Clinical Study Protocol
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Study Code D419AC00002
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Date 18 Jun 2021
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Synopsis, Section 7.2.2 Duration of treatment and criteria for retreatment
Duration of treatment was modified so that patients in all groups can continue therapy until disease 
progression rather than stopping at 12 months.  Emerging data from ongoing MEDI4736 studies is 
suggestive of some patients losing clinical benefit after they complete the 12 months of therapy.
In all groups, patients with PD (unconfirmed and confirmed) who, in the Investigator’s opinion, 
would continue to receive benefit from their assigned treatment, and who meet the criteria for 
treatment in the setting of PD, may continue to receive treatment.  It was also clarified that patients 
on MEDI4736 alone will not be permitted to continue immunotherapy, if the progression occurs 
after confirmed response to immunotherapy treatment within the target lesion, and if progression 
events occurred in the target lesions while the patient was receiving immunotherapy during the same 
treatment period. 
Sections 1.2.1 and 1.2.3 - MEDI4736 + tremelimumab combination therapy and MEDI4736 
monotherapy dose rationale
Reference made to current IB for further details on safety profile of studies D4190C00006 and CD-
ON-MEDI4736-1108.
Section 1.2.5 - Rationale of retreatment option
The rationale for the retreatment option is amended to enable patients in the MEDI4736 + 
tremelimumab combination group who complete 4 dosing cycles (providing clinical benefit per 
Investigator judgement), and subsequently have PD during treatment with MEDI4736 alone, to 
restart combination treatment, if they also meet eligibility criteria.  
Section 1.3.2.1 - MEDI4736 + tremelimumab
Pneumonitis, colitis, diarrhoea, and AST and ALT elevations were added as “identified risks”. The 
potential risks, based on the mechanism of action of MEDI4736 and related molecules, are updated 
to “hepatitis/hepatotoxicity, neuropathy/neuromuscular toxicity, endocrinopathy, dermatitis, and 
nephritis.  In addition, pancreatitis is an important potential risk.  Other inflammatory responses 
with potential immune-mediated aetiology reported with MEDI4736 and similar molecules include 
myocarditis, pericarditis, and uveitis” in accordance with the current Investigator Brochure. A 
sentence was added to refer to current IB for further details on the safety profile of MEDI4736 as 
monotherapy or combination therapy. 
Section 1.4 – Study design
The timing for patients to provide a tumor tissue sample was clarified as being the enrolment visit.
Section 3.1 – Inclusion criteria
Patients must have tumors that lack sensitizing EGFR mutation (e.g., exon 19 deletion or exon 21 
L858R, exon 21 L861Q, exon 18 G719X, or exon 20 S7681 mutation) and ALK rearrangement.  (If 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736)
Study Code D419AC00002
Version 9
Date 18 Jun 2021
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a patient has squamous histology or is known to have a tumor with a KRAS mutation, then EGFR 
and ALK testing is not required).
This inclusion criterion was updated to clarify that testing for epidermal growth factor receptor 
(EGFR) and anaplastic lymphoma kinase (ALK) can occur locally or centrally. “Activating EGFR 
mutation” was changed to “sensitizing EGFR mutation” to align with global MYSTIC study.
Section 3.2 - Exclusion criteria

Sarcomatoid variant of NSCLC is added as an exclusion criteria.

The part of the exclusion criteria of brain metastases or spinal cord compression and off steroids 
and anticonvulsants for at least 1 month prior to study treatment is amended to and off steroids 
for at least 14 days prior to study treatment.  In addition, following radiotherapy and/or surgery, 
patients with brain metastases must wait 4 weeks after the intervention and must confirm stability 
with imaging before randomization. 

Tuberculosis (clinical evaluation) has been added to hepatitis B, hepatitis C and human 
immunodeficiency virus as part of the active infection exclusion criterion.  The exclusion 
criterion Known history of clinical diagnosis of tuberculosis has been deleted.  In addition 
supplementary information on the diagnoses are given: 

HIV diagnosis requires positive HIV 1 or 2 antibodies.  

Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) 
result.  Patients with a past or resolved HBV infection (defined as the presence of hepatitis B 
core antibody and absence of HBsAg) are eligible.  

Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain 
reaction is negative for HCV ribonucleic acid (RNA).

Calculated creatinine clearance >50 mL/min as determined by Cockcroft-Gault (using actual 
body weight) or 24 hour urine collection

Known allergy to other humanized mAbs was added based on comments from EMA in the 
review of the global MYSTIC protocol.
Section 3.3 – Patient enrolment and randomization and Study Plan Tables

Item 3 was updated to add below paragraph to provide more clarity on EGFR and ALK mutation 
testing:

The sample should be sent only for the patient with known EGFR and ALK status. If a patient 
has squamous histology or is known to have a tumor with a KRAS mutation, then EGFR and 
ALK testing is not required. If EGFR and ALK status is unknown, then the tumor sample 
(archive or fresh, primary or metastatic) should be used firstly for (local or central) EGFR and 
ALK mutation testing in accordance to inclusion criterion 4. If local laboratory will perform the 
test, a well-validated, local regulatory-approved kit must be used.

To provide more clarity the study plan tables were updated to include EGFR and ALK testing as 
optional for patient with unknown status of ALK and/or EGFR NSCLC (if a patient has 
squamous histology or is known to have a tumor with a KRAS mutation, then EGFR and ALK 
testing is not required).

Clinical Study Protocol
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Study Code D419AC00002
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Date 18 Jun 2021
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progression, available readings of CT/MRI from local practice will be collected from the 
patients’ medical charts while information on subsequent anticancer treatment and/or PFS2 is 
collected”.

Tumor evaluations were updated to add a window period: “Every 6 weeks ± 1 week for the first 
48 weeks relative to the date of randomization, and then every 8 weeks ± 1 week thereafter.

Schedule of pregnancy tests were updated from “as clinically indicated” to be performed at 
screening and subsequent visits during MEDI4736 + tremelimumab combination therapy and 
MEDI4736 monotherapy treatment and retreatment periods. This change was based on 
comments from EMA in the review of global MYSTIC protocol.

A footer was inserted in Table 4 to clarify that ADA sample collection is not required for patients 
who are in follow-up after retreatment
Section 5.1 - Efficacy Assessments
The timing for performing the baseline assessment was modified to no more than 28 days before 
randomization rather than no more than 28 days before the start of IP treatment.
Section 5.1 Efficacy assessments and Study Plan Tables
Sections were updated to clarify when confirmatory scans must occur (preferably at the next 
scheduled visit). The confirmatory scan must be no sooner than 4 weeks after the initial suspected 
progression and preferably at the next scheduled visit (in the absence of clinically significant 
deterioration).
Section 5.2.1 - Laboratory safety assessments
In Table 5, provision is made that if the amylase and lipase analyses could not be performed in a 
local laboratory, then 1 or the other would be performed in line with local practice.
In Table 6, coagulation was updated to specify that APTT and INR will be assessed at Screening as 
indicated in the table footnote.
Section 5.2.4 – Vital signs
Blood pressure may now be measured in a supine or semi-supine position rather than just a supine 
position.
An update was also made so that on subsequent infusion days after first infusion, patients in the 
MEDI4736 + tremelimumab and MEDI4736 monotherapy treatment groups will be monitored at the 
start of the infusion and then per institution standard and as clinically indicated.  
Section 6 – Safety reporting and medical management
In accordance with the new protocol template, the following first 3 sub-sections of Section 6 were 
reordered from:

Clinical Study Protocol
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Study Code D419AC00002
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6.1 Definition of serious adverse events
6.2 Recording of adverse events
6.3 Definition of adverse events
to
6.1 Definition of adverse events
6.2 Definition of serious adverse events
6.3 Recording of adverse events
Appendices and Section 6.7 – Management of investigational product-related toxicities 
Appendices were updated with the addition of Appendix F which contains the new version of the 
Dosing Modification and Toxicity Management Guidelines for Immune-mediated, Infusion-related, 
and Nonimmune-mediated Reactions (MEDI4736 Monotherapy, Tremelimumab Monotherapy, or 
MEDI4736 + Tremelimumab Combination Therapy. The old version formerly inserted as Table 8 
in the main body of the protocol was deleted.  A new version of EORTC QLQ-C30 was included in 
Appendix E.
Section 6.7.1 - MEDI4736 + tremelimumab and MEDI4736 monotherapy adverse events of 
special interest (AESI)
This section was updated to reduce the emphasis on MEDI4736 and tremelimumab’s biochemical 
properties in relation to AESIs, and also to remove the explanation of MEDI4736’s main AESIs and 
refer the reader to the current IB where these are explained in full, together with specific guidelines 
for their evaluation and treatment.
Sections 7.2.1 Treatment regimes
The paragraph was amended to delete the part stating that for SoC therapies, a particular treatment 
will not be used in patients who have previously received that treatment for advanced or metastatic 
disease. This change is based on comments from EMA during the review of global MYSTIC 
protocol.
Sections 7.1.1 and 7.1.2. – MEDI4736 and tremelimumab
The section for MEDI4736 and tremelimumab is updated with the current recommendations for 
preparation and dose calculations. 
Section 7.7 – Concomitant and other treatments
In the section on prohibited medications, the following amends are made:

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736)
Study Code D419AC00002
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Date 18 Jun 2021
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Systematic corticosteroid will be permitted for the prevention of chemotherapy-related toxicities 
(nausea/vomiting prevention and prophylaxis).
Drugs with laxative properties should be used with caution rather than avoided during treatment 
with and for 90 days after last dose of tremelimumab during the study.
Sunitinib should not be given within 3 months of a dose of tremelimumab (acute renal failure has 
been reported with combination therapy of tremelimumab and sunitinib).
Herbal and natural remedies in general, rather than those for constipation only, should be avoided 
during treatment with and for 90 days after the last dose of tremelimumab during the study.
Version 1, 12 June 2015
Initial creation.

Clinical Study Protocol
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Study Code D419AC00002
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This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
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.

Clinical Study Protocol
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Study Code D419AC00002
Version 9
Date 18 Jun 2021
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Tumor assessments will be performed every 6 weeks for the first 48 weeks and then every 
8 weeks until confirmed disease progression, with categorization of objective tumor response 
by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).  
Objectives
Primary Objectives:
Outcome Measures:
To assess the efficacy of durvalumab compared to 
SoC in patients with PD-L1 TC ≥25% (all 
randomized patients)
OS
To assess the efficacy of durvalumab compared to 
SoC in patients with PD-L1 TC ≥25% and low 
risk of early mortalitya
OS
Secondary Objectives:
Outcome Measures:
To assess the efficacy of durvalumab compared to 
SoC in terms of OS
OS in patients with 

PD-L1 TC ≥50%

PD-L1 TC ≥50% and low risk of early mortality
To further assess the efficacy of durvalumab 
compared to SoC in terms of PFS, ORR, DoR, 
OS18, OS24, APF12, and PFS2 
PFS, ORR, DoR, APF12 using Investigator assessments 
according to RECIST 1.1, PFS2 using local standard 
clinical practice, OS18 and OS24 respectively in patients 
with 

PD-L1 TC ≥25% 

PD-L1 TC ≥25% and low risk of early mortality 

PD-L1 TC ≥50%

PD-L1 TC ≥50% and low risk of early mortality
To assess disease-related symptoms and HRQoL in 
patients treated with durvalumab compared to SoC 
using the EORTC QLQ-C30 v3 and the LC13 
module
EORTC QLQ-C30, EORTC QLQ-LC13, and changes in 
Eastern Cooperative Oncology Group (ECOG) 
performance status in patients with 

PD-L1 TC ≥25% 

PD-L1 TC ≥25% and low risk of early mortality 
To investigate the immunogenicity of durvalumab 
Presence of ADAs for durvalumab in patients with

PD-L1 TC ≥25% 

PD-L1 TC ≥25% and low risk of early mortality 
a.
The population at low risk of early mortality consists of patients identified by a prognostic model developed by 
AstraZeneca as having low risk of early mortality. 
Safety Objective:
Outcome Measures:
To assess the safety and tolerability profile of 
durvalumab compared to SoC 
AEs, physical examinations, laboratory findings, and vital 
signs

Clinical Study Protocol
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Study Code D419AC00002
Version 9
Date 18 Jun 2021
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Target subject population
Adult patients (age≥18 years) with histologically or cytologically confirmed advanced (stage 
IV) NSCLC who are treatment naive, EGFR and ALK wild type, and with PD-L1-high 
expression.
Duration of treatment
Unless specific treatment discontinuation criteria are met, patients in durvalumab group will 
continue therapy until disease progression, or unacceptable toxicity whichever occurs first. 
Patients in the SoC group will continue up to disease progression (in general up to 6 cycles of 
treatment plus maintenance if eligible). 
Progression during treatment
During the treatment period patients in both arms may continue receiving therapy in the 
setting of unconfirmed radiologic progressive disease (PD) according to Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST 1.1), at the Investigator’s discretion, until 
progression is confirmed.  A confirmatory scan is required following a RECIST 1.1 overall 
time point assessment of progression (PD), preferably at the next scheduled visit and no 
earlier than 4 weeks after the previous assessment of PD.  Patients in both arms with PD by 
RECIST 1.1 (unconfirmed and confirmed) who, in the Investigator’s opinion, continue to 
receive benefit from their assigned treatment and who meet the criteria for treatment in the 
setting of PD may continue to receive their assigned treatment for as long as they are gaining 
clinical benefit. However, patients in the immunotherapy arm will not be permitted to 
continue immunotherapy if progression occurs after confirmed response (CR or PR as defined 
by RECIST 1.1) to immunotherapy treatment in the target lesions (regardless of the 
appearance of new lesions) i.e. the response and progression events both occurred in the target 
lesions while receiving immunotherapy during the treatment period.
Follow up of patients post discontinuation of study drug
Patients who have discontinued study treatment due to toxicity or symptomatic deterioration, 
clinical progression, or who have commenced subsequent anticancer therapy, will be followed 
up until confirmed disease progression and for survival.
Survival
All patients randomised in the study will be followed up for survival. 
Post final Data Cut Off (DCO)
Patients who continue to receive benefit from their assigned treatment at the scheduled DCO 
for final analysis and final database lock may continue to receive their assigned treatment for 
as long as they and their physician feel they are gaining clinical benefit. For patients 
continuing to receive durvalumab treatment following the scheduled DCO for final analysis, it 
is recommended that the patients continue the scheduled site visits. 

Clinical Study Protocol
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Study Code D419AC00002
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Date 18 Jun 2021
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Investigators should continue to monitor and document data for all study patients in the source 
notes after scheduled DCO for final analysis and final database lock. Dependent on the 
analysis results, a decision may be made to continue further data collection for a longer period 
with intent to analyse long-term OS and safety data to fulfil 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 into 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 
continue treatment and only SAEs will be collected.
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 PEARL and 
evaluated as a combined dataset.
Investigational product, and mode of administration
Durvalumab (MEDI4736)

Durvalumab (MEDI4736) 20 mg/kg via IV infusion Q4W, starting on Week 0
Standard of Care therapy
Patients randomized to SoC therapy will receive 1 of the following:

Paclitaxel + carboplatin: Paclitaxel 175 mg/m2 and carboplatin AUC 5 or 6 via IV 
infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles or until documented PD.

Gemcitabine + cisplatin (squamous patients only): Gemcitabine 1000 or 1250 
mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + cisplatin 75 or 80 
mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles or until 
documented PD.

Gemcitabine + carboplatin (squamous patients only): Gemcitabine 1000 or 1250 
mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + carboplatin area 
under the curve (AUC) 5 or 6 via IV infusion on Day 1 of each 21-day cycle, for 4 
to 6 cycles or until documented PD.

Pemetrexed + cisplatin (non-squamous patients only): Pemetrexed 500 mg/m2 and 
cisplatin 75 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles 
or until documented PD.  Non-squamous patients who have not progressed after 4 
cycles will be eligible for pemetrexed maintenance therapy.

Clinical Study Protocol
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Study Code D419AC00002
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
Pemetrexed + carboplatin (non-squamous patients only): Pemetrexed 500 mg/m2
and carboplatin AUC 5 or 6 via IV infusion on Day 1 of each 21-day cycle, for 4 to 
6 cycles or until documented PD.  Non-squamous patients who have not progressed 
after 4 cycles will be eligible for pemetrexed maintenance therapy.
Statistical methods
The primary objectives of this study are to assess the efficacy of durvalumab compared with 
SoC in terms of overall survival (OS) in advanced NSCLC patients with EGFR and ALK 
wild-type and PD-L1-high expression (TC ≥ 25%) tumors, and in the PD-L1 TC ≥ 25% and 
low risk of early mortality population. OS will be defined as the time from the date of 
randomization until death by any cause. To strongly control for type I error at a 5% level (2 
sided), an alpha of 4% (2 sided) will be used for the OS comparison of durvalumab versus 
SoC in the PD-L1 TC ≥ 25% population, and an alpha of 1% (2 sided) will be used for the OS 
comparison of durvalumab versus SoC in the PD-L1 TC ≥ 25% and low risk of early mortality 
population. The study will be considered to have met its primary objective if any of the dual 
primary OS results are statistically significant.
Secondary efficacy variables include OS in patients with PD-L1 TC ≥ 50%, and OS in 
patients with PD-L1 TC ≥ 50% and low risk of early mortality, as well as progression free 
survival (PFS), objective response rate (ORR), duration of response (DoR), proportion of 
patients alive at 18 months from randomization (OS18), proportion of patients alive at 24 
months from randomization (OS24), proportion of patients alive and progression free at 12 
months from randomization (APF12), and time from randomization to second progression 
(PFS2) in patients with PD-L1 TC ≥ 25%, PD-L1 TC ≥ 25% and low risk of early mortality, 
PD-L1 TC ≥ 50%, and PD-L1 TC ≥ 50% and low risk of early mortality. All tumor-
assessment-related endpoints are as assessed by Investigators.
Efficacy data will be summarized and analyzed using an intent-to-treat (ITT) basis and the 
treatment groups will be compared on the basis of randomized treatment, regardless of the 
treatment actually received. Patients who were randomized but did not subsequently go on to 
receive study treatment are included in the ITT population.
Approximately 650 patients will be randomized 1:1 to durvalumab or SoC.  The 
randomization will be stratified based on level of PD-L1 expression (25-49% versus ≥50%), 
histology and smoking status (squamous versus non-squamous + never smoker versus non-
squamous + former/current smoker). The final (primary) analysis of OS will be performed 
when all of the following conditions have been met.

approximately 521 OS events (approximately 80% maturity) have occurred across the 
durvalumab and SoC treatment groups in the PD-L1 TC ≥ 25% population 
           And

approximately 414 OS events (approximately 76% maturity) have occurred across the 
durvalumab and SoC treatment groups in the PD-L1 TC ≥ 25% and low risk of early 
mortality population. 

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Study Code D419AC00002
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One interim analysis to assess the superiority of the durvalumab group (compared to SoC 
group) in terms of OS will be performed when all of the following conditions have been met

approximately 85% of the target 521 OS events (approximately 68% maturity) have 
been achieved across the durvalumab and SoC treatment groups in the PD-L1 TC ≥ 
25% population
And

approximately 85% of the target 414 OS events (approximately 64% maturity) have 
been achieved across the durvalumab and SoC treatment groups in the PD-L1 TC ≥ 
25% and low risk of early mortality population 
And

a minimum 12 months follow-up from last patient randomized to the study.
Durvalumab versus SoC (OS in the PD-L1 TC ≥ 25% population)
With an estimated 521 OS events, the trial will have approximately 86% power to demonstrate 
statistical significance at the 2-sided alpha level of 3.334% (with overall alpha for OS 4%) for 
the comparison of durvalumab versus SoC, allowing for 1 interim analysis conducted at 
approximately 85% of the target events. The alpha level will be controlled by using the Lan 
and Demets (Lan and DeMets 1983) spending function that approximates an O’Brien Fleming 
approach.
Durvalumab versus SoC (OS in the PD-L1 TC ≥ 25% and low risk of early mortality 
population)
With an estimated 414 OS events, the trial will have approximately 87% power to demonstrate 
statistical significance at the 2-sided alpha level of 0.862% (with overall alpha for OS 1%) for 
the comparison of durvalumab versus SoC, allowing for 1 interim analysis conducted at 
approximately 85% of the target events.
The primary OS will be analyzed using a stratified log-rank test. The effect of treatment will 
be summarized by the HR estimated from a stratified Cox model with corresponding 95% 
confidence interval (CI) and p-value. 
Safety data will be summarized descriptively and will not be formally analyzed.

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TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
PROTOCOL SYNOPSIS................................................................................... 24
TABLE OF CONTENTS................................................................................... 30
1.
INTRODUCTION ............................................................................................. 41
1.1
Background and rationale for conducting this study ........................................... 41
Immunotherapies ............................................................................................... 42
Durvalumab ....................................................................................................... 43
Rationale for conducting this study .................................................................... 44
1.2
Rationale for study design, doses and control groups.......................................... 45
Study population rationale.................................................................................. 45
1.2.1.1
Rationale for selecting patients with PD-L1-high expression status.................... 45
1.2.1.2
Rationale for selecting patients who are most appropriate for treatment 
with durvalumab monotherapy........................................................................... 45
Durvalumab dose rationale................................................................................. 46
Rationale for Standard of Care as a comparator.................................................. 47
Rationale for endpoints ...................................................................................... 47
1.3
Benefit/risk and ethical assessment .................................................................... 48
Potential benefits................................................................................................ 48
1.3.1.1
Durvalumab ....................................................................................................... 48
Potential risks .................................................................................................... 48
1.3.2.1
Durvalumab ....................................................................................................... 49
Overall benefit-risk and ethical assessment ........................................................ 49
1.4
Study Design...................................................................................................... 50
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................. 53
2.
STUDY OBJECTIVES...................................................................................... 54
2.1
Primary objectives ............................................................................................. 54
2.2
Secondary objectives.......................................................................................... 54
2.3
Safety objective.................................................................................................. 54
2.4
Exploratory objectives ....................................................................................... 55
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL..................... 55
3.1
Inclusion criteria ................................................................................................ 55

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3.2
Exclusion criteria ............................................................................................... 56
3.3
Patient enrolment and randomization ................................................................. 60
3.4
Procedures for handling incorrectly enrolled patients ......................................... 61
3.5
Methods for assigning treatment groups............................................................. 61
3.6
Methods for ensuring blinding ........................................................................... 62
3.7
Methods for unblinding...................................................................................... 62
3.8
Restrictions........................................................................................................ 62
3.9
Discontinuation of investigational product ......................................................... 64
Procedures for discontinuation of a patient from investigational product ............ 65
3.10
Criteria for withdrawal of the patient from the study .......................................... 65
Screen failures ................................................................................................... 65
Withdrawal of the informed consent................................................................... 66
3.11
Discontinuation of the study............................................................................... 67
4.
STUDY PLAN AND TIMING OF PROCEDURES........................................... 67
4.1
Enrolment/screening period................................................................................ 87
4.2
Treatment period................................................................................................ 87
4.3
Follow-up period................................................................................................ 87
5.
STUDY ASSESSMENTS.................................................................................. 88
5.1
Efficacy assessments.......................................................................................... 88
Central reading of scans ..................................................................................... 89
Survival assessments.......................................................................................... 89
5.2
Safety assessments............................................................................................. 90
Laboratory safety assessments............................................................................ 90
Physical examination ......................................................................................... 92
Electrocardiograms ............................................................................................ 92
Vital signs.......................................................................................................... 93
5.3
Other assessments.............................................................................................. 94
Patient-reported outcomes.................................................................................. 94
5.3.1.1
EORTC QLQ-C30 ............................................................................................. 94
5.3.1.2
EORTC QLQ-LC13........................................................................................... 94
5.3.1.3
.......................................................................................................... 94
Administration of the patient-reported outcome questionnaires .......................... 95
ECOG performance status.................................................................................. 96
Pneumonitis (ILD) investigation ........................................................................ 96
5.4
ADA.................................................................................................................. 97
Collection of samples to measure for the presence of ADAs............................... 97
Storage and destruction of ADA samples ........................................................... 97
CCI

Clinical Study Protocol
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5.5
Biomarker analysis............................................................................................. 98
Collection of patient samples for PD-L1 testing ................................................. 98
...................................................................................... 99
Storage, re-use, and destruction of biological samples........................................ 99
Labeling and shipment of biological samples ................................................... 100
Chain of custody of biological samples ............................................................ 100
Withdrawal of informed consent for donated biological samples...................... 100
5.6
Pharmacogenetics ............................................................................................ 101
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT........................... 101
6.1
Definition of adverse events............................................................................. 101
Causality collection.......................................................................................... 101
Relationship to protocol procedures ................................................................. 101
Adverse events based on signs and symptoms .................................................. 102
Adverse events based on examinations and tests .............................................. 102
Hy’s law .......................................................................................................... 102
Disease progression.......................................................................................... 103
New cancers..................................................................................................... 103
Deaths.............................................................................................................. 103
Safety Data To Be Collected following the final DCO of the study .................. 103
6.2
Definitions of serious adverse event ................................................................. 104
6.3
Recording of adverse events............................................................................. 104
Time period for collection of adverse events .................................................... 104
Follow-up of unresolved adverse events........................................................... 104
Variables.......................................................................................................... 105
6.4
Reporting of serious adverse events ................................................................. 106
6.5
Regulatory reporting requirements for SAEs.................................................... 107
6.6
Overdose.......................................................................................................... 107
Durvalumab ..................................................................................................... 107
Standard of Care .............................................................................................. 108
6.7
Pregnancy ........................................................................................................ 108
Maternal exposure............................................................................................ 108
Paternal exposure............................................................................................. 108
6.8
Medication Error.............................................................................................. 109
6.9
Management of investigational product-related toxicities ................................. 110
Specific toxicity management and dose modification information –
Durvalumab ..................................................................................................... 110
Adverse events of special interest..................................................................... 112
Standard of Care agents.................................................................................... 113
6.10
Study governance and oversight....................................................................... 113
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................. 113
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7.1
Identity of investigational product(s)................................................................ 113
Durvalumab (MEDI4736)................................................................................ 114
Standard of Care treatment............................................................................... 115
7.2
Dose and treatment regimens ........................................................................... 115
Treatment regimens.......................................................................................... 116
Duration of treatment ....................................................................................... 117
7.3
Labeling........................................................................................................... 118
7.4
Storage............................................................................................................. 119
7.5
Compliance...................................................................................................... 119
7.6
Accountability.................................................................................................. 119
7.7
Concomitant and other treatments .................................................................... 119
Other concomitant treatment ............................................................................ 121
Durvalumab drug drug interactions .................................................................. 121
7.8
Post study access to study treatment................................................................. 121
8.
STATISTICAL ANALYSES BY ASTRAZENECA........................................ 121
8.1
Statistical considerations .................................................................................. 121
8.2
Sample size estimate ........................................................................................ 122
8.3
Definitions of analysis sets............................................................................... 123
Full analysis set................................................................................................ 124
PD-L1 TC ≥25% and low risk of early mortality analysis set......................... 125
PD-L1 TC ≥50% analysis set......................................................................... 125
PD-L1 TC ≥50% and low risk of early mortality analysis set......................... 125
Safety analysis set............................................................................................ 125
PD-L1 TC ≥25% and low risk of early mortality safety analysis set............... 125
8.4
Outcome measures for analyses........................................................................ 125
Calculation or derivation of efficacy variables.................................................. 125
8.4.1.1
Secondary endpoints ........................................................................................ 126
Calculation or derivation of safety variables..................................................... 128
8.4.2.1
Adverse events................................................................................................. 128
8.4.2.2
Other significant adverse events....................................................................... 129
8.4.2.3
Safety assessments........................................................................................... 129
Calculation or derivation of patient-reported outcome variables ....................... 130
8.4.3.1
EORTC QLQ-C30 ........................................................................................... 130
8.4.3.2
Lung cancer module (EORTC QLQ-LC13)...................................................... 132
8.4.3.3
........................... 133
8.4.3.4
Immunogenicity analysis.................................................................................. 133
.............................................. 134
8.5
Methods for statistical analyses........................................................................ 134
Analysis of two primary endpoints – overall survival....................................... 137
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Progression-free survival.................................................................................. 139
Objective response rate .................................................................................... 140
Duration of response ........................................................................................ 140
Proportion of patients alive at 18 months and 24 months.................................. 140
Proportion of patients alive and progression free at 12 months ......................... 141
Time from randomization to second progression .............................................. 141
Patient reported outcomes ................................................................................ 141
8.5.8.1
EORTC QLQ-C30 ........................................................................................... 141
8.5.8.2
EORTC QLQ-LC13......................................................................................... 142
8.5.8.3
....................................................................................................... 142
Healthcare resource use.................................................................................... 142
Safety data ....................................................................................................... 143
Immunogenicity analysis.................................................................................. 143
Biomarker data................................................................................................. 143
Interim analysis................................................................................................ 143
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA....................... 144
9.1
Training of study site personnel ....................................................................... 144
9.2
Monitoring of the study.................................................................................... 144
Source data ...................................................................................................... 145
Study agreements............................................................................................. 145
Archiving of study documents.......................................................................... 145
9.3
Study timetable and end of study...................................................................... 145
9.4
Data management by AstraZeneca or delegate ................................................. 145
10.
ETHICAL AND REGULATORY REQUIREMENTS..................................... 146
10.1
Ethical conduct of the study ............................................................................. 146
10.2
Patient data protection...................................................................................... 146
10.3
Ethics and regulatory review ............................................................................ 147
10.4
Informed consent ............................................................................................. 147
10.5
Changes to the protocol and informed consent form......................................... 148
10.6
Audits and inspections ..................................................................................... 148
11.
LIST OF REFERENCES ................................................................................. 149
LIST OF TABLES
Table 1
Highly effective methods of contraception (<1% failure rate)................64
Table 2
Schedule of assessments for Durvalumab treatment period....................69
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Table 3
Schedule of assessments for Standard of Care therapy treatment 
period....................................................................................................76
Table 4
Schedule of assessments for patients who have 
discontinued/completed treatment with Durvalumab or Standard 
of Care therapy......................................................................................83
Table 5
Clinical chemistry (serum or plasma) ....................................................91
Table 6
Hematology and Coagulation ................................................................91
Table 7
Urinalysis..............................................................................................91
Table 8
List of investigational products for this study ...................................... 114
Table 9
Summary of outcome variables and analysis populations..................... 123
Table 10
Mean change and visit response in health-related quality of life .......... 130
Table 11
Visit response for health-related quality of life and disease-related 
symptoms............................................................................................ 132
Table 12
Pre-planned statistical and sensitivity analyses to be conducted........... 135
Table 13
Summary of methods of assessment .................................................... 166
Table 14
Evaluation of target lesions ................................................................. 170
Table 15
Evaluation of non-target lesions .......................................................... 171
Table 16
Overall visit response.......................................................................... 172
LIST OF FIGURES
Figure 1
Overall study design..............................................................................51
Figure 2
Study flow chart....................................................................................52
Figure 3
Durvalumab (MEDI4736) dosing scheme ........................................... 116
LIST OF APPENDICES
Appendix A
Additional Safety Information............................................................. 156
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document............................................................................ 158
Appendix C
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ...................................................................... 159
Appendix D
Guidelines for Evaluation of Objective Tumor Response..................... 164
Appendix E
Patient Reported Outcomes ................................................................. 174

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Appendix F
Changes Related to Mitigation of Study Disruptions Due to Cases 
of Civil Crisis, Natural Disaster, or Public Health Crisis, including 
COVID-19 Outbreak........................................................................... 180

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or special 
term
Explanation
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse events of special interest
ALK
Anaplastic lymphoma kinase
ALT
Alanine aminotransferase
APF12
Proportion of patients alive and progression free at 12 months from randomization
AST
Aspartate aminotransferase
AUC
Area under the curve
AUCss
Area under the curve at steady state
BICR
Blinded Independent Central Review
BoR
Best objective response
BP
Blood pressure
CD
Cluster of differentiation
CI
Confidence interval
Cmax,ss
Maximum plasma concentration at steady state
CR
Complete response
CSA
Clinical study agreement
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
CTLA-4
Cytotoxic T–lymphocyte-associated antigen 4
Ctrough,ss
Trough plasma concentration at steady state
DCR
Disease control rate
DCO
Data Cut Off 
DLT
Dose-limiting toxicity
DoR
Duration of response
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
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Abbreviation or special 
term
Explanation
eCRF
Electronic case report form
EDoR
Expected duration of response
EGFR
Epidermal growth factor receptor
EM
Early mortality
EORTC
European Organisation for Research and Treatment of Cancer
ESMO
European Society for Medical Oncology
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration
FU
Fluorouracil
GCP
Good Clinical Practice
GI
Gastrointestinal
GMP
Good Manufacturing Practice
hCG
Human chorionic gonadotropin
HIV
Human immunodeficiency virus
HR
Hazard ratio
HRQoL
Health-related quality of life
IB
Investigator’s Brochure
ICI 
Immune checkpoint inhibitors
ICF
Informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IFN
Interferon
IgG
Immunoglobulin G
IHC
Immunohistochemistry
IMT
Immunomodulatory therapy
IP
Investigational product 
imAE
Immune-mediated adverse event
irRECIST
Immune-related RECIST criteria 
ITT
Intent-to-Treat
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
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Abbreviation or special 
term
Explanation
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
NCI
National Cancer Institute
NE
Not evaluable
NLR
Neutrophil to lymphocyte ratio
NSCLC
Non–small-cell lung cancer
OAE
Other significant adverse event
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PDx
Pharmacodynamic(s)
PFS
Progression-free survival
PFS2
Progression-free survival after subsequent anticancer therapy
PK
Pharmacokinetic(s)
PR
Partial response
PRO
Patient-reported outcome
Q2W
Every 2 weeks
Q3W
Every 3 weeks
Q4W
Every 4 weeks
Q6W
Every 6 weeks
Q8W
Every 8 weeks
QLQ-C30 v3
30-item core quality of life questionnaire, version 3
QLQ-LC13
13-item lung cancer quality of life questionnaire
QoL
Quality of life
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RCC
Renal cell carcinoma
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
RR
Response rate
RT-QPCR
Reverse transcription quantitative polymerase chain reaction
SAE
Serious adverse event

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Abbreviation or special 
term
Explanation
SAP
Statistical analysis plan
SCCHN
Squamous cell carcinoma of the head and neck
SD
Stable disease
SoC
Standard of Care
sPD-L1
Soluble programmed cell death ligand 1
T3
Triiodothyronine
T4
Thyroxine
TKI
Tyrosine-kinase inhibitor
TMGs
Toxicity management guidelines
TSH
Thyroid-stimulating hormone
UC
Urothelial carcinoma
ULN
Upper limit of normal
US
United States
WBDC
Web-Based Data Capture
WHO
World Health Organization 

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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Lung cancer has been the most common cancer in the world for several decades, with an 
estimated 1.8 million new cases in 2012 (12.9% of all new cancers), and was also the most 
common cause of death from cancer in 2012, with 1.59 million deaths globally (19.4% of the 
total cancer deaths; Gandhi et al 2018
Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, DeAngelis F, et al. 
Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 
2018;378:2078-92.
GLOBOCAN 2012). The incidence rate of lung cancer in China is relatively higher and also 
increasing with a more rapid rate than in western countries (Chen, et al 2014). Non-small-cell 
lung cancer (NSCLC) represents approximately 80% to 85% of all lung cancers. At the time 
of diagnosis approximately 70% of patients with NSCLC already have advanced disease not 
amenable to surgical resection.  Furthermore, a significant percentage of patients with early 
stage NSCLC who have undergone surgery subsequently develop distant recurrence and die as 
a result of their lung cancer (Pisters and Le Chevalier 2005). 
Despite advances in the diagnosis, imaging, staging, and treatment of NSCLC, the estimated 
overall 5-year survival for patients with Stage IV NSCLC on a global scale remains to be low;
11% and 17% in Europe and US respectively (D’Addario et al 2010, Howlander et al 2014).  
In China, the 5-year survival is less than 20% (Zhou 2014). Patients presenting with advanced 
NSCLC demonstrate different biological behavior and lead to different survival outcome 
depending on the presence or absence of targetable oncogenes (i.e. EGFR sensitizing mutation 
or ALK translocation). Presence of an EGFR sensitizing mutation or ALK translocation is 
often associated with a longer survival of around 24 to 36 months following the introduction 
of targeted treatments for these genetic alterations. On the contrary NSCLC with Wild type 
EGFR and ALK status usually correlates with poor prognosis (overall survival: 12 months or 
even less). Standard of care treatment is with platinum-based chemotherapy. (Fukuoka et al 
2011). Up to 30% patients may respond to the 1st line chemotherapy, nevertheless the 
durations of responses (DoR) are limited and toxicities can be a major limiting factor, which 
indicates a high unmet medical need in this population. Maintenance therapy with either 
continuation or switch has also been recommended for certain histologic subtypes of NSCLC.
For example maintenance with pemetrexed has been shown to improve OS and PFS 
particularly in non-squamous histologies (Chen, et al 2014, Ciuleanu et al 2009, Paz-
Ares et al 2013).
Common first-line treatment regimens for advanced NSCLC are typically platinum-based 
doublets including carboplatin and paclitaxel, carboplatin and gemcitabine (squamous only), 
carboplatin and pemetrexed (non-squamous only), cisplatin and gemcitabine (squamous only), 
and cisplatin and pemetrexed (non-squamous only). Platinum-based doublet chemotherapy 
regimens vary to some extent with regard to convenience, associated toxicities, and cost. The 

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selection of a specific regimen is often dictated by local practice and individualized on a case-
by-case basis. In addition to systemic chemotherapy, single-agent immunotherapy and 
combination therapy of immunotherapy with chemotherapy are approved for the first-line 
treatment of metastatic NSCLC. Despite combination therapy demonstrating an improvement 
in OS and progression free survival (PFS) versus SoC chemotherapy alone, certain subgroups 
of patients may not tolerate the combination of immunotherapy and chemotherapy (Gandhi et 
al 2018). Therefore, there is still a significant unmet medical need for additional treatment 
options for use in this patient population. 
Immune checkpoint inhibitors (ICIs) have demonstrated success as treatment across multiple 
tumor types. Together, programmed cell death 1 (PD-1) and PD-L1 antibodies (e.g., 
pembrolizumab, nivolumab, and atezolizumab) have been approved in various regions for the 
treatment of multiple oncology indications including malignant melanoma, NSCLC, renal cell 
carcinoma (RCC), UC, head and neck squamous cell carcinoma (HNSCC), and Hodgkin’s 
lymphoma. Durvalumab, an anti-PD-L1 antibody, has been approved to treat locally advanced 
or metastatic urothelial carcinoma, unresectable stage III non-small cell lung cancer, and 
extensive-stage small cell lung cancer (administered in combination with chemotherapy). 
Refer to the package insert (or label) for your specific country, as applicable. Approval in 
NSCLC was based on results from the PACIFIC study (see section 1.3.1.1). 
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 T-
cell activation. Programmed cell death 1 (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 PD-1, an inhibitory signal is 
transmitted into the T cell, which reduces cytokine production and suppresses T cell 
proliferation.  Tumor cells exploit this immune checkpoint pathway as a mechanism to evade 
detection and inhibit immune response.
PD-L1 is constitutively expressed by B-cells, dendritic cells, and macrophages (Qin et al 
2016).  Importantly, PD-L1 is commonly over expressed on tumor cells or on non-transformed 
cells in the tumor microenvironment (Pardoll 2012).  PD-L1 expressed on the tumor cells 
binds to PD-1 receptors on the activated T-cells 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-

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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 2008) 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 e.g. in bladder carcinoma (Alexandrov et al, 2013) may contribute to the 
responses seen with immune therapy.
In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is constitutively 
expressed by regulatory T cells and upregulated on activated T cells. CTLA-4 delivers a 
negative regulatory signal to T cells upon binding of CD80 (B7.1) or CD86 (B7.2) ligands on 
antigen-presenting cells (Fife and Bluestone, 2008).  Blockade of CTLA-4 binding to 
CD80/86 by anti-CTLA-4 antibodies results in markedly enhanced T-cell activation and 
antitumor activity in animal models, including killing of established murine solid tumors and 
induction of protective antitumor immunity.  Therefore, it is expected that treatment with an 
anti CTLA-4 antibody will lead to increased activation of the human immune system, 
increasing antitumor activity in patients with solid tumors.
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 antigen 4 (CTLA-4) 
and programmed death ligand 1 (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 
whilst nivolumab and pembrolizumab, two anti-PD-1 agents and atezolizumab, an anti PD-L1 
agent have been granted approvals by agencies 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 is 
data from agents in the anti-PD-1/PD-L1class showing clinical activity in a wide range of 
tumor types.
Durvalumab
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with 
PD-1 on T cells and CD80 (B7.1) on immune cells (IC). 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 

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throughout this document.)  The proposed mechanism of action (MOA) 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 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 
The primary OS will be analyzed using proliferation of IFN-γ (Stewart et al 2015).  In vivo 
studies have shown that durvalumab inhibits tumor growth in xenograft models via a T cell 
dependent 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 are summarized in Section 1.3.1.1 and 6.9.2. Refer to the current 
durvalumab Investigator’s Brochure (IB) for a complete summary of non-clinical and clinical 
information including safety, efficacy and pharmacokinetics; see Section 6.9 for guidance on 
management of durvalumab-related toxicities.  
Rationale for conducting this study
Current therapies for advanced NSCLC with EGFR and ALK wild type have poor outcomes, 
with responses to systemic chemotherapy in the first-line setting of up to 30% (Pirker et al 
2013), and a median OS of approximately 10 to 12 months (Bonomi 2010, 
D’Addario et al 2010, Scagliotti et al 2008, Schiller et al 2002).  Responses are also limited in 
duration.  Systemic chemotherapy is associated with significant side effects, including 
neutropenia, nausea, vomiting and dehydration, and alopecia (Sandler et al 2006, 
Scagliotti et al 2008).  There is still a significant unmet medical need for additional treatment 
options for use in this patient population. 
As an antibody that blocks the interaction between PD-L1 and its receptors, durvalumab may 
relieve PD-L1-dependent immunosuppressive effects and, therefore, enhance the cytotoxic 
activity of anti-tumor T-cells.  This hypothesis is supported by emerging clinical data from 
other mAbs targeting the PD-L1/PD-1 pathway, which provide early evidence of clinical 
activity and a manageable safety profile. (Brahmer et al, 2012, Topalian et al 2012) Higher 
responses have been observed in patients with PD-L1-positive tumors than patients with PD-
L1-negative tumors.  In addition, durvalumab has shown durable responses in NSCLC in 
Study 1108 (see Section 1.3.1.1).
Based on the preliminary clinical efficacy and safety data observed in patients with NSCLC in 
Study 1108, AstraZeneca plans to determine the activity of durvalumab as first-line treatment 
in patients with NSCLC.  The preliminary efficacy, safety, and tolerability data of durvalumab 
in Study 1108 support the development of these treatments in NSCLC. The primary objectives
of this study are to assess the efficacy of durvalumab compared with standard of care (SoC) in 
terms of overall survival (OS) in advanced NSCLC patients with EGFR and ALK wild-type 

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with a score above the cut-off are identified as high risk of EM, and patients at or below the 
cut-off are identified as low risk of EM.
Durvalumab dose rationale
A durvalumab dose of 
 is supported by in vitro data, non-clinical activity, 
clinical PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in patients 
with advanced solid tumors and from a Phase I trial performed in Japanese patients with 
advanced solid tumor (D4190C00002).
PK/Pharmacodynamic data
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging 
from 
 durvalumab exhibited non-linear (dose 
dependent) PK consistent with target-mediated drug disposition.  The PK 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 3 mg/kg.   The expected half-life with 
doses
 is approximately 21 days.  A dose-dependent suppression in peripheral 
sPD-L1 was observed over the dose range studied, consistent with engagement of durvalumab 
with PD-L1.  A low level of immunogenicity has been observed. No patients have 
experienced immune-complex disease following exposure to durvalumab (For further 
information on immunogenicity, please see the current IB).  
A population PK model was developed using the data from Study 1108 (
 
 (Fairman et al 2014). Multiple simulations indicate that a 
similar overall exposure is expected following both 
 
regimens, as represented by AUCss (4 weeks).  Median Cmax,ss is expected to be higher with 
 and median Ctrough,ss is expected to be higher with 10 mg/kg 
Q2W (~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 PK, pharmacodynamics, and clinical activity in diverse cancer populations; (c) 
maintain sufficient PK exposure in case of ADA impact; and (d) achieve PK exposure that 
yielded maximal antitumor activity in animal models.
Given the similar area under the plasma drug concentration-time curve (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 
 regimens are expected to have similar efficacy and safety 
profiles, supporting further development with a dose of 
  
Clinical data
Refer to the current durvalumab Investigator’s Brochure for a complete summary of clinical 
information including safety, efficacy and pharmacokinetics at the 
 regimen.
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1.3
Benefit/risk and ethical assessment
The following sections include summaries of the potential benefits and risks associated with 
durvalumab and the overall benefit/risk assessment.
Potential benefits
1.3.1.1
Durvalumab
The majority of the safety and efficacy data currently available for durvalumab are based on 
the first time in-human, single-agent study (Study 1108) in patients with advanced solid 
tumors.  Data from Study 1108 were presented at the ESMO 2014 Congress.  As of 
21 August 2014, 162 patients with NSCLC were evaluable for response analysis.  The disease 
control rate (DCR) at 12 weeks in patients receiving 10 mg/kg durvalumab Q2W was 39%, 
and the ORR was 15% (26% [12 out of 47 patients] with known PD-L1-positive NSCLC [i.e.,
≥ 25% PD-L1 expression] and 10% [7 out of 74 patients] with known PD-L1-low/negative 
NSCLC [i.e., <25% PD-L1 expression]).  A total of 24% of patients receiving 10 mg/kg 
durvalumab Q2W had SD for ≥ 12 weeks (including 21% [10 out of 47 patients] with known 
PD-L1-positive NSCLC and 32% [24 out of 74 patients] with known PD-L1-negative 
NSCLC).  Responses were ongoing in 88% of patients with NSCLC, with an objective 
response duration ranging from 0.1 to 32.4 weeks (Antonia et al 2014b).
PACIFIC study is a double-blind, placebo-controlled Phase III study of durvalumab after 
chemoradiation therapy in patients with Stage III, locally advanced, unresectable NSCLC. 713 
patients with stage III unresectable NSCLC who have not progressed following definitive 
platinum-based concurrent chemoradiation were recruited. Durvalumab treatment 
demonstrated a statistically significant (HR: 0.51; 95% CI: 0.41, 0.63; p‑value <0.0001) and 
clinically meaningful prolongation of PFS compared with placebo. Median PFS improvement 
of 11.6 months compared with placebo (17.2 vs 5.6 months). The dual primary endpoint OS 
was also statistically significant (HR: 0.68; 99.73% CI: 0.469, 0.997; p‑value 0.00251) and 
clinically meaningful prolonged in durvalumab arm compared with placebo. Median OS in 
durvalumab arm was not reached, compared with 28.7 months in placebo arm. The treatment 
effects were sustained over time: 12-month OS 83.1% (durvalumab) vs. 75.3% (placebo); 24-
month OS 66.3% (durvalumab) vs. 55.6% (placebo) (Antonia et al 2018).
Data from ongoing studies with durvalumab and other agents targeting the PD-1/PD-L1 
pathway suggest, as shown in a number of tumor types (e.g., NSCLC, renal cell carcinoma, 
and melanoma), that monotherapy may be more efficacious (in terms of ORR) in patients who 
are PD-L1-positive. 
Potential risks
Overall risks
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed cell 
death ligand 1 (PD-L1) as well as those directed against programmed cell death-1 (PD-1) or 
cytotoxic T-lymphocyte antigen-4 (CTLA-4), aim to boost endogenous immune responses 

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directed against tumor cells. 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 AEs such as colitis 
and diarrhoea, 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.
1.3.2.1
Durvalumab
Risks with durvalumab include, but are not limited to, diarrhea/colitis, pneumonitis/ILD, 
endocrinopathies (i.e., events of hypophysitis/hypopituitarism, adrenal insufficiency, hyper-
and hypo-thyroidism, type I diabetes mellitus and diabetes insipidus), hepatitis/increases in 
transaminases, nephritis/increases in creatinine, rash/dermatitis(including pemphigoid), 
myocarditis, myositis/polymyositis, immune thrombocytopenia,  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).
For information on all identified and potential risks with durvalumab, please always refer to 
the current version of the durvalumab IB.
In monotherapy clinical studies, AEs at an incidence of > 20% include events such as fatigue, 
cough, decreased appetite, dyspnea and nausea. Approximately 10% of patients discontinued 
the drug due to an 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 (please see the Dosing Modification and 
the current version of Toxicity Management Guidelines in Dosing Modifications and Toxicity 
Management).
A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab IB.
Overall benefit-risk and ethical assessment
There remains a significant unmet medical need for additional treatment options for patients 
with EGFR and ALK wild-type, advanced NSCLC who have not received prior chemotherapy 
or any systemic therapy for advanced NSCLC.  The study design aims to minimize potential 

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risks such that intensive monitoring, including early safety assessment, is in place for those 
risks deemed to be most likely based on prior experience with the IPs (i.e., durvalumab and 
SoC).
Based upon the available non-clinical and clinical safety data, the limited survival benefit 
provided by the currently available treatment options to patients, the limited life expectancy 
due to malignant disease, the activity seen with durvalumab in NSCLC and the strength of the 
scientific hypotheses under evaluation; the durvalumab treatment proposed for evaluation in 
this study may have the potential to provide meaningful clinical benefit with a manageable 
safety and tolerability profile by generating durable clinical responses, thereby improving 
quality of life (QoL) and potentially extending survival.  
Therefore, the investigation of the potential therapeutic efficacy of durvalumab in patients 
with PD-L1-high expression tumors is acceptable, and the overall benefit/risk assessment 
supports the proposed study design.
1.4
Study Design 
This is a randomized, open-label, multi-center Phase III study to determine the efficacy and 
safety of and durvalumab versus platinum-based SoC chemotherapy in the first-line treatment 
of advanced NSCLC patients who are EGFR and ALK wild-type and have PD-L1-high 
expression.  A schematic diagram of the overall study design is shown in Figure 1, and a 
detailed study flow chart is shown in Figure 2.The study will randomize approximately 650 
patients from selected sites in China and other countries who will be randomized in a 1:1 ratio 
to 2 treatment arms (durvalumab or SoC therapy) in a stratified manner according to level of 
PD-L1 expression (25-49% versus ≥50%), histology and smoking status (squamous versus 
non-squamous + never smoker versus non-squamous + former/current smoker). This is to 
ensure the uniform distribution of main predictive factors of response, e.g. PD-L1 intensity 
and smoking status in each treatment group.
Patients will provide a tumor tissue sample at enrolment (newly acquired or archived sample 
<3 months old) to determine PD-L1 expression status (defined by the Ventana SP263 PD-L1 
IHC assay in which ≥ 25% PD-L1membrane expression in tumoral tissue is considered as 
high expression.
Doses and treatment regimens are described in Section 7.2.  Assessments will be conducted as 
indicated in Table 2, Table 3, and Table 4. 

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Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster or public health crisis 
(e.g., during quarantines and resulting site closures, regional travel restrictions and 
considerations if site personnel or study participants become infected with severe acute 
respiratory syndrome coronavirus 2 [SARS-CoV-2] or similar pandemic infection), which 
would prevent the conduct of study-related activities at study sites, thereby compromising the 
study site staff or the participant’s ability to conduct the study. The investigator or designee 
should contact the study sponsor to discuss whether the mitigation plans below should be 
implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with GCP, and minimise risks to study integrity. Where allowable by local health 
authorities, ethics committees, health care provider guidelines (e.g., hospital policies) or local 
government, these changes may include the following options: 
-
Obtaining [consent/reconsent] for the mitigation procedures (note, in the case of verbal 
[consent/reconsent], the informed consent form [ICF] should be signed at the 
participant’s next contact with the study site).
-
Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices. 
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix F. 

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2.
STUDY OBJECTIVES
2.1
Primary objectives
Primary Objectives:
Outcome Measures:
To assess the efficacy of durvalumab compared to 
SoC in patients with PD-L1 TC ≥25% (all 
randomized patients)
OS
To assess the efficacy of durvalumab compared to 
SoC in patients with PD-L1 TC ≥25% and low 
risk of early mortalitya
OS
2.2
Secondary objectives
Secondary Objectives:
Outcome Measures:
To assess the efficacy of durvalumab compared to 
SoC in terms of OS
OS in patients with 

PD-L1 TC ≥50%

PD-L1 TC ≥50% and low risk of early mortality
To further assess the efficacy of durvalumab 
compared to SoC in terms of PFS, ORR, DoR, 
OS18, OS24, APF12, and PFS2
PFS, ORR, DoR, APF12 using Investigator assessments 
according to RECIST 1.1, PFS2 using local standard 
clinical practice, OS18 and OS24 respectively in patients 
with 

PD-L1 TC ≥25% 

PD-L1 TC ≥25% and low risk of early mortality 

PD-L1 TC ≥50%

PD-L1 TC ≥50% and low risk of early mortality
To assess disease-related symptoms and HRQoL in 
patients treated with durvalumab compared to SoC 
using the EORTC QLQ-C30 v3 and the LC13 
module
EORTC QLQ-C30, EORTC QLQ-LC13, and 
changes in Eastern Cooperative Oncology Group (ECOG) 
performance status in patients with 

PD-L1 TC ≥25% 

PD-L1 TC ≥25% and low risk of early mortality
To investigate the immunogenicity of durvalumab
Presence of ADAs for durvalumab in patients with

PD-L1 TC ≥25% 

PD-L1 TC ≥25% and low risk of early mortality
a.
The population at low risk of early mortality consists of patients identified by a prognostic model developed by 
AstraZeneca as having low risk of early mortality. 
2.3
Safety objective
Safety Objective:
Outcome Measures:
To assess the safety and tolerability profile of 
durvalumab compared to SoC 
AEs, physical examinations, laboratory findings, and vital 
signs

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lesions used for fresh biopsies should not be target lesions, unless there are no other 
lesions suitable for biopsy.  Fine needle aspirate specimens are not acceptable.  
Specimens from metastatic bone lesions are typically unacceptable unless there is a 
significant soft tissue component.  The tumor specimen submitted to establish 
eligibility should be of sufficient quantity to allow for PD-L1 IHC and other 
r analyses (if applicable) and is preferred in formalin-fixed 
paraffin embedded blocks.
6.
World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1 at enrolment
7.
At least 1 lesion, not previously irradiated, that can be accurately measured at 
baseline as ≥10 mm in the longest diameter (except lymph nodes which must have a 
short axis ≥15 mm) with CT or MRI and that is suitable for accurate repeated 
measurements as per RECIST 1.1 guidelines.  
8.
Must have a life expectancy of at least 12 weeks.
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
Cancer Related:
1.
Prior chemotherapy or any other systemic therapy for advanced NSCLC. Patients 
who have received prior platinum-containing adjuvant, neoadjuvant, or definitive 
chemoradiation for locally advanced disease are eligible, provided that progression 
has occurred >6 months from last therapy.
2.
Prior exposure to immune-mediated therapy including, but not limited to, other 
anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 
(anti-PD-L2) antibodies, excluding therapeutic anticancer vaccines.  
3.
Radiotherapy treatment to more than 30% of the bone marrow or with a wide field 
of radiation within 4 weeks of the first dose of study drug.  Note: Local treatment of 
isolated lesions, excluding target lesions, for palliative intent is acceptable.
4.
Brain metastases or spinal cord compression unless the patient is stable 
(asymptomatic, no evidence of new or emerging brain metastases) and off steroids 
for at least 14 days prior to start of study treatment. Asymptomatic brain metastases 
discovered during screening period must confirm stability in no less than 2 weeks 
by imaging (intravenous contrast-enhanced MRI (preferred) or IV contrast-
enhanced CT).   Following radiotherapy and/or surgery, patients with brain 
metastases must wait 4 weeks following the intervention and must confirm stability 
with imaging before randomization.  Patients with suspected brain metastases at 
screening should have a CT/MRI of the brain prior to study entry.
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5.
History of leptomeningeal carcinomatosis
6.
Mixed small-cell lung cancer and NSCLC histology, sarcomatoid variant 
Haematological, Biochemical, and Organ Function
7.
Haemoglobin < 9.0 g/dL or haemoglobin ≥9.0 g/dL but with transfusion 4 weeks 
prior to the screening and randomization.
8.
Absolute neutrophil count<1.5 × 109 /L.
9.
Platelet count<100 × 109/L.
10.
Serum bilirubin>1.5 × the ULN.  This will not apply to patients with confirmed 
Gilbert’s syndrome, who will be allowed in consultation with their physician.
11.
ALT and AST >2.5 × ULN; for patients with hepatic metastases, ALT and AST 
>5 × ULN.
12.
Calculated creatinine clearance <50 mL/min as determined by Cockcroft-Gault 
(using actual body weight) or 24-hour urine collection.
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)
General:
13.
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [e.g., colitis or Crohn’s disease], diverticulitis with the 
exception of diverticulosis, celiac disease or other serious gastrointestinal chronic 
conditions associated with diarrhoea), systemic lupus erythematosus, Sarcoidosis 
syndrome, or Wegener syndrome (granulomatosis with polyangiitis), Graves’ 
disease, rheumatoid arthritis, hypophysitis, uveitis, etc. within the past 3 years prior 
to the start of treatment.  The following are exceptions to this criterion:

Patients with vitiligo or alopecia

Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on 
hormone replacement or psoriasis not requiring systemic treatment

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
Any chronic skin condition that does not require systemic therapy

Patients without active disease in the last 5 years may be included but only after 
consultation with the study physician

Patients with celiac disease controlled by diet alone
14.
History of active primary immunodeficiency.
15.
Active infection, including tuberculosis (clinical evaluation), hepatitis B, hepatitis 
C, or human immunodeficiency virus (HIV, positive HIV 1 or 2 antibodies).  Active 
hepatitis B virus (HBV) is defined by a known positive HBV surface antigen 
(HBsAg) result.  Patients with a past or resolved HBV infection (defined as the 
presence of hepatitis B core antibody and absence of HBsAg) are eligible. Patients 
positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain 
reaction is negative for HCV ribonucleic acid (RNA).
16.
Current or prior use of immunosuppressive medication within 14 days before the 
first dose of durvalumab. The following are exceptions to this criterion:

Intranasal, inhaled, topical steroids, or local steroid injections 
(e.g., 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 (e.g., CT scan 
premedication)
17.
Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP.  
Note: Patients, if enrolled, should not receive live vaccine during the study and up 
to 30 days after the last dose of IP.
18.
Major surgical procedure (as defined by the Investigator) within 28 days prior to the 
first dose of IP.  Note: Local surgery of isolated lesions for palliative intent is 
acceptable.
19.
History of allogenic organ transplantation.
20.
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 study drug and of low potential risk for 
recurrence

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
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease

Adequately treated carcinoma in situ without evidence of disease (e.g., cervical 
cancer in situ)
21.
Medical contraindication to platinum (cisplatin or carboplatin)-based doublet 
chemotherapy.
22.
Positive 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 oophorectomy with last menses 
>1 year ago, had chemotherapy-induced menopause with >1 year interval since 
last menses, or underwent surgical sterilization (bilateral oophorectomy or 
hysterectomy).
23.
Female patients who are pregnant or breast-feeding or male or female patients of 
reproductive potential who are not willing to employ highly effective birth control 
from screening to 90 days after the last dose of durvalumab.
24.
Known allergy or hypersensitivity to IP or any excipient or to other humanized 
mAbs.
25.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site).
26.
Concurrent enrolment in another clinical study, unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional 
study.
27.
Any condition that, in the opinion of the Investigator, would interfere with the 
evaluation of IP or interpretation of patient safety or study results, including, but not 
limited to, ongoing or active infection, symptomatic congestive heart failure, 
uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial 
lung disease, or psychiatric illness/social situations that would limit compliance 

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6.
Define the SoC treatment (based on the most appropriate option for the patient) that 
the patient would receive if randomized to the SoC group prior to randomization of 
the patient. This must be completed for all patients.
Note, for all patients with non-squamous tumor histology who are scheduled to 
receive pemetrexed if randomized to the SoC group, folic acid and vitamin B12 
should commence prior to randomization for up to 7 days, in line with local 
practice.  This is to ensure SoC treatment can begin on Day 1.
7.
Obtain a unique randomization number via the IVRS/IWRS.  Numbers will start at 
001 and will be assigned strictly sequentially by IVRS/IWRS as patients are eligible 
for entry into the study.  The system will randomize the eligible patient to either of 
the treatment groups.
If the patient is ineligible and not randomized, the IVRS/IWRS should be contacted to 
terminate the patient in the system. 
Patients will begin treatment on Day 1.  Patients must not be treated unless all eligibility 
criteria have been met.  
If a patient withdraws from participation in the study, then his or her enrolment/randomization 
code cannot be reused.  Withdrawn patients will not be replaced.
3.4
Procedures for handling incorrectly enrolled patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive study medication.  There can be no exceptions to this rule.  Patients 
who are enrolled but found to not meet all the eligibility criteria must not be randomized and 
must not be initiated on treatment and must be withdrawn from the study as a screen failure.
When a patient does not meet all the eligibility criteria but is randomized in error or 
incorrectly started on treatment, the Investigator should inform the Study Physician 
immediately, and the Study Physician and the Investigator should discuss whether to continue 
or discontinue the patient from treatment.  The Study Physician must ensure that all decisions 
are appropriately documented.
3.5
Methods for assigning treatment groups
The actual treatment 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 group. 
Patients will be identified to the IVRS/IWRS per country regulations.  Randomization codes 
will be assigned strictly sequentially, within each stratum, as patients become eligible for 

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randomization.  The IVRS/IWRS will provide the kit identification number to be allocated to 
the patient at the randomization visit.  
3.6
Methods for ensuring blinding
Not applicable; this study is not blinded.
3.7
Methods for unblinding 
Not applicable; this study is not blinded.
3.8
Restrictions
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after:
1.
Female patients 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 1) from the time of screening and 
throughout the total duration of the drug treatment and the drug washout period 
(90 days after the last dose of durvalumab monotherapy).; Non-sterilised male 
partners of a female patient of childbearing potential must use a male condom 
plus spermicide (or male condom in countries where spermicides are not 
approved) 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 
durvalumab monotherapy). However, periodic abstinence, the rhythm method, 
and the 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 1).
Note: Females of childbearing potential are defined as those who are not 
surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or 
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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. 

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 1 that results in a low failure rate 
(i.e., less than 1% per year) when used consistently and correctly are described in Table 1.  
Note that some contraception methods are not considered highly effective (e.g., 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).
Patients in the SoC group: Follow the prescribing information relating to contraception, the 
time limits for such precautions, and any additional restrictions for agents in the SoC group.
3.
All patients: Patients should not donate blood or blood components while 
participating in this study and for 90 days following the last dose of IP.
4.
Restrictions relating to concomitant medications are described in Section 7.7.
The acceptable methods of contraception are described in Table 1. A highly effective method 
of contraception is defined as one that results in a low failure rate (i.e., less than 1% per year) 
when used consistently and correctly. Not all methods of acceptable contraception are highly 
effective.

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Table 1
Highly effective methods of contraception (<1% failure rate)
Barrier/Intrauterine methods
Hormonal methods

Copper T intrauterine device

Levonorgesterel-releasing intrauterine 
system (e.g., Mirena®)a

Implants: Etonogestrel-releasing implants: 
e.g. Implanon® or Norplan® 

Intravaginal Devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices: e.g. NuvaRing®  

Injection: Medroxyprogesterone injection: 
e.g. Depo-Provera®  

Combined Pill: Normal and low dose 
combined oral contraceptive pill

Patch: Norelgestromin/ethinylestradiol-
releasing transdermal system: e.g. Ortho 
Evra®   

Minipillc: 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
3.9
Discontinuation of investigational product
An individual patient will not receive any further IP (durvalumab or SoC) 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 3.10.2). 

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 ection 6.9.1) or as defined 
in the local prescribing information for the SoC agent.

Pregnancy or intent to become pregnant.

Non-compliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from study treatment (e.g., refusal to adhere to 
scheduled visits).

Initiation of alternative anticancer therapy including another investigational agent

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
Clinical progression, i.e. Investigator determination that the patient is no longer 
benefiting from treatment with IP, with or without radiological progression by 
RECIST 1.1.
Procedures for discontinuation of a patient from investigational product
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 6).  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 Table 4).  
Patients who permanently discontinue drug for reasons other than objective RECIST disease 
progression should continue to have RECIST scans performed Q6W ± 1w for the first 48 
weeks (relative to the date of randomization), and then Q8W ± 1w thereafter until confirmed 
objective disease progression/death (whichever comes first) as defined in Table 2, Table 3 and 
Table 4.
If a patient is discontinued for unconfirmed progression then the patient should also continue 
to have RECIST scans performed Q6W ± 1w for the first 48 weeks (relative to the date of 
randomization), and then Q8W ± 1w thereafter until confirmed objective disease progression 
or until death (whichever comes first) as defined in Table 2, Table 3 and Table 4.
All patients will be followed for survival until the end of the study. If the study reaches 
statistical significance for OS at interim or final analyses, follow-up may continue in order to 
estimate the long-term benefit for durvalumab.
Patients who decline to return to the site for evaluations should be contacted by telephone as 
indicated in Table 4 as an alternative.
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IVRS/IWRS.
3.10
Criteria for withdrawal of the patient from the study
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” (i.e., patient does not meet the required inclusion/exclusion 
criteria).  This reason for study withdrawal is only valid for screen failures (i.e., not 
randomized patients).  Patients can be rescreened a single time, but they cannot be 
re-randomized. 

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Withdrawal of the informed consent
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 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. The 
patient will return electronic PRO devices, if applicable.  
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 (e.g., survival 
contact telephone calls)

withdrawal to the use of any samples (see Section 5.5.6)
3.10.2.1
Survival status for withdrawn consent and lost to follow up patients
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (see Section 9.3), such that there is insufficient information to 
determine 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.  If contact with a missing patient is 
re-established, the patient should not be considered lost to follow-up and evaluations should 
resume according to the protocol.
In order to support key end points of PFS and OS analyses, 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 “lost to follow-up.”

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 SURVIVE module 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
SURVIVE module will be updated).  

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3.11
Discontinuation of the study 
The study may be stopped if, in the judgment of AstraZeneca, study patients are placed at 
undue risk because of clinically significant findings that meet any of the following criteria:

Meet individual stopping criteria or are otherwise considered significant 

Are assessed as causally related to study drug

Are not considered to be consistent with continuation of the study
In addition, the study may be stopped based on the findings of the interim safety analysis 
conducted by the Independent Data Monitoring Committee (IDMC) (see Section 6.10).
Regardless of the reason for termination, all data available for the patients at the time of 
discontinuation of follow-up must be recorded in the eCRFs.  All reasons for discontinuation 
of treatment must be documented.
In terminating the study, AstraZeneca will ensure that adequate consideration is given to the 
protection of the patients’ interests.  If this study is discontinued, all other studies involving 
durvalumab will remain open to enrolment and screening, if deemed appropriate by 
AstraZeneca.
4.
STUDY PLAN AND TIMING OF PROCEDURES 
The procedures for the screening and the treatment periods in this study are presented for the 
durvalumab group in Table 2 and for the SoC therapy group in Table 3.  The procedures for 
the follow-up period are presented in Table 4. Patients who continue beyond C13 continue 
with all C13 assessments until termination of treatment (Table 2).
For all treatment arms

PRO and tumor efficacy (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 monotherapy arm

Patients may delay dosing under certain circumstances.   

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
Dosing may be delayed per Toxicity Management Guidelines, due to 
either an immune or a non-immune-related AE.

If dosing must be delayed for reasons other than treatment-related 
toxicity, dosing will resume as soon as feasible

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-lives of durvalumab (see current Investigator Brochures for 
durvalumab).  
Standard of Care Arm:

Patients may delay and subsequently resume dosing per local standard clinical 
practice.

If dosing must be delayed for reasons other than treatment-related toxicity, 
dosing will occur as soon as feasible.

Clinical Study Protocol
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Table 2
Schedule of assessments for Durvalumab treatment period   
PD-L1 
Testing
Screening
C1
C2
C3
C4
C5
C6
C7
C8 to C12
C131 etc.
For 
details 
see 
Sectio
n
Week
-4 to -1
0
4
8
12
16
20
24
28, 32, 36, 
40, 44
48 etc.
Day
Prior to 
Day 1
-28 to -1
1
29
57
85
113
141
169
197, 225, 
253, 281, 
309
337 etc.
Window (days)
NA
+32
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
Informed consent
X3
4.1, 
10.4
Study procedures
Physical exam (full)
X
5.2.2
Targeted physical exam (based on 
symptoms)
X
X
X
X
X
X
X
X
X
5.2.2
Vital signs4
X
X
X
X
X
X
X
X
X
X
5.2.4
                                               
1 Patients who continue on treatment will be assessed in the same manner
2Every effort should be made to minimize the time between randomization and starting treatment. (i.e. on the same day after randomization)
3 Informed consent of study procedures and tumor biopsy sample may be obtained prior to the 28-day screening window, if necessary, in order to permit tumor biopsy sample 
acquisition and analysis (PD-L1 status and, if unknown, EGFR and ALK status) prior to randomization.
4 Body weight is recorded along with vital signs.

Clinical Study Protocol
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PD-L1 
Testing
Screening
C1
C2
C3
C4
C5
C6
C7
C8 to C12
C131 etc.
For 
details 
see 
Sectio
n
Week
-4 to -1
0
4
8
12
16
20
24
28, 32, 36, 
40, 44
48 etc.
Day
Prior to 
Day 1
-28 to -1
1
29
57
85
113
141
169
197, 225, 
253, 281, 
309
337 etc.
Window (days)
NA
+32
±3
±3
±3
±3
±3
±3
±3
±3
ECG5
X
As clinically indicated
5.2.3
Concomitant medications
<-------------------------------------------------------------------------------------------------------------------->
7.7
Demography, including baseline 
characteristics and tobacco use
X
X
4.1
Eligibility criteria
X
X
3.1, 3.2
Laboratory assessments6
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
Table
5
Hematology
X
X
X
X
X
X
X
X
X
X
Table 
6
                                               
5Any clinically significant abnormalities detected require a confirmatory ECG.
6 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.

Clinical Study Protocol
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Study Code D419AC00002
Version 9
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PD-L1 
Testing
Screening
C1
C2
C3
C4
C5
C6
C7
C8 to C12
C131 etc.
For 
details 
see 
Sectio
n
Week
-4 to -1
0
4
8
12
16
20
24
28, 32, 36, 
40, 44
48 etc.
Day
Prior to 
Day 1
-28 to -1
1
29
57
85
113
141
169
197, 225, 
253, 281, 
309
337 etc.
Window (days)
NA
+32
±3
±3
±3
±3
±3
±3
±3
±3
APTT and INR 
X
As clinically indicated
Table 
6
TSH, free T3, and free T47
X
X
X
X
X
X
X
X
X
X
5.2.1
Urinalysis
X
As clinically indicated
Table 
7
Hepatitis B and C and HIV
X
5.2.1
Pregnancy test8
X
X
X
X
X
X
X
X
X
X
5.2.1
Monitoring
WHO/ECOG performance status
X
X
X
X
X
X
X
X
X
X
5.3.3
AE/SAE assessment
<-------------------------------------------------------------------------------------------------------------------->
6.3.1
                                               
7 Free T3 and free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
8 For women of childbearing potential only.  A urine or serum pregnancy test is acceptable.  

Clinical Study Protocol
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PD-L1 
Testing
Screening
C1
C2
C3
C4
C5
C6
C7
C8 to C12
C131 etc.
For 
details 
see 
Sectio
n
Week
-4 to -1
0
4
8
12
16
20
24
28, 32, 36, 
40, 44
48 etc.
Day
Prior to 
Day 1
-28 to -1
1
29
57
85
113
141
169
197, 225, 
253, 281, 
309
337 etc.
Window (days)
NA
+32
±3
±3
±3
±3
±3
±3
±3
±3
Drug accountability
X
X
X
X
X
X
X
X
X
7.6
Pre-randomization medication9
Folic acid
X
Discontinue as randomized to durvalumab
3.3
IM Vitamin B12
X
Discontinue as randomized to durvalumab
3.3
IP administration
Durvalumab10
X
X
X
X
X
X
X
X
X
7.2.1
PRO assessments11
                                               
9 To be administered in line with local practice for patients with non-squamous tumors who will receive pemetrexed if randomized to SoC group.
10 Results for urea and electrolytes, full blood count, and liver function tests must be available before commencing an infusion (within 3 days).
11 In instances where the PRO assessments coincide with a clinic visit, the research nurse or study coordinator should verify that the questionnaire was completed before the 
visit.  If not, the patient should complete the questionnaire prior to any other study procedures and before discussion of disease progression to avoid biasing the patient’s 
responses to the questions.

Clinical Study Protocol
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Study Code D419AC00002
Version 9
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PD-L1 
Testing
Screening
C1
C2
C3
C4
C5
C6
C7
C8 to C12
C131 etc.
For 
details 
see 
Sectio
n
Week
-4 to -1
0
4
8
12
16
20
24
28, 32, 36, 
40, 44
48 etc.
Day
Prior to 
Day 1
-28 to -1
1
29
57
85
113
141
169
197, 225, 
253, 281, 
309
337 etc.
Window (days)
NA
+32
±3
±3
±3
±3
±3
±3
±3
±3
EORTC QLQ-C30, 
X
Every 4 weeks for the first 8 weeks relative to the date of 
randomization, then every 8 weeks thereafter until second 
progression/death (whichever comes first)
5.3.1.1, 
5.3.1.3
EORTC QLQ-LC13
X
Every 2 weeks for the first 8 weeks relative to the date of 
randomization, then every 4 weeks thereafter until second 
progression/death (whichever comes first)
5.3.1.2
Other laboratory assessments and assays
Immunogenicity assessment (ADA 
sampling to identify ADA responses in 
patient circulation)
X
X
X
5.4.1
Tumor biopsy (newly acquired or archived 
<3 months old)
X12
5.5.1
                                               
12 Informed consent of study procedures and tumor biopsy sample may be obtained prior to the 28-day screening window, if necessary, in order to permit
tumor biopsy sample acquisition and analysis prior to randomization.
CCI

Clinical Study Protocol
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product; MRI Magnetic resonance imaging; NSCLC Non-small-cell lung cancer; PBMC Peripheral blood mononuclear cell; PD Progressive disease; SAE 
Serious adverse event; SNP Single nucleotide polymorphism; TSH Thyroid-stimulating hormone; T3 Triiodothyronine; T4 Thyroxine; WHO World Health 
Organization.

Clinical Study Protocol
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Study Code D419AC00002
Version 9
Date 18 Jun 2021
76 (183)
Table 3
Schedule of assessments for Standard of Care therapy treatment period
PD-L1 
Testing
Screenin
g
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 to C17
C18, C19, 
etc.
For details 
see Section
Week
-4 to -1
0
3
6
9
12
15
18
21
24
27, 30, 33, 36, 39, 42, 
45, 48
51, 54, etc.
Day
Prior to 
Day 1
-28 to -1
1
22
43
64
85
106
127
148
169
190, 211, 232, 253, 
274, 295, 316, 337
358, 379, etc.
Window (days)
NA
+3
16
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
Informed consent
X17
4.1, 10.4
Study procedures
Physical exam (full)
X
5.2.2
Targeted physical exam 
(based on symptoms)
X
X
X
X
X
X
X
X
X
X
X
5.2.2
Vital signs18
X
X
X
X
X
X
X
X
X
X
X
X
5.2.4
                                               
16 Every effort should be made to minimize the time between randomization and starting treatment. (i.e., on the same day after randomization)
17 Informed consent of study procedures and tumor biopsy sample may be obtained prior to the 28-day screening window, if necessary, in order to permit tumor biopsy sample 
acquisition and analysis prior to randomization
18 Before every infusion or administration and as clinically indicated.

Clinical Study Protocol
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Study Code D419AC00002
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Date 18 Jun 2021
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Table 3
Schedule of assessments for Standard of Care therapy treatment period
PD-L1 
Testing
Screenin
g
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 to C17
C18, C19, 
etc.
For details 
see Section
Week
-4 to -1
0
3
6
9
12
15
18
21
24
27, 30, 33, 36, 39, 42, 
45, 48
51, 54, etc.
Day
Prior to 
Day 1
-28 to -1
1
22
43
64
85
106
127
148
169
190, 211, 232, 253, 
274, 295, 316, 337
358, 379, etc.
Window (days)
NA
+3
16
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
ECG19
X
As clinically indicated
5.2.3
Concomitant medications
<----------------------------------------------------------------------------------------------------------------------------------------------------->
7.7
Demography, including 
baseline characteristics and 
tobacco use
X
X
4.1
Eligibility criteria
X
X
3.1, 3.2
Laboratory assessments
Clinical chemistry20
X
X
X
X
X
X
X
X
X
X
X
X
Table 5
                                               
19 Any clinically significant abnormalities detected require a confirmatory ECG.
20 To be collected every 3 weeks prior to the start of infusion and as clinically indicated. 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.

Clinical Study Protocol
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Study Code D419AC00002
Version 9
Date 18 Jun 2021
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Table 3
Schedule of assessments for Standard of Care therapy treatment period
PD-L1 
Testing
Screenin
g
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 to C17
C18, C19, 
etc.
For details 
see Section
Week
-4 to -1
0
3
6
9
12
15
18
21
24
27, 30, 33, 36, 39, 42, 
45, 48
51, 54, etc.
Day
Prior to 
Day 1
-28 to -1
1
22
43
64
85
106
127
148
169
190, 211, 232, 253, 
274, 295, 316, 337
358, 379, etc.
Window (days)
NA
+3
16
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Hematology21
X
X
X
X
X
X
X
X
X
X
X
X
Table 6
APTT and INR
X
As clinically indicated
Table 6
TSH, free T3, and free T422
X
X
X
5.2.1
Urinalysis
X
As clinically indicated
Table 7
Hepatitis B and C and HIV
X
5.2.1
Pregnancy test23
X
As clinically indicated
5.2.1
Monitoring
                                               
21 To be collected every 3 weeks prior to the start of infusion and as clinically indicated. 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.
22 Free T3 and free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
23 For women of childbearing potential only.  A urine or serum pregnancy test is acceptable.

Clinical Study Protocol
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Study Code D419AC00002
Version 9
Date 18 Jun 2021
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Table 3
Schedule of assessments for Standard of Care therapy treatment period
PD-L1 
Testing
Screenin
g
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 to C17
C18, C19, 
etc.
For details 
see Section
Week
-4 to -1
0
3
6
9
12
15
18
21
24
27, 30, 33, 36, 39, 42, 
45, 48
51, 54, etc.
Day
Prior to 
Day 1
-28 to -1
1
22
43
64
85
106
127
148
169
190, 211, 232, 253, 
274, 295, 316, 337
358, 379, etc.
Window (days)
NA
+3
16
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
WHO/ECOG performance 
status
X
X
X
X
X
X
X
X
X
X
X
X
5.3.3
AE/SAE assessment 
<---------------------------------------------------------------------------------------------------------------------------------------------------->
6.3.1
Pre-randomization medication24
Folic acid
X
Continue in line with local practice
3.3
IM Vitamin B12
X
Continue in line with local practice
3.3
SoC administration
Platinum-based 
chemotherapy
X
Cycle every 3 weeks
7.2.1
                                               
24  To be administered in line with local practice for patients with non-squamous tumors who will receive pemetrexed if randomized to SoC group.

Clinical Study Protocol
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Study Code D419AC00002
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Table 3
Schedule of assessments for Standard of Care therapy treatment period
PD-L1 
Testing
Screenin
g
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 to C17
C18, C19, 
etc.
For details 
see Section
Week
-4 to -1
0
3
6
9
12
15
18
21
24
27, 30, 33, 36, 39, 42, 
45, 48
51, 54, etc.
Day
Prior to 
Day 1
-28 to -1
1
22
43
64
85
106
127
148
169
190, 211, 232, 253, 
274, 295, 316, 337
358, 379, etc.
Window (days)
NA
+3
16
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
PRO assessments25
EORTC QLQ-C30, 
X
Every 4 weeks relative for the first 8 weeks relative to the date of randomization, 
then every 8 weeks thereafter until second progression/death (whichever comes first)
5.3.1.1, 
5.3.1.3
EORTC QLQ-LC13 
X
Every 2 weeks for the first 8 weeks relative to the date of randomization, 
then every 4 weeks thereafter until second progression/death (whichever comes first)
5.3.1.2
                                               
25 In instances where the PRO assessments coincide with a clinic visit, the research nurse or study coordinator should verify that the questionnaire was completed before the 
visit.  If not, the patient should complete the questionnaire prior to any other study procedures and before discussion of disease progression to avoid biasing the patient’s 
responses to the questions.
CCI

Clinical Study Protocol
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Study Code D419AC00002
Version 9
Date 18 Jun 2021
81 (183)
Table 3
Schedule of assessments for Standard of Care therapy treatment period
PD-L1 
Testing
Screenin
g
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 to C17
C18, C19, 
etc.
For details 
see Section
Week
-4 to -1
0
3
6
9
12
15
18
21
24
27, 30, 33, 36, 39, 42, 
45, 48
51, 54, etc.
Day
Prior to 
Day 1
-28 to -1
1
22
43
64
85
106
127
148
169
190, 211, 232, 253, 
274, 295, 316, 337
358, 379, etc.
Window (days)
NA
+3
16
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Other laboratory assessments and assays
Tumor biopsy (newly 
acquired or archived 
<3 months old)
X26
5.5.1
EGFR and ALK test
X27
3.3
Tumor evaluation (CT or 
MRI) (RECIST 1.1)28
X
Every 6 weeks ± 1 week for the first 48 weeks relative to the date of randomization, 
and then every 8 weeks ± 1 week thereafter
5.1
                                               
26 Informed consent of study procedures and tumor biopsy sample may be obtained prior to the 28-day screening window, if necessary, in order to permit  tumor biopsy sample 
acquisition and analysis prior to randomization
27 For patients with unknown status of ALK and/or EGFR NSCLC.  
28 RECIST 1.1 assessments will be performed on CT/MRI images of the chest and abdomen (including liver and adrenal glands).  Additional anatomy should be imaged based 
on signs and symptoms of individual patients at baseline and follow-up.  Baseline assessments 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 start of study treatment.  The radiological progression confirmatory scans should be performed no 

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Table 4
Schedule of assessments for patients who have discontinued/completed treatment with Durvalumab or 
Standard of Care therapy
Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
12 months and 
every 2 months (±2 
weeks)
30
2
3
4
6
8
10
Physical examination (full)1
X
Vital signs (temperature, respiratory rate, 
blood pressure, and pulse)
X
Weight
X
Pregnancy test2
X
As clinically indicated
AE/SAE assessment3
X
X
X
Concomitant medications
X
X
X
WHO/ECOG performance status
At time points consistent with tumor assessments; at 30, 60, and 90 days; and then at initiation of subsequent 
anticancer therapy4
                                               
1 Physical exams are described in Section 5.2.2.
2 For women of childbearing potential only.  A urine or serum pregnancy test is acceptable.
3 The AE/SAE follow-up for SoC is only 30 days
4 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 performance status should be provided when information on subsequent anticancer therapy is provided, where possible.

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Table 4
Schedule of assessments for patients who have discontinued/completed treatment with Durvalumab or 
Standard of Care therapy
Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
12 months and 
every 2 months (±2 
weeks)
30
2
3
4
6
8
10
Subsequent anticancer therapy5 and second 
progression assessment6
<---------------------------------------------------------------------------------------------------------------------------------->
Survival status7
X
X
X
X
X
X
X 
Hematology
X
X
X
Clinical chemistry
X
X
X
TSH, free T3, and free T48
X
                                               
5 Details of any treatment for NSCLC (including surgery) post the last dose of study treatment must be recorded in the eCRF.
6 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. For patients who discontinue their assigned IP following confirmed progression, available readings of CT/MRI from local 
practice will be collected from the patients’ medical charts while information on subsequent anticancer treatment and/or PFS2 is collected.
7 Patients may be contacted in the week following data cut-offs to confirm survival status.  Details of any treatment for NSCLC (including surgery) post the last dose of study 
treatment must be recorded in the eCRF.
8 Free T3 and free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.

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Table 4
Schedule of assessments for patients who have discontinued/completed treatment with Durvalumab or 
Standard of Care therapy
Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
12 months and 
every 2 months (±2 
weeks)
30
2
3
4
6
8
10
Immunogenicity assessment (ADA 
sampling) to identify ADA responses in 
patient circulation (durvalumab group only) 
9
X
X
EORTC QLQ-C30, 
Every 4 weeks relative for the first 8 weeks relative to the date of randomization, then every 8 weeks thereafter 
until second progression/death (whichever comes first)
EORTC QLQ-LC1311
Every 2 weeks for the first 8 weeks relative to the date of randomization, then every 4 weeks thereafter until 
second progression/death (whichever comes first)
X
                                               
9 For patients in the durvalumab group only. Immunogenicity samples for durvalumab are collected 90 days (3 months) (± 7 days) after treatment with the applicable drug ends. 
In addition a final immunogenicity sample is taken 6 months (± 7 days) after treatment with the applicable drug ends.
10 Patients will complete PROs using handheld devices at home.
11 Patients will complete PROs using handheld devices at home.
CCI
CCI

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Table 4
Schedule of assessments for patients who have discontinued/completed treatment with Durvalumab or 
Standard of Care therapy
Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
12 months and 
every 2 months (±2 
weeks)
30
2
3
4
6
8
10
Tumor assessment (CT or MRI)12
Every 6 weeks ± 1 week for the first 48 weeks (relative to the date of randomization), and then every 8 weeks 
± 1 week thereafter until confirmed objective disease progression/death (whichever comes first).  Additional 
scans to be completed per standard practice post progression.13
ADA Anti-drug antibody; AE Adverse event; CT Computed tomography; ECOG Eastern Cooperative Oncology Group; eCRF electronic case repot form; 
EORTC QLQ-C30 Eastern Cooperative Oncology Group Quality of Life Questionnaire; EORTC QLQ-LC13 EORTC QLQ Lung Cancer 13;
 IP Investigational product; MRI Magnetic resonance imaging; NSCLC Non-small-cell lung 
cancer; PD Progressive disease; PFS2 Time to second progression; RECIST Response Evaluation Criteria In Solid Tumors; SAE Serious adverse event; 
TSH Thyroid-stimulating hormone; T3 Triiodothyronine; T4 Thyroxine; WHO World Health Organization.
                                               
12 Only for patients yet to progress, RECIST 1.1 assessments will be performed on CT/MRI images of the chest and abdomen (including liver and adrenal glands). Additional 
anatomy should be imaged based on signs and symptoms of individual patients.  The radiological progression confirmatory scans should preferably be performed no less 
than 4 weeks after the prior assessment of PD and preferably at the next scheduled visit (in the absence of clinically significant deterioration). If an unscheduled assessment 
was performed 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). All confirmatory scans should be recorded on the database.
13 If the patient continues to derive benefit from study treatment, then scans should continue to be collected following the original schedule and analysed by RECIST1.1, even
after confirmed radiographic progression.
CCI

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4.1
Enrolment/screening period
All screening and enrolment procedures will be performed according to the assessment 
schedule in Table 2 and Table 3.  Demographic data and other characteristics will be recorded 
including date of birth or age, gender, and smoking history.  A standard medical and surgical 
history will be obtained.
Written informed consent and any locally required privacy act document authorization must 
be obtained prior to performing any protocol-specific procedures, including PD-L1 testing and 
other screening/baseline evaluations.  All patients will be required to provide consent to 
supply a sample of their tumor (archived or newly acquired biopsy) for entry into this study.  
This consent is included in the main patient informed consent form (ICF).  
Whenever feasible, patients must first be confirmed to have PD-L1-high expression and 
EGFR and ALK wild-type NSCLC before proceeding with the rest of screening 
procedures. Screening/baseline evaluations may be performed over more than 1 visit.  
Informed consent may be obtained prior to the 28-day screening window, if necessary, in 
order to permit tumor biopsy sample acquisition and analysis prior to screening completion 
and randomization. If laboratory or 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 laboratory and imaging results must have been obtained within 28 
days of randomization.
4.2
Treatment period
All procedures to be conducted during the treatment period will be performed according to the 
assessment schedule (see Table 2 and Table 3). 
Whenever vital signs, electrocardiograms (ECGs), and blood draws are scheduled for the 
same nominal time, the assessments should occur in the following order: ECG, vital signs, and 
then blood draws.
4.3
Follow-up period
All procedures to be conducted during the follow-up period will be performed according to 
the assessment schedule (see Table 4).
Whenever vital signs, ECGs, and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: ECG, vital signs, and then blood draws.  
For patients who require IP treatment to be held for toxicity and subsequently discontinue 
therapy without restarting IP, all follow-up assessments will be based on the date of the last 
dose of IP.

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5.
STUDY ASSESSMENTS
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 eCRFs as specified 
in this study protocol and in accordance with the instructions provided.
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
the provision of answers to data queries according to the clinical study agreement (CSA).  The 
Investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be archived 
at the study site.
5.1
Efficacy assessments
RECIST 1.1 criteria will be used to assess patient response to treatment by determining PFS, 
ORR, DoR and APF12 using Investigator assessment.  The RECIST 1.1 guidelines for 
measurable, non-measurable, target, and non-target lesions and the objective tumor response 
criteria (CR, PR, SD, or PD) are presented in Appendix D.  PFS2 defined by local standard 
clinical practice, and OS will also be evaluated.
The assessment of tumor burden at baseline uses CT or MRI scans of the chest and abdomen 
(including liver and adrenal glands).  Any other areas of disease involvement should be 
additionally imaged based on the signs and symptoms of individual patients.
The baseline imaging assessment should be performed no more than 28 days before 
randomization and ideally as close as possible to the start of the assigned IP.  Efficacy for all 
patients will be assessed by objective tumor assessments every 6 weeks for the first 48 weeks 
(relative to the date of randomization; Table 2, Table 3, and Table 4) then Q8W thereafter, 
until confirmed objective disease progression per RECIST 1.1 (irrespective of the reason for 
stopping treatment or subsequent therapy).  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 (including SoC) due to toxicity in the absence of confirmed 
objective progression, objective tumor assessments per the scheduled assessments should be 
continued every 6 weeks for 48 weeks (relative to randomization) and then every 8 weeks 
until confirmed objective disease progression, every effort should be made to confirm a 
clinically significant deterioration by imaging. 
A confirmatory scan is required for patients in both groups following prior demonstration of 
PD provided the subject is clinically stable. The confirmatory scan should occur no earlier 
than 4 weeks after the prior assessment of PD and preferably at the next scheduled imaging 
visit in the absence of clinically significant deterioration. Treatment with durvalumab or SoC 
may continue between the initial assessment of radiologic progression and confirmation of 
progression. Progression would be considered confirmed per RECIST 1.1 criteria available in 
Appendix D using Investigator assessments.

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Radiologic progression would be considered confirmed if the following criteria are met:

≥ 20% increase in the sum diameters of target lesions (TLs) compared with the 
nadir at 2 consecutive visits, with an absolute increase of at least 5 mm in sum of 
diameters compared to nadir,                                                                                                                

and/or significant progression (worsening) of non-target lesions (NTLs) and/or of 
pre-existing new lesions at the confirmatory scan time-point compared with the 
immediate prior time-point (Note: Pre-existing new lesions are evaluated as NTLs 
at the confirmatory scan time-point),

and/or additional new unequivocal lesions at the confirmatory scan time-point.
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) prior to 
progression, then the patient should still continue to be followed until confirmed objective 
disease progression. Categorization of objective tumor response assessment will be based on 
the RECIST 1.1 criteria of response: CR, PR, SD, and PD.  Target lesion progression will be 
calculated in comparison to when the tumor burden was at a minimum (i.e., smallest sum of 
diameters previously recorded on study).  In the absence of progression, tumor response (CR 
or PR) and SD will be calculated in comparison to the baseline tumor measurements obtained 
before starting treatment.
Following confirmed progression, patients should continue to be followed up for survival 
every 1 to 2 months as outlined in the study plan (Table 4).  Subsequent anticancer therapy 
information will be collected at time points indicated in Table 4.
It is important to follow the assessment schedule as closely as possible.  Please refer to the 
study plans (Table 2 and Table 3 [screening and the treatment period] and Table 4 for 
follow-up of patients who have completed or discontinued IP treatment) and Appendix E.
Central reading of scans
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed Contract Research Organization (CRO) for quality control 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. If a BICR is 
implemented, 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.
Survival assessments
Assessments for survival must be made every 2 months following treatment discontinuation.  
Survival information may be obtained via telephone contact with the patient, patient’s family, 

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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 data 
cut-off for the primary analysis and all subsequent survival analyses to provide complete 
survival data.  These contacts should generally occur within 7 days of the data cut off.
5.2
Safety assessments
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, hematology, coagulation, 
and urinalysis will be taken at the times indicated in the assessment schedules and as clinically 
indicated (see Table 2, Table 3, and Table 4). 
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 5 (clinical chemistry), Table 6
(hematology and coagulation), and Table 7 (urinalysis).
Pregnancy tests on either urine (human chorionic gonadotropin [hCG]) or blood (serum 
β-hCG) samples will be performed for pre-menopausal women of childbearing potential at 
Screening as specified in the assessment schedule (see Table 2, Table 3, and Table 4).  Tests
will be performed by the hospital’s local laboratory.  If results are positive, the patient must 
not start or continue treatment.  In the event of a suspected pregnancy during the study, the 
test should be repeated.
Other safety tests to be performed at Screening include assessment for hepatitis B surface 
antigen, hepatitis C antibodies, HIV antibodies, thyroid-stimulating hormone (TSH), free 
triiodothyronine (T3), and free thyroxine (T4).

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Table 5
Clinical chemistry (serum or plasma)
Albumin
Glucose
Alkaline phosphatase
Lactate dehydrogenase
Alanine aminotransferase
Lipasea
Amylasea
Magnesium
Aspartate aminotransferase
Potassium
Bicarbonated
Sodium
Calcium 
Total bilirubinb
Chloride
Total protein
Creatinine 
Urea or blood urea nitrogen, depending on local practice
Gamma glutamyltransferasec
Uric acid
a    In the event that amylase and lipase analyses cannot performed, 1 or the other will be performed in line with    local 
practice. 
b    If total bilirubin is ≥2 × ULN (and evidence of Gilbert’s syndrome) then fractionate into direct and indirect bilirubin.
c    At baseline and as clinically indicated.
d   Bicarbonate (where available) is to be performed at baseline and if clinically indicated.
Table 6
Hematology and Coagulation
Hematology
Basophils
Mean corpuscular volume
Eosinophils
Monocytes
Haematocrit
Neutrophils
Haemoglobin
Platelet count
Lymphocytes
Red blood cell count
Mean corpuscular haemoglobin
Total white cell count
Coagulationa
Activated partial thromboplastin time 
international normalized ratio
a       Activated partial thromboplastin time and international normalized ratio are to be assessed at screening and as clinically 
indicated.
Table 7
Urinalysis
Urinalysis should be done at baseline (screening) and then as clinically indicated
Bilirubin
Ketones
Blood
pH
Colour and appearance
Protein

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Bilirubin
Ketones
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 C 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 30 days (±3 days), 2 months 
(±1 week) and 3 months (±1 week) after permanent discontinuation of IP (see Table 4).
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 6.1.4.
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from study treatment 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.
Physical examination
Physical examinations will be performed according to the assessment schedules (see Table 2, 
Table 3, and Table 4).  Full physical examinations will include assessments of the head, eyes, 
ears, nose, and throat and the respiratory, cardiovascular, 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 6.1.4.
Electrocardiograms
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study (see Table 2, Table 3, and Table 4).  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, 2 additional 12-lead ECGs should be 
obtained over a brief period (e.g., 30 minutes) to confirm the finding.  
Situations in which ECG results should be reported as AEs are described in Section 6.1.4.

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Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the assessment schedules (see Table 2, Table 3, and Table 4).  Body weight is 
also recorded along with vital signs.
Supine or semi-supine BP will be measured using a semi-automatic BP recording device with 
an appropriate cuff size, after the patient has rested for at least 5 minutes.  BP and pulse will 
be collected from patients in the durvalumab treatment group before, during, and after each 
infusion at the following times (based on a 60-minute infusion):
First infusion
On the first infusion day, patients in the durvalumab monotherapy will be monitored and vital 
signs collected/recorded in eCRF prior to, during and after infusion of IP as presented in the 
bulleted list below.  
Blood pressure (BP) and pulse will be collected from patients in the I-O arms before, during, 
and after each 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 minutes [i.e., 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)
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.  A 1-hour 
observation period is recommended after the first infusion of durvalumab.  
Subsequent infusions
BP, pulse and other vital signs should be measured, 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 CRF page. 
Patients in the SoC group will be monitored pre-dose and as clinically indicated before every 
infusion or administration.
Situations in which vital signs results should be reported as AEs are described in Section 
6.1.4. For any adverse events of infusion reactions please enter the vital signs values into the 
CRF.

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patient should not receive help from relatives, friends, or clinic staff to answer the 
PRO questionnaires.  

The research nurse or appointed site staff must monitor compliance; minimizing 
missing data is a key aspect of study success.  Compliance must be checked at each 
study visit and should be checked more frequently to identify problems early.  If 
compliance drops below 85%, a check-in call from the site to ask the patient if 
he/she has any difficulties is highly recommended.
ECOG performance status
WHO/ECOG performance status will be assessed at the times specified in the assessment 
schedules (see Table 2, Table 3, and Table 4) 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 (e.g., 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.
5.
Dead.
Any significant changes from baseline or screening must be reported as an AE.
Pneumonitis (ILD) investigation
If new or worsening pulmonary symptoms (e.g. dyspnoea) or radiological abnormality 
suggestive of pneumonitis/interstitial lung disease is observed, toxicity management as 
described in detail in the Dosing Modification and Toxicity Management Guidelines (see 
Section 6.9.1) will be applied. The results of the full diagnostic workup (including high-
resolution computed tomography (HRCT), blood and sputum culture, haematological 
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.  
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 will be collected.

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•
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)
•
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 which are related to disease 
progression.  
(iii) Additional Clinical chemistry: CRP, LDH
5.4
ADA
Collection of samples to measure for the presence of ADAs
The presence of ADA will be assessed in serum samples taken according to the assessment 
schedules (see Table 2 and Table 4). 
Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for 
durvalumab using validated assays.  Tiered analysis will be performed to include screening, 
confirmatory, and titer assay components, and positive-negative cut points previously 
statistically determined from drug-naïve validation samples will be employed. 
Storage and destruction of ADA samples
ADA samples will be stored for a maximum of 15 years from the end of study, after which 
they will be destroyed. ADA samples may be disposed of or destroyed and anonymized by 
pooling.  Additional analyses may be conducted on the anonymized, to further evaluate and 
validate the analytical method.  Results from such analyses may be reported separately from 
the clinical study report (CSR).
ADA samples collected in China will be destroyed after the finalization of the bioanalytical 
report (or completion of 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.

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
Ensure that the laboratory (ies) holding the samples is/are immediately informed 
about the withdrawn consent and that samples are disposed of or destroyed, the 
action is documented, and the study site informed.

Ensure that the patient and AstraZeneca are informed about the sample disposal.
5.6
Pharmacogenetics
Not Applicable, Pharmacogenetic samples will not be collected in this study.
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of adverse events
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition during or following exposure to a pharmaceutical product, 
whether or not the condition is considered to be causally related to the product.  An 
undesirable medical condition can be a symptom (e.g., nausea or chest pain), sign 
(e.g., tachycardia or enlarged liver), or the abnormal result of an investigation (e.g., laboratory 
findings or ECG).  In clinical studies, an AE can include an undesirable medical condition 
occurring at any time, including run-in or washout periods, even if no study treatment has 
been administered.
The term ‘AE’ is used to include both serious and non-serious AEs.
Causality collection
The Investigator will assess the causal relationship between the IPs 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 medications 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 A.
Relationship to protocol procedures
The Investigator is also required to provide an assessment of the relationship of SAEs to 
protocol procedures on the SAE report form.  This includes both non-treatment–emergent 
(i.e., SAEs that occur prior to the administration of durvalumab and 30 days after last dose of 
SoC) and treatment-emergent SAEs.  A protocol-related SAE may occur as a result of a 

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procedure or intervention required during the study (e.g., blood collection).  The following 
guidelines should be used by Investigators to assess the relationship of SAEs to the protocol:

Protocol related: The event occurred due to a procedure or intervention that was 
described in the protocol for which there is no alternative etiology present in the 
patient’s medical record.

Not protocol related: The event is related to an etiology other than the procedure or 
intervention that was described in the protocol.  The alternative etiology must be 
documented in the study patient’s medical record.
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 personnel: “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 generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
Adverse events based on examinations and tests
The results from protocol-mandated laboratory tests and vital signs measurements 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 the IPs.
If deterioration in a laboratory value or vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory result 
or vital sign will be considered as additional information.  Whenever possible, the reporting 
Investigator should use the clinical rather than the laboratory term (e.g., anaemia versus low 
haemoglobin 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.
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. Further instruction on cases of increases in liver biochemistry 
and evaluation of Hy’s law are shown in Appendix C.

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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.
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.
Deaths
All deaths that occur during the study, or within the protocol-defined follow-up period after 
the administration of the last dose of study treatment, must be reported as follows:

Death clearly resulting from disease progression should be reported to the Study 
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 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 Drug 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 study drug 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 
study drug then it should also be reported as an SAE.
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 toxicity management 

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guidelines (Dosing Modifications and Toxicity Management). All data post the final DCO 
and database closure will be recorded in the patient notes but, with the exception of Serious 
Adverse Events, 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 6.4. 
6.2
Definitions of serious adverse event
An SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout, or 
follow-up) that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability or incapacity 

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above
For further guidance on the definition of an SAE, see Appendix A.
6.3
Recording of adverse events
Time period for collection of adverse events
AEs and SAEs will be collected from the time of the patient signing the informed consent
form until the follow-up period is completed (90 days after the last dose of durvalumab and 30 
days after last dose of SoC).  AEs and SAEs collected prior to randomization will be reported 
as pre-randomization AEs and SAEs. If an event that starts post the defined safety follow-up 
period noted above is considered to be due to a late onset toxicity to study drug then it should 
be reported as an AE or SAE as applicable.
Follow-up of unresolved adverse events
During the course of the study, all AEs and SAEs should be proactively followed up for each 
patient for as long as the event is ongoing.  Every effort should be made to obtain a resolution 
for all events, even if the events continue after the patient has discontinued study drug or the 
study has completed. 
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.  

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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.
Variables 
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 (report only the maximum CTCAE grade for a calendar 
day)

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

Whether the AE caused the patient’s withdrawal from the study (yes or no)

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 

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Whether an autopsy was performed

Causality assessment in relation to study procedure(s)

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
Description of the AE
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 Section 6.2.  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 it is not an SAE unless it meets the criteria 
shown in Section 6.2.  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 Section 6.2.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not they are considered causally related to the IPs or 
to any study procedure.  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then the Investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1 day, i.e., immediately, but 
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 
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 in which important or relevant information is missing, active 
follow-up is undertaken immediately.  The Investigator or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day, i.e., immediately, but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigator or other site personnel indicates that an AE is serious in the WBDC 
system, an automated e-mail alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel will 
report an SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator or study site personnel how to 
proceed.
The reference documents for the definition of expectedness or listedness are the IBs for 
durvalumab.

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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.
6.5
Regulatory reporting requirements for SAEs
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.        
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators.             
For all studies except those utilizing medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then 
file it along with the Investigator’s Brochure or and will notify the IRB/IEC, if appropriate 
according to local requirements.
6.6
Overdose
Durvalumab 
Use of IP 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 in the Overdose eCRF 
module.

An overdose without associated symptoms will only be reported in the Overdose 
eCRF module.
If an overdose of an AstraZeneca study drug 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.

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For overdoses associated with an SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
Standard of Care
For patients randomized to the SoC group please refer to the local prescribing information for 
treatment of cases of overdose. If any overdose is associated with an AE or SAE please record 
the AE/SAE diagnosis or symptoms in the relevant AE modules of the eCRF.
6.7
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
Maternal exposure
Female patients must not become pregnant during the study and for up to 90 days after the last 
dose of durvalumab. 
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 
should inform the appropriate AstraZeneca representatives within 1 day, i.e., immediately, but 
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 within 1 to 
5 calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and 
90 days after the last dose of durvalumab.  Please follow the local prescribing information 
relating to contraception and the time limit for such precautions for SoC agents.
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 

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or congenital abnormality) occurring from the date of the first dose until 90 days after the last 
dose 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 (EC)/Internal Review Boards (IRB) prior to use.
6.8
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 patient or 
has the potential to cause harm to the patient. 
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 patient.
Medication error includes situations where an error. 

Occurred.

was identified and intercepted before the patient received the drug.

did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion.

Dispensing error e.g. medication prepared incorrectly, even if it was not actually 
given to the patient.

Drug not administered as indicated, for example, wrong route or wrong site of 
administration.

Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as 
a solid tablet.

Drug not stored as instructed e.g. kept in the fridge when it should be at room 
temperature.

Wrong patient received the medication (excluding IVRS/IWRS errors).

Wrong drug administered to patient (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.

Subject accidentally missed drug dose(s) e.g. forgot to take medication.

Accidental overdose (will be captured as an overdose).

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
Subject 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.  
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 i.e., 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 completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 6.4) and within 30 days for all other medication errors.
6.9
Management of investigational product-related toxicities
For guidance on the management of IP-related toxicities, please see Dosing Modifications and 
Toxicity Management.
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 of the assigned IP along with appropriate continuing supportive 
care. If medically appropriate, dose modifications are permitted.

It is important to note that these guidelines are prepared by the Sponsor to 
assist the Investigator in the exercise of his or her clinical judgment in treating 
these types of toxicities.

All dose modifications should be documented with clear reasoning and 
documentation of the approach taken.
All toxicities will be graded according to NCI CTCAE, Version 4.03.
Specific toxicity management and dose modification information –
Durvalumab
Comprehensive toxicity management guidelines (TMGs) have been developed to assist 
investigators with the recognition and management of toxicities associated with use of the 
immune-checkpoint inhibitors, durvalumab [MED4736] (PD-L1 inhibitor) and tremelimumab 
(CTLA-4 inhibitor). Given the similar underlying mechanism of toxicities observed with these 
two compounds, these TMGs are applicable to the management of patients receiving either 
drug as monotherapy or both drugs in combination. Additionally, these guidelines are 
applicable when either drug is used alone or both drugs are used in combination and, also 

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other anti-cancer drugs (i.e., antineoplastic chemotherapy, targeted agents) are administered 
concurrently or sequentially as part of a protocol-specific treatment regimen. The TMGs 
provide information for the management of immune mediated reactions, infusion-related 
reactions, and non-immune-mediated reactions that may be observed with checkpoint inhibitor 
monotherapy or combination checkpoint inhibitor regimens, with specific instructions for 
checkpoint inhibitor-specific dose modifications (including discontinuation) and treatment 
interventions. Investigators are advised however to use local practice guidelines and consult 
local references for the management of toxicities observed with other anti-cancer treatment.
The most current version of the TMGs is provided to the investigative site as an Annex to 
Protocol document entitled, “Dosing Modification and Toxicity Management Guidelines for 
Immune-Mediated, Infusion-Related, and Non-Immune–Mediated Reactions (MEDI4736 
Monotherapy or Combination Therapy with Tremelimumab or Tremelimumab 
Monotherapy),” and is maintained within the Site Master File.
Patients should be thoroughly evaluated, and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the Immune-mediated 
adverse event (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 3.9 of 
this protocol and the TMGs). Following the first dose of IP, subsequent administration of 
durvalumab can be modified based on toxicities observed as described in the Dosing 
Modification and Toxicity Management Guidelines. 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 
durvalumab monotherapy regimen by the reporting Investigator.
Dose reductions are not permitted.  In case of doubt, the Investigator should consult with 
the Study Physician.
Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent medications 
per institutional standard may be administered prior to infusion at the discretion of the 
Investigator for primary prophylaxis against infusion-related reactions.  In the event of Grade
≤ 2 infusion-related reaction, the infusion rate of IP may be decreased by 50% or interrupted 
until resolution of the event (up to 4 hours) and re-initiated at 50% of the initial rate until 
completion of the infusion.  In patients experiencing Grade ≤ 2 infusion-related reaction, 
subsequent infusions may be administered at 50% of the initial rate.  If a patient experiences 
an infusion-related reaction, acetaminophen and/or an antihistamine (e.g., diphenhydramine) 
and/or corticosteroid or equivalent medications per institutional standard may be administered 
prior to subsequent infusions at the discretion of the Investigator for secondary prophylaxis of 
infusion-related reactions.  If the infusion-related reaction is Grade 3 or higher in severity, 
treatment with IP will be discontinued.
As with any antibody, allergic reactions to dose administration are possible.  Appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately 

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available, and study personnel must be trained to recognize and treat anaphylaxis.  The study 
site must have immediate access to emergency resuscitation teams and equipment in addition 
to the ability to admit patients to an intensive care unit if necessary.
Adverse events of special interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring. 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 
investigational product.
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 immune-mediated adverse event (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 in regards to an event being an imAE, the Investigator 
should promptly contact the Study Physician.
AESIs observed with durvalumab may include:

Diarrhea/Colitis and intestinal perforation

Pneumonitis / ILD

Hepatitis / transaminase increases

Endocrinopathies (hypo- and hyper-thyroidism, adrenal insufficiency, 
hypophysitis/hypopituitarism and Type 1 diabetes mellitus)

Rash/Dermatitis

Nephritis 

Pancreatitis  

Myocarditis

Myositis/polymyositis

Neuropathy / Neuromuscular toxicity such as Guillain-Barré, and myasthenia gravis

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, rheumatological events, 

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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 aetiology are also considered AESIs.
Further information on these risks (e.g. presenting symptoms) can be found in the current 
version of the durvalumab Investigator’s Brochures. More specific guidelines for their 
evaluation and treatment are described in detail in the Dosing Modification and Toxicity 
Management Guidelines (please see Section 6.9.1). 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 
study drug/study regimen by the reporting investigator.
Standard of Care agents
Investigators should follow local standard clinical practice regarding dose modifications for 
agents used in the SoC arm.  For specific information regarding the individual agent used in 
this study, please refer to the local prescribing information for the relevant agent. 
6.10
Study governance and oversight
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.
An IDMC comprised of independent experts will be convened and will meet approximately 
6 months after the study has started or after the first 30 patients have been randomized and 
received at least 2 cycles of treatment, whichever occurs first, to review safety assessments 
and make recommendations to continue, amend, or stop the study based on safety findings.  
The committee will meet approximately every 6 months thereafter until a decision to unblind 
the study is made. In addition, the IDMC will review the unblinded interim analysis 
summaries of efficacy data.
Full details of the IDMC procedures, processes, and interim analyses can be found in the 
statistical analysis plan and the IDMC Charter.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
AstraZeneca will supply durvalumab (MEDI4736) while the SoC treatments (paclitaxel + 
carboplatin, gemcitabine + cisplatin, gemcitabine + carboplatin, pemetrexed + cisplatin, 

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pemetrexed + carboplatin, and pemetrexed maintenance) will be supplied locally unless 
central supply is required in participating country (Table 8).  
Table 8
List of investigational products for this study
Investigational product
Dosage form and strength
Manufacturer
Durvalumab (MEDI4736)
50 mg/mL, solution for infusion 
after dilution
MedImmune
Standards of Care
Paclitaxela
IV (as sourced locally)
Sourced locally
Carboplatina
IV (as sourced locally)
Sourced locally
Gemcitabinea
IV (as sourced locally)
Sourced locally
Cisplatina
IV (as sourced locally)
Sourced locally
Pemetrexeda
IV (as sourced locally)
Sourced locally
a
Under certain circumstances when local sourcing is not feasible, a Standard of Care treatment may be supplied centrally 
by AstraZeneca.
Durvalumab (MEDI4736)
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for 
infusion.  The solution contains 50 mg/mL durvalumab (MEDI4736), 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% (weight/volume) 
polysorbate 80; it has a pH of 6.0 and density of 1.054 g/mL.  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. Investigational product should be kept in original packaging until use to prevent 
prolonged light exposure.
Preparation of Durvalumab (MEDI4736) doses for administration with an IV bag
The dose of durvalumab (MEDI4736) for administration must be prepared by the 
Investigator’s or site’s designated IP manager using aseptic technique.  Total time from needle 
puncture of the durvalumab (MEDI4736) vial to the start of administration should not exceed:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
A dose of 20 mg/kg will be administered using an IV bag containing 0.9% weight/volume 
(w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) concentration 
ranging from 1 to 20 mg/mL, and delivered through an IV administration set with a 0.2 μm or 
0.22 μm filter.  Add calculated volume (i.e. 20 mg/kg) of durvalumab (MEDI4736) to the IV 
bag. The IV bag size should be selected such that the final concentration is within 1 to 20 
mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag.

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Standard infusion time 1 hour, however if there are interruptions during infusion, the total 
allowed infusion time should not exceed 8 hours 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.
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.
Patient weight at baseline should be used for dosing calculations unless there is a ≥ 
10% change in weight.  Dosing day weight can be used for dosing calculations instead of 
baseline weight per institutional standard.  
Preparations are to be in accordance with the study-specific drug handling instructions.
Dose calculation
The volume of durvalumab (MEDI4736) (in mL) to add to the IV bag is calculated as follows:
20 mg/kg × patient weight (kg) ÷ durvalumab (MEDI4736) concentration (nominal: 50 
mg/mL).
Example: For a patient weighing 80 kg, dosed at 20 mg/kg, 32 mL [20 mg/kg × 80 kg divided 
by 50 mg/mL] of durvalumab (MEDI4736) is to be added to an IV bag containing 0.9% (w/v) 
saline or 5% (w/v) dextrose.  The IV bag size should be selected such that the final 
concentration is within 1 to 20 mg/mL.  The bag is mixed by gentle inversion to ensure 
homogeneity of the dose in the bag and the diluted durvalumab (MEDI4736) is administered 
as described above.
Standard of Care treatment
Each SoC agent will be sourced as commercially available material/locally sourced, 
prescribed according to local regulations, and will be administered according to prescribing 
information or treatment guidance in general use by the Investigating site.  Under certain 
circumstances when local sourcing is not feasible, a SoC will be supplied centrally by 
AstraZeneca.  This will be labeled with local language translated text in accordance with 
regulatory guidelines.
7.2
Dose and treatment regimens
Patients will be randomized in a 1:1 ratio to receive treatment with durvalumab or SoC.

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Treatment regimens
Durvalumab
Patients in the durvalumab treatment group will receive 20 mg/kg durvalumab (MEDI4736) 
via IV infusion Q4W unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met (see Figure 3).  
Standard infusion time is 1 hour. In the event that there are interruptions during infusion, the 
total allowed time should not exceed 8 hours at room temperature.
Figure 3
Durvalumab (MEDI4736) dosing scheme
Standard of Care treatment
Patients in the SoC group will receive 1 of the following treatments until documented PD 
(confirmed or unconfirmed), initiation of alternative anticancer therapy, unacceptable toxicity, 
withdrawal of consent to continued treatment, or other reasons to discontinue treatment 
criterion occur:

Paclitaxel + carboplatin: Paclitaxel 175mg/m2 and carboplatin AUC 5 or 6 via IV 
infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles or until documented PD

Gemcitabine + cisplatin (squamous patients only): Gemcitabine 1000 or 
1250 mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + cisplatin 75 or 
80 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles or until 
documented PD 

Gemcitabine + carboplatin (squamous patients only): Gemcitabine 1000 or 
1250 mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + carboplatin 
AUC 5 or 6 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles or until 
documented PD 

Pemetrexed + cisplatin (non-squamous patients only): Pemetrexed 500 mg/m2 and 
cisplatin 75 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles 
or until documented PD. Non-squamous patients who have not progressed after 
4 cycles will be eligible for pemetrexed maintenance therapy.

Pemetrexed + carboplatin (non-squamous patients only): Pemetrexed 500 mg/m2
and carboplatin AUC 5 or 6 via IV infusion on Day 1 of each 21-day cycle, for 4 to 
6 cycles or until documented PD. Non-squamous patients who have not progressed 
after 4 cycles will be eligible for pemetrexed maintenance therapy.

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For all SoC therapies, a particular treatment (paclitaxel, gemcitabine, cisplatin, carboplatin, or 
pemetrexed) will not be used in patients experienced recurrence or progression of disease 
within 6 months of prior multimodal therapy using that particular treatment. 
A confirmatory scan is required for all patients in the SoC group, even if a subsequent 
treatment is started.
Duration of treatment 
Duration of treatment
Unless specific treatment discontinuation criteria are met, patients in both groups will 
continue therapy until disease progression.
Progression during treatment
During the treatment period patients in both arms may continue receiving therapy in the 
setting of unconfirmed radiologic progressive disease (PD) according to Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST 1.1), at the Investigator’s discretion, until 
progression is confirmed. A confirmatory scan is required following a RECIST 1.1 overall 
time point assessment of progression (PD), preferably at the next scheduled visit and no 
earlier than 4 weeks after the previous assessment of PD.  Patients in all arms with PD by 
RECIST 1.1 (unconfirmed and confirmed) who, in the Investigator’s opinion, continue to 
receive benefit from their assigned treatment and who meet the criteria for treatment in the 
setting of PD may continue to receive their assigned treatment for as long as they are gaining 
clinical benefit.  
Patients in the immunotherapy arm will not be permitted to continue immunotherapy if 
progression occurs after confirmed response (CR or PR as defined by RECIST 1.1) to 
immunotherapy treatment in the target lesions (regardless of the appearance of new lesions) 
i.e. the response and progression events both occurred in the target lesions while receiving 
immunotherapy during the same treatment period.
Patients with rapid tumor progression or with symptomatic progression that requires urgent 
medical intervention (e.g., central nervous system metastasis, respiratory failure due to tumor 
compression, spinal cord compression) will not be eligible for continuing durvalumab.
For all patients who are treated through progression, the investigator should ensure patients do 
not have any significant, unacceptable or irreversible toxicities that indicate continuing would 
not further benefit the patient.
Criteria for treatment in the setting of PD:
-
Absence of clinical symptoms or signs that indicate clinically significant deterioration;
-
Absence of any significant, unacceptable, or irreversible toxicities that indicate that 
continuing treatment will not provide further benefit.

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Patients who AstraZeneca and the Investigator determine may not continue treatment after PD 
will be followed up for survival.  Patients who have discontinued treatment due to toxicity or 
symptomatic deterioration, or who have commenced subsequent anticancer therapy, will be 
followed up until confirmed disease progression and for survival.
Post final Data Cut Off (DCO)
Patients who continue to receive benefit from their assigned treatment at the scheduled DCO 
for final analysis and final database lock may continue to receive their assigned treatment for 
as long as they and their physician feel they are gaining clinical benefit. For patients 
continuing to receive durvalumab treatment following the scheduled DCO for final analysis, it 
is recommended that the patients continue the scheduled site visits. 
Investigators should continue to monitor and document data for all study patients in the source 
notes after scheduled DCO for final analysis and final database lock. Dependent on the 
analysis results, 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 into 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 
continue treatment and only SAEs will be collected.
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 PEARL and 
evaluated as a combined dataset.
7.3
Labeling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfill GMP Annex 13 requirements for labelling.  
Label text will be translated into the local language.
IP will be provided with either single panel labels or multi language booklet labels.
Label text prepared for durvalumab (MEDI4736) 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.

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7.4
Storage
The Investigator, or an approved representative (e.g., pharmacist), will ensure that 
Durvalumab is stored in original carton box, in a secured area, in refrigerated temperatures 
(2°C to 8°C) 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 monitor upon 
detection.  A calibrated temperature monitoring device will be used to record the temperature 
conditions in the drug storage facility.  Storage conditions stated in the IB may be superseded 
by the label storage.
7.5
Compliance
The administration of all study drugs (including IP) should be recorded in the appropriate 
sections of the eCRF.
Treatment compliance will be assured by reconciliation of site drug accountability logs.
7.6
Accountability
The study drug provided for this study will be used only as directed in the study protocol.  The 
study personnel will account for all study drugs dispensed to and returned from the patient.
Drug accountability should be performed until the patient stops study treatment completely.  
Study site personnel will account for all study drugs received at the site, for all unused study 
drugs, and for appropriate destruction of study drugs.  Certificates of delivery, destruction, and 
return should be signed.
7.7
Concomitant and other treatments 
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 90 
days follow up period following the last dose of study drug.  Any concomitant medication(s), 
including herbal preparations, taken during the study 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 to Section 6.9 for guidance on management of IP-related toxicities. For agents in 
the SoC arm, please refer to the local prescribing information with regards to warnings, 
precautions, and contraindications.
Prohibited medication/class of drug:
Usage:
Additional investigational anticancer therapy 
concurrent with those under investigation in this 
study
Should not be given whilst the patient is on IP treatment 
(including SoC) 

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Prohibited medication/class of drug:
Usage:
mAbs against CTLA-4, PD-1, or PD-L1
Should not be given whilst the patient is on IP treatment 
(including SoC).
Any concurrent chemotherapy, local therapy 
(except palliative radiotherapy, surgery, 
radiofrequency ablation for non-target lesions), 
biologic therapy, traditional Chinese Medicine, or 
hormonal therapy for the purpose of cancer 
treatment
Should not be given whilst the patient is on IP treatment 
(including SoC).  (Concurrent use of hormones for 
non-cancer-related conditions [e.g., insulin for diabetes and 
hormone replacement therapy] is acceptable).
Immunosuppressive medications, including, but not 
limited to: systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or its 
equivalent, methotrexate, azathioprine, and TNF-α 
blockers  
Should not be given concomitantly (including SoC), 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 
combination agent where the prescribing information for 
the agent requires the use of steroids for documented 
hypersensitivity reactions.
• Use in patients with contrast allergies.  
• In addition, use of inhaled, topical, and intranasal 
corticosteroids is 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 (e.g., chronic obstructive 
pulmonary disease, radiation, nausea, etc.).
Live attenuated vaccines
Should not be given through 30 days after the last dose of
IP (including SoC) during the study.
EGFR TKIs
Should not be given concomitantly (including SoC). 
Should be used with caution in the 90 days 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.
Rescue/supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(e.g., acetaminophen or diphenhydramine) deemed 
necessary by the Investigator 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

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Rescue/supportive medication/class of drug:
Usage:
Best supportive care (including antibiotics, 
nutritional support, growth factor support, 
correction of metabolic disorders, optimal symptom 
control, and pain management [including palliative 
radiotherapy, etc.])
Should be used when necessary for all patients
Inactivated viruses, such as those in the influenza 
vaccine
Permitted
Other concomitant treatment
Medications other than those described above, which is considered necessary for the patient’s 
safety and well-being may be given at the discretion of the Investigator and should be 
recorded in the appropriate sections of the eCRF.
As a result of imAEs that could potentially be experienced by patients on durvalumab, steroids 
and other immunosuppressant rescue medication must be made available to this patient 
population. 
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 monoclonal antibody 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 metabolising cytochrome P450 pathways. As a result, there are no 
expected pharmacokinetic 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.
7.8
Post study access to study treatment
After the final analysis, AstraZeneca will continue to supply open-label drug to patients 
receiving durvalumab (see Section 7.2.2).
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
All statistical analyses will be performed by AstraZeneca or its representatives.  
A comprehensive statistical analysis plan (SAP) will be prepared and finalized within 3 
months of the first patient randomization and any subsequent amendments will be 
documented, with final amendments completed prior to reporting of the data.  The primary
aim of the study is to compare the efficacy and safety of durvalumab to SoC.  

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Depending on the extent of any impact, summaries of data relating to patients diagnosed with 
COVID-19, and impact of COVID-19 on study conduct (in particular missed visits, delayed or 
discontinued IP, and other protocol deviations) may be generated. More detail will be provided in 
the SAP
8.2
Sample size estimate
The study will randomize approximately 650 eligible patients 1:1 to durvalumab or SoC. 
The primary objectives of this study are to assess the efficacy of durvalumab compared with 
standard of care (SoC) in terms of overall survival (OS) in advanced NSCLC patients with 
EGFR and ALK wild-type and PD-L1-high expression (TC ≥ 25%) tumors, and in the PD-L1 
TC ≥ 25% and low risk of early mortality population. To strongly control for type I error at a 
5% level (2 sided), an alpha of 4% (2 sided) will be used for the OS comparison of 
durvalumab versus SoC in the PD-L1 TC ≥ 25% population, and an alpha of 1% (2 sided) will 
be used for the OS comparison of durvalumab versus SoC in the PD-L1 TC ≥ 25% and low 
risk of early mortality population. The study will be considered to have met its primary 
objective if any of the dual primary OS results are statistically significant. 
There will be 2 data cut-offs in the study. The alpha will be split between the 2 OS analyses 
using the Lan and DeMets (Lan and DeMets 1983) spending function that approximates an 
O’Brien Fleming approach, with the boundaries for the treatment comparison derived based 
upon the exact number of OS events at the time of analysis to strongly control the overall type 
I error at a 5% level (2 sided).
One interim analysis to assess the superiority of the durvalumab group (compared to SoC 
group) in terms of OS will be performed when all of the following conditions have been met

approximately 85% of the target 521 OS events (approximately 68% maturity) have 
been achieved across the durvalumab and SoC treatment groups in the PD-L1 TC ≥
25% population
And

approximately 85% of the target 414 OS events (approximately 64% maturity) have 
been achieved across the durvalumab and SoC treatment groups in the PD-L1 TC ≥ 
25% and low risk of early mortality population
And

a minimum 12 months follow-up from last patient randomized to the study. 
The final (primary) analysis of OS will be performed when all of the following conditions 
have been met

approximately 521 OS events (approximately 80% maturity) have occurred across the 
durvalumab and SoC treatment groups in the PD-L1 TC ≥25% population
And

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
approximately 414 OS events (approximately 76% maturity) have occurred across the 
durvalumab and SoC treatment groups in the PD-L1 TC ≥ 25% and low risk of early 
mortality population. 
Durvalumab versus SoC (OS in the PD-L1 TC ≥25% population)
The sizing assumes a 6 months delay in separation of the OS curves between the two groups, 
hence the use of an average hazard ratio. If OS at 18 months was 46% with durvalumab and 
36% with SoC (with a 12.9-month median OS [Chen, et al 2014, Ciuleanu et al 2009, Paz-
Ares et al 2013, Scagliotti et al 2008] , i.e., Weibull distribution was assumed with shape 
parameter = 1.164459) and assuming the true average OS HR is 0.75, an estimated 521 death 
events (approximately 80% maturity) are expected to have occurred at 47 months from the 
time the first patient has been randomized with a 25-month recruitment period. With an 
estimated 521 deaths, the trial will have approximately 86% power to demonstrate statistical 
significance at the 2-sided alpha level of 3.334% (with overall alpha for OS 4%) for the 
comparison of durvalumab versus SoC, allowing for 1 interim analysis conducted at 
approximately 85% of the target events. The smallest treatment difference that could be 
statistically significant will be an average HR of 0.83. 
Durvalumab versus SoC (OS in the PD-L1 TC ≥25% and low risk of early mortality 
population)
The sizing assumes a 3 months delay in separation of the OS curves between the two groups, 
hence the use of an average hazard ratio. If OS at 18 months was 52% with durvalumab and 
39% with SoC (with a 13.8-month median OS, i.e., Weibull distribution was assumed with 
shape parameter = 1.164459) and assuming the true average OS HR is 0.69, an estimated 414 
death events (approximately 76% maturity) are expected to have occurred at 46 months from 
the time the first patient has been randomized with a 25-month recruitment period. With an 
estimated 414 deaths, the trial will have approximately 87% power to demonstrate statistical 
significance at the 2-sided alpha level of 0.862% (with overall alpha for OS 1%) for the 
comparison of durvalumab versus SoC, allowing for 1 interim analysis conducted at 
approximately 85% of the target events. The smallest treatment difference that could be 
statistically significant will be an average HR of 0.77. 
Non-uniform accrual of patients is assumed when estimating the analysis times. The total 
proportion of patients randomized at time t following the start of the study is assumed to be 
(t/D)1.5, where D is the accrual duration.
8.3
Definitions of analysis sets
Definitions of the analysis sets are provided in this section and analysis sets for each outcome 
variable are provided in Table 9.
Table 9
Summary of outcome variables and analysis populations
Outcome variable
Population
Efficacy data

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Outcome variable
Population
OS (primary)
Full analysis set (ITT population, i.e., PD-L1 TC ≥
25%)
OS (primary)
PD-L1 TC ≥25% and low risk of early mortality 
analysis set
OS
PD-L1 TC ≥50% analysis set
OS
PD-L1 TC ≥50% and low risk of early mortality 
analysis set
PFS, ORR, DoR, OS18, OS24, APF12, PFS2, PROs, 
and symptom endpoints
Full analysis set (ITT population, i.e., PD-L1 TC ≥
25%)
PFS, ORR, DoR, OS18, OS24, APF12, PFS2, PROs, 
and symptom endpoints
PD-L1 TC ≥25% and low risk of early mortality 
analysis set
PFS, ORR, DoR, OS18, OS24, APF12, PFS2
PD-L1 TC ≥50% analysis set
PFS, ORR, DoR, OS18, OS24, APF12, PFS2
PD-L1 TC ≥50% and low risk of early mortality 
analysis set
Demography
Full analysis set (ITT population, i.e., PD-L1 TC ≥
25%)
Demography
PD-L1 TC ≥25% and low risk of early mortality 
analysis set
Safety Data
Exposure
Safety analysis Set
PD-L1 TC ≥25% and low risk of early mortality 
safety analysis set
AEs
Safety analysis Set
PD-L1 TC ≥25% and low risk of early mortality 
safety analysis set
Laboratory measurements
Safety analysis Set
PD-L1 TC ≥25% and low risk of early mortality 
safety analysis set
Vital signs
Safety analysis Set
PD-L1 TC ≥25% and low risk of early mortality 
safety analysis set
ECGs
Safety analysis Set
PD-L1 TC ≥25% and low risk of early mortality 
safety analysis set
Full analysis set
The full analysis set (FAS) will include all randomized patients (i.e., patients with PD-L1 TC 
≥ 25%). The full analysis set will be used for all efficacy analyses (including PROs). 
Treatment groups will be compared on the basis of randomized study treatment, regardless of 

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the treatment actually received. Patients who were randomized but did not subsequently go on 
to receive study treatment are included in the analysis in the treatment group to which they 
were randomized.
PD-L1 TC ≥25% and low risk of early mortality analysis set
The PD-L1 TC ≥ 25% and low risk of early mortality population consists of patients identified 
by a prognostic model developed by AstraZeneca as having low risk of early mortality. The 
model is based on tumor type and six key routine laboratory parameters at baseline including 
NLR, neutrophils, albumin, lactate dehydrogenase, gamma glutamyltransferase and aspartate 
aminotransferase. All six parameters are required in the model. The model produces a score 
representing the probability of death occurring in ≤ 12 weeks for each patient. The model is 
then converted to a status that assigns patients to prognostic categories of high or low risk. 
Patients with a score above the cut-off are identified as high risk of EM, and patients at or 
below the cut-off are identified as low risk of EM. If any of the six parameters is missing, then 
the patient will be identified as unknown risk of EM. 
PD-L1 TC ≥50% analysis set
The PD-L1 TC ≥ 50% analysis set will include the subset of patients in the FAS whose PD-L1 
status is PD-L1 TC ≥ 50% as defined by the Ventana SP263 PD-L1 IHC assay (i.e., ≥ 50% of 
tumor cells with membrane positive for PD-L1).
PD-L1 TC ≥50% and low risk of early mortality analysis set
The PD-L1 TC ≥ 50% and low risk of early mortality population consists of patients with PD-
L1 TC ≥ 50% and identified by a prognostic model developed by AstraZeneca as having low 
risk of early mortality.
Safety analysis set
The safety analysis set (SAS) will consist of all patients who received at least 1 dose of study 
treatment. Safety data will not be formally analyzed but summarized using the safety analysis 
set, according to the treatment received, that is, erroneously treated patients (e.g., those 
randomized to treatment A but actually given treatment B) will be summarized according to 
the treatment they actually received.
PD-L1 TC ≥ 25% and low risk of early mortality safety analysis set
The PD-L1 TC ≥ 25% and low risk of early mortality safety analysis set will include patients 
identified by a prognostic model developed by AstraZeneca as having low risk of early 
mortality and who received at least 1 dose of study treatment.
8.4
Outcome measures for analyses
Calculation or derivation of efficacy variables
OS will be evaluated as a primary endpoint from all-cause mortality. The analysis of the 
secondary endpoints, PFS, ORR, DoR, and APF12, will be based on Investigator tumor 

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assessments according to RECIST 1.1. In addition, time to secondary progression (PFS2) will 
be defined by local clinical practice. OS18 and OS24 will also be analyzed. 
Primary endpoint – 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 following the date of data cut-off for the analysis (these 
contacts should generally occur within 7 days of the data cut-off). If patients are confirmed to 
be alive or if the death date is after the data cut-off date, these patients will be censored at the 
date of data cut-off. Death dates may be found by checking publicly available death registries.
8.4.1.1
Secondary endpoints
Investigator RECIST 1.1 based endpoints
All RECIST assessments, whether scheduled or unscheduled, will be included in the 
calculations. This is also regardless of whether a patient discontinues study treatment 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 28 days prior to randomization. 
Please refer to Appendix D for the definitions of CR, PR, SD, and PD.
Progression-free survival
PFS (per RECIST 1.1 using Investigator assessments) 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 randomized 
therapy or receives another anticancer therapy prior to progression. 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 two consecutive missed visits. If the 
patient has no evaluable visits or does not have baseline data, they will be censored at day 1 
unless they die within 2 visits of baseline.  
The PFS time will always be derived based on scan/assessment dates not visit dates.
RECIST 1.1 assessments/scans contributing towards a particular visit may be performed on 
different dates. The following rules will be applied:

The date of progression will be determined based on the earliest of the scan dates of 
the component that triggered the progression. 

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
When censoring a patient for PFS, the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment. 
Note: For target lesions, only the latest scan date is recorded out of all scans performed at that 
assessment for the target lesions, and similarly for non-target lesions, only the latest scan date 
is recorded out of all scans performed at that assessment for the non-target lesions.
Objective response rate
ORR (per RECIST 1.1 using Investigator assessments) is defined as the percentage of patients 
with an unconfirmed response of CR or PR. 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. 
Confirmed ORR which is defined as the percentage of patients with a confirmed response of 
CR or PR will be derived. A confirmed response of CR/PR means that a response of CR/PR is 
recorded at 1 visit and confirmed by repeat imaging not less than 4 weeks after the response 
was first observed with no evidence of progression between the initial and CR/PR 
confirmation visit.
Duration of response
DoR (per RECIST 1.1 using Investigator assessments) will be defined as the time from the 
date of first documented response until the first date of documented progression or death in 
the absence of disease progression. The 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 towards 
the first visit response of CR or PR. If a patient does not progress following a response, then 
their DoR will be censored at the PFS censoring time. 
Proportion of patients alive at 18 months and 24 months from randomization
The proportion of patients alive at 18 months (OS18) and 24 months (OS24) will be defined 
as the Kaplan-Meier estimate of OS at 18 and 24 months. 
Proportion of patients alive and progression free at 12 months
The APF12 will be defined as the Kaplan-Meier estimate of proportion of patients alive and 
progression free at 12 months based on PFS (per RECIST 1.1 as assessed using Investigator 
assessments) analysis. 
Time from randomization to second progression (PFS2)
PFS2 will be defined as the time from the date of randomization to the earliest of the 
progression event subsequent to that used for the PFS endpoint or death. The date of 
second progression will be recorded by the Investigator in the eCRF and defined according to 
local standard clinical practice and may involve any of the following: objective radiological 

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imaging, symptomatic progression, or death. The site will be asked whether the patient has 
had a second progression event on a regular basis (every 6 weeks for the first 48 weeks 
relative to the date of randomisation and then every 8 weeks thereafter) following the first 
progression event used for the secondary variable PFS (the first progression) and the status 
recorded. Actual timing of assessments for a second progression event will, as mentioned, be 
according to local standard practice. Patients alive and for whom a second disease progression 
has not been observed should be censored at the last time known to be alive and without a 
second disease progression, that is, censored at the latest of the PFS or PFS2 assessment date 
if the patient has not had a second progression or death.
Best objective response
Best objective response (BoR) is calculated based on the overall visit responses per RECIST 
1.1 using Investigator assessments, described in Appendix D. It is the best response a patient 
has had during their time in the study, but prior to starting any subsequent cancer therapy, up 
until RECIST progression or the last evaluable assessment in the absence of RECIST 1.1 
progression.
Categorization of BoR will be based on RECIST (Appendix D) using the following response 
categories: CR, PR , SD, PD, and NE. 
BoR will be determined programmatically based on RECIST 1.1 using all Investigator 
assessments up until the first progression event. For patients whose progression event is death, 
BoR will be calculated based upon all evaluable RECIST 1.1 assessments prior to death.
For patients who die with no evaluable RECIST 1.1 assessments, if the death occurs ≤91 days
(i.e., 2*(6 weeks) + 1 week) after randomization, then BoR will be assigned to the progression 
(PD) category. For patients who die with no evaluable RECIST assessments, if the death 
occurs > 91 days (i.e., 2*(6 weeks ) + 1 week after the date of randomization then BoR will be 
assigned to the NE category. 
BoR based on confirmed response will also be derived.
Calculation or derivation of safety variables
8.4.2.1
Adverse events
Data from all cycles of treatment will be combined in the presentation of safety data. AEs 
(both in terms of Medical Dictionary for Regulatory Activities [MedDRA] preferred terms 
and CTCAE grade) will be listed individually by patient.  
Any AE occurring before treatment with IP and without worsening after the first dose 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 the last dose of durvalumab, or within 30 days 
of the last dose of SoC may be included in the AE summaries, but the majority of those 
summaries will omit those AEs observed after a patient has received further therapy for 
cancer. Further details will be provided in the SAP. Any events in this period that occur after a 

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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 
durvalumab, or more than 30 days after discontinuation of SoC will be produced. These 
events will not be included in AE summaries. 
8.4.2.2
Other significant adverse events
During the evaluation of the AE data, an AstraZeneca 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 other significant adverse 
events (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. 
8.4.2.3
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 study 
treatment.  
The QTcF will be derived during creation of the reporting database using the reported ECG 
values (RR and QT).
QTcF = QT/RR^ (1/3) where RR is in seconds
Corrected calcium will be derived during creation of the reporting database using the 
following formulas:
Corrected calcium (mmol/L) = Total calcium (mmol/L) + ([40 – albumin (G/L)] x 0.02)
The denominator used in laboratory summaries will only include evaluable patients, in other 
words those who had sufficient data to have the possibility of an abnormality.  
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.

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Calculation or derivation of patient-reported outcome variables
PRO questionnaires will be assessed using the EORTC QLQ-C30 with the QLQ-LC13 
module (HRQoL and lung cancer specific symptoms), and 
. All 
items/questionnaires will be scored according to published scoring guidelines or the 
developer’s guidelines, if published guidelines are not available. 
8.4.3.1
EORTC QLQ-C30
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 EORTC QLQ-C30 will be scored 
according to the EORTC QLQ-C30 scoring manual (Fayers et al 2001). An outcome variable 
consisting of a score from 0 to 100 will be derived for each of the symptom scales/symptom 
items, each of the functional scales, and the global health status scale in the EORTC 
QLQ-C30 according to the EORTC QLQ-C30 Scoring Manual. Higher scores on the global 
health status and functioning scales indicate better health status/function, but higher scores on 
symptom scales/items represent greater symptom severity.
Definition of clinically meaningful changes
Changes in score compared with baseline will be evaluated. A minimum clinically meaningful 
change is defined as an absolute change in the score from baseline of ≥10 for scales/items 
from the EORTC QLQ-C30 (Osoba et al 1998). For example, a clinically meaningful 
improvement in physical function (as assessed by EORTC QLQ-C30) is defined as an 
increase in the score from baseline of ≥10, whereas a clinically meaningful deterioration is 
defined as a decrease in the score from baseline of ≥10. At each post-baseline assessment, the 
change in symptoms/functioning from baseline will be categorized as improvement, 
no change or deterioration as shown in Table 10.
Table 10
Mean change and visit response in health-related quality of life
Score
Change from baseline
Visit response
EORTC QLQ-C30 Global quality 
of life score
≥+10
Improvement
≤-10
Deterioration
Otherwise
No change
EORTC QLQ-C30 symptom 
scales/items
≥+10
Deterioration
≤-10
Improvement
Otherwise
No change
EORTC QLQ-C30 functional 
scales
≥+10
Improvement
≤-10
Deterioration
Otherwise
No change
CCI

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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. If there is evidence that the missing 
data are systematic, missing values will be handled to ensure that any possible bias is 
minimized.
Time to HRQoL/function/symptom deterioration
Time to deterioration will be analyzed for all QLQ-C30 scales/items. Dyspnea, fatigue and 
appetite loss from the QLQ-C30 will be key symptoms of interest. 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 function scales or the global health status/HRQoL 
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 study treatment or receives another anticancer therapy prior to HRQoL/function 
deterioration. Patients with a single deterioration and no further assessments will be treated as 
deteriorated in the analysis. 
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 (as measured by EORTC QLQ-C30) has 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 they will be censored at day 1.  
Symptom improvement rate
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 from baseline score ≥10 for EORTC QLQ-C30 symptom scales) in 
that symptom from baseline.  
HRQoL/function improvement rate
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 from baseline score ≥10 for EORTC QLQ-C30 functional scales 
and global health status/HRQoL) in that scale from baseline.  

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8.4.3.2
Lung cancer module (EORTC QLQ-LC13)
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 side-effects (sore mouth, dysphagia, peripheral neuropathy, and 
alopecia), and pain medication.  
Definition of clinically meaningful changes
Changes in score compared with baseline will be evaluated.  A minimum clinically 
meaningful change is defined as an absolute change in the score from baseline of ≥10 for 
scales/items from the QLQ-LC13 (Osoba et al 1998). For example, a clinically meaningful 
deterioration or worsening in chest pain (as assessed by the QLQ-LC13) is defined as an 
increase in the score from baseline of ≥10, whereas a clinically meaningful improvement is 
defined as a decrease in the score from baseline of ≥10. At each post-baseline assessment, the 
change in symptoms from baseline will be categorized as an improvement, no change or 
deterioration as shown in Table 11.
Table 11
Visit response for health-related quality of life and disease-related 
symptoms
Score
Change from baseline
Visit response
QLQ-LC13 symptom scales/items
≥+10
Deterioration
≤-10
Improvement
Otherwise
No change
Time to symptom deterioration
For each of the following key symptom scales/items in the QLQ-LC13, time to deterioration 
will be analyzed: 

Dyspnea (multi-item scale based on 3 questions: were you short of breath when you 
rested; walked; climbed stairs)

Cough: 1 item (how much did you cough?)

Hemoptysis: 1 item (did you cough up blood?)

Pain (3 individual items): a) Have you had pain in your chest; b) your arm or 
shoulder; c) other parts of your body?)
The scoring approach for the QLQ-LC13 is identical in principle to that for the symptom 
scales/single items of the EORTC QLQ-C30. 
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 study treatment or receives another anticancer therapy prior to symptom 

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Baseline will be the last assessment of the variable under consideration prior to the intake of 
the first dose of IP, except for efficacy variables. For efficacy variables, baseline is defined as 
the last visit prior to randomization unless otherwise stated.
Results of all statistical analysis will be presented using appropriate 95% confidence intervals 
(CIs) and 2-sided p-values, unless otherwise stated.
The following table (Table 12) details which endpoints are subjected to statistical analysis, 
together with pre-planned sensitivity analyses, making it clear which analysis is regarded as 
primary for that endpoint. 
The efficacy and safety in China subgroup may be analysed to facilitate a benefit-risk 
assessment for regulatory submission in China. Details of this analysis will be specified in the 
Statistical Analysis Plan.
Table 12
Pre-planned statistical and sensitivity analyses to be conducted
Endpoints analyzed
Notes
Overall survival
Stratified log-rank test for:
Primary analysis for the ITT population
Primary analysis for the PD-L1 TC ≥25% and low risk of early mortality 
population
Secondary analysis for the PD-L1 TC ≥50% population (stratified only 
for histology and smoking status)
Secondary analysis for the PD-L1 TC ≥50% and low risk of early 
mortality population (stratified only for histology and smoking status)
Sensitivity analysis: max-combo test in:

ITT population

PD-L1 TC ≥25% and low risk of early mortality population
Progression-free survival
Stratified log-rank test for:
Secondary analysis using Investigator RECIST 1.1 assessments 

ITT population

PD-L1 TC ≥25% and low risk of early mortality population

PD-L1 TC≥50%

PD-L1 TC≥50% and low risk of early mortality population
Objective response rate
Logistic regression for:
Secondary analysis using Investigator assessments (RECIST 1.1) 

ITT population

PD-L1 TC ≥25% and low risk of early mortality population

PD-L1 TC ≥50%

PD-L1 TC ≥50% and low risk of early mortality population

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Endpoints analyzed
Notes
Duration of response
Kaplan-Meier estimates for
Secondary analysis using Investigator assessments (RECIST 1.1) 

ITT population

PD-L1 TC ≥25% and low risk of early mortality population

PD-L1 TC ≥50%

PD-L1 TC ≥50% and low risk of early mortality population
Proportion of patients alive at 18 
months (OS18) and 24 months 
(OS24)
Kaplan Meier estimates of survival rate at 18 months and 24 months in 

ITT population 

PD-L1 TC ≥25% and low risk of early mortality population

PD-L1 TC ≥50%

PD-L1 TC ≥50% and low risk of early mortality population
Proportion of patients alive and 
progression free at 12 months 
Kaplan Meier estimates of progression free survival at 12 months 

ITT population

PD-L1 TC ≥25% and low risk of early mortality population

PD-L1 TC ≥50%

PD-L1 TC ≥50% and low risk of early mortality population
Time from randomization to 
second progression 
Stratified log-rank test  

ITT population

PD-L1 TC ≥25% and low risk of early mortality population

PD-L1 TC ≥50%

PD-L1 TC ≥50% and low risk of early mortality population
Time to deterioration (EORTC 
QLQ-C30 and QLQ-LC13 
endpoints)
Stratified log-rank test in

ITT population

PD-L1 TC ≥25% and low risk of early mortality population
Multiple testing strategy
In order to strongly control the type I error at 5% (2-sided), a multiple testing procedure 
(MTP) with gatekeeping strategy will be employed across the 2 primary OS endpoints of OS 
in ITT population, OS in the PD-L1 TC ≥ 25% and low risk of early mortality population and 
selected secondary endpoints. 
OS will be tested at 1 interim and a final time point. The OS tests for the same comparison 
(i.e., shown in 1 box in the MTP) will be considered as 1 test family. As long as one test in the 
family can be rejected, the family is rejected thus the assigned total alpha to the family can be 
recycled to the next MTP level. The testing procedure stops when the entire test mass is 
allocated to non-rejected hypotheses. Implementation of this pre-defined ordered testing 
procedure, including recycling, will strongly control type I error at 5% (2-sided) (Burman et al 
2009).  

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The overall 5% type 1 error will be initially split between the 2 primary endpoints: an alpha 
level of 4% will be allocated to the analysis of OS in the ITT population and an alpha level of 
1% will be allocated to the analysis of OS in the PD-L1 TC ≥ 25% and low risk of early 
mortality population. The first layer of MTP is shown in Figure 4. If either primary 
comparison is significant, the available alpha level will be recycled to the other primary 
comparison. If primary comparisons are both significant, the available alpha level may be 
recycled to other comparisons. The recycle scheme of these additional comparisons, if 
included in MTP, will be specified in SAP prior to DBL.
The alpha level allocated to OS will be controlled at the interim and final time points by using 
the Lan and Demets (Lan and DeMets 1983) spending function that approximates an O’Brien 
Fleming approach, where the alpha level applied at the interim depends upon the proportion of 
information available. Separate Lan DeMets spending functions will be used for 2 primary 
endpoints and secondary endpoints.
Figure 4 First layer of the multiple testing procedure for controlling type I error rate
Analysis of two primary endpoints – overall survival
Primary analysis of OS in the ITT population will be performed using a stratified log-rank 
test, adjusting for level of PD-L1 expression 25-49% versus ≥50% and histology and smoking 
status (squamous versus non-squamous + never smoker versus non-squamous + 
former/current smoker).  The effect of durvalumab versus SoC will be estimated by the HR 
from stratified Cox proportional hazards model together with its corresponding CI and p-value 
(Cox 1972).  Primary analysis of OS in the PD- L1 TC ≥ 25% and low risk of early mortality
population will be conducted in the same manner. 
A secondary analysis of OS will be performed using a stratified log-rank test, adjusting for 
only histology and smoking status using the PD-L1 TC ≥50% analysis set, and the PD- L1 
TC ≥ 50% and low risk of early mortality analysis set. The corresponding HR will be 
estimated using a stratified Cox model.
The max-combo test will be conducted as a sensitivity analysis on the OS data in both the ITT 
and the PD- L1 TC ≥ 25% and low risk of early mortality population, to test for treatment 
differences in the case of nonproportional hazards. The analysis will be based on adaptive 

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procedure involving selection of best test statistics with log rank test (G0,0) and the Fleming-
Harrington (FH) test (G0,1 , G1,0 and G1,1) with alpha correction (Lin et al 2019). 
Kaplan-Meier plots will be presented by treatment group. 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.
The boundaries (i.e. adjusted alpha levels) for the treatment comparison at the interim and 
final analyses for OS will be derived based upon the exact number of OS events using the Lan 
and DeMets approach that approximates the O’Brien Fleming spending function (see Section 
8.2).
Subgroup analyses will be conducted comparing OS between durvalumab versus SoC in the 
following subgroups of the FAS (but not limited to):  

Sex (male versus female)

Age at randomization (<65 versus ≥65 years of age)

Level of PD-L1 expression (25-49% vs ≥50%)

Histology and Smoking status (squamous versus non-squamous + never smoker 
versus non-squamous + former/current)

Region (China versus other)

Race (Asian versus Non-Asian)

Baseline liver metastases (Yes versus No)

Baseline ECOG (0 versus >=1)

Baseline risk status of early mortality identified by a prognostic model developed 
by AstraZeneca (Low risk, High risk, Unknown)
Other baseline variables may also be assessed if there is clinical justification or an imbalance 
is observed between the treatment groups. The purpose of the subgroup analyses is to assess 
the consistency of treatment effect across expected prognostic and/or predictive factors.
No adjustment to the significance level for testing of the subgroup and sensitivity analyses 
will be made since all these analyses will be considered supportive of the primary analysis of 
OS.
Cox proportional hazards modeling will be employed to assess the effect of covariates on the 
HR estimate. Before embarking on more detailed modeling, an initial model will be 
constructed, containing treatment and the stratification factors alone, to ensure that any output 
from the Cox modeling is likely to be consistent with the results of the stratified log-rank test.

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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 time points. The midpoint 
between the time of progression and the previous evaluable RECIST assessment will be 
analyzed using a log-rank test. 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 even in 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. This 
analysis will be supported by a Kaplan-Meier plot of the time to censoring where the 
censoring indicator of the PFS analysis is reversed.
Subgroup analyses will be conducted comparing PFS (per RECIST 1.1 using Investigator 
assessments) between durvalumab versus SoC using the same methodology as described in 
Section 8.5.1 for primary endpoint of OS. 
Objective response rate
The ORR will be based on the programmatically derived RECIST 1.1 using the Investigator 
tumor data. ORR will be compared between durvalumab versus SoC using logistic regression 
models adjusting for the same factor as the primary endpoint (level of PD-L1 expression, 
histology and smoking status). The results of the analysis will be presented in terms of an odds 
ratio together with its associated profile likelihood CI and p-value (based on twice the change 
in log-likelihood resulting from the addition of a treatment factor to the model).  This analysis 
will be performed in the analysis sets as mentioned in Table 12.
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 for all patients (i.e., the FAS).  
For each treatment group, best objective response (BoR) will be summarized by n (%) for 
each category (CR, PR, SD, PD, and NE).  No formal statistical analysis is planned for BoR. 
Analysis of confirmed ORR/BoR will also be conducted in the similar manner. 
Duration of response
Descriptive data will be provided for the duration of response  including the associated 
Kaplan-Meier curves (without any formal comparison or p-value attached). This analysis will 
be performed in the analysis sets as mentioned in Table 12. 
DoR will also be assessed for the subgroup of patients who had a confirmed response. 
Proportion of patients alive at 18 months and 24 months
The OS18 and OS24 will be summarized (using the Kaplan-Meier curve) and presented by 
treatment arm. 

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This analysis will be performed in the analysis sets as mentioned in Table 12.
Proportion of patients alive and progression free at 12 months
The APF12 will be summarized (using the Kaplan-Meier curve) and presented by treatment 
arm. 
This analysis will be performed in the analysis sets as mentioned in Table 12.
Time from randomization to second progression
PFS2 is defined as the time from the date of randomization to the earliest of the progression 
event subsequent to that used for the PFS endpoint or death. It will be assessed using local 
practice guideline. PFS2 will be analyzed using a stratified log-rank tests, using the same 
methodology as described for the PFS endpoint. The effect of durvalumab versus SoC will be 
estimated by the HR together with its corresponding CI and p-value. Kaplan-Meier plots will 
be presented by treatment group. Summaries of the number and percentage of patients who 
have an event as well as who were censored will be provided along with the medians for each 
treatment.
For supportive purposes, the time to the start of subsequent therapy will be analyzed using the 
same methodology and model. The HR for the treatment effect together with its 95% CI will 
be presented. In addition, a Kaplan-Meier plot of the time to the start of subsequent therapy 
will be presented by treatment arm and the time between progression and starting subsequent 
therapy will be assessed. No multiplicity adjustment will be applied as these are viewed as 
supportive endpoints.
A summary table of first subsequent therapies by treatment arm will be provided, as well as 
response to first subsequent therapy by treatment arm.
This analysis will be performed in the analysis sets as mentioned in Table 12.
Patient reported outcomes
Any formal comparison for PRO in the MTP will be included in the SAP. The analysis of 
PRO data will be performed in the analysis sets as mentioned in Table 12.
8.5.8.1
EORTC QLQ-C30
Time to deterioration will be analyzed using a stratified log-rank test, using the same 
methodology as described for the primary OS endpoint.
The effect of durvalumab versus SoC will be estimated by the HR together with its 
corresponding CI and p-value. Kaplan-Meier plots will be presented by treatment arm. 
Summaries of the number and percentage of patients who have an event as well as who were 
censored will be provided along with the medians for each treatment.
A summary of the symptom improvement rate for each of the 3 symptom scales and the 
5 individual symptom items will be produced. Similarly, a summary of QoL/function 

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The Lan and DeMets spending function that approximates an O’Brien Fleming approach will 
be used to account for multiplicity introduced by including the 1 interim analysis for 
superiority (Lan and DeMets 1983).
The criterion for superiority is a statistically significant improvement in OS at the interim 
analysis.  If exactly 85% of the OS events required at the time of the final OS analysis are 
available at the time of the interim analysis, the 2-sided significance level to be applied for the 
OS in the ITT population at the interim and final analysis would be 2.325% and 3.334%, 
respectively; and the 2-sided significance level to be applied for the OS in the PD- L1 TC ≥ 
25% and low risk of early mortality population at the interim and final analysis would be 
0.466% and 0.862% respectively.
If the interim analyses indicate superiority, then subsequent analyses of the further secondary 
endpoints will be performed. 
If the interim results do not meet the criterion of stopping for superiority, then follow-up will 
continue. OS will be retested at the final analysis.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first patient is enrolled in the study, an AstraZeneca representative will review and
discuss the requirements of the clinical study protocol and related documents with the 
investigational staff and train them in any study-specific procedures and IVRS/IWRS, WBDC, 
and any electronic PRO systems to be utilized.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to

Provide information and support to the Investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, data are being 
accurately and timely recorded in the eCRFs, biological samples are handled in 
accordance with the Laboratory Manual, and study drug accountability checks are 
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
Perform source data verification (a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice and other records relevant to the 
study), including verification of informed consent of participating patients.  This 
will require direct access to all original records for each patient (e.g., clinic charts).

Ensure that withdrawal of informed consent for the use of the patient’s biological 
samples is reported, biological samples are identified and disposed of or destroyed 
accordingly, and the action is documented and reported to the patient
The AstraZeneca representative will be available between visits if the Investigators or other 
staff at the centers need information and advice about the study conduct.
Source data
Refer to the CSA for the location of source data.
Study agreements
The Principal Investigator at each center should comply with all the terms, conditions, and 
obligations of the CSA, or equivalent, for this study.  In the event of any inconsistency 
between this clinical study protocol and the CSA, the terms of clinical study protocol shall 
prevail with respect to the conduct of the study and the treatment of patients.  In all other 
respects not relating to study conduct or treatment of patients, the terms of the CSA shall 
prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place or before any patients are enrolled.
Archiving of study documents
The Investigator will follow the principles outlined in the CSA.
9.3
Study timetable and end of study
The end of the study is defined as the “last visit of the last patient undergoing the study.”  The 
Investigator will be notified by AstraZeneca when recruitment is complete.
The study is expected to start in Q1 2017 and end by Q1 2021.  
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP) or if recruitment is slow.  AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study involving durvalumab.
9.4
Data management by AstraZeneca or delegate
Data management will be performed by a chosen vendor according to the Data Management 
Plan.  AEs and medical/surgical history will be classified according to the terminology of the 

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latest version of MedDRA.  Medications will be classified according to the AstraZeneca Drug 
Dictionary.  Classification coding will be performed by the chosen vendor.
The data collected through third party sources will be obtained and reconciled against study 
data.
Data queries will be raised for inconsistent, impossible, or missing data.  All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.
When all data have been coded, validated, signed, and locked, a clean file will be declared.  
Any treatment-revealing data may be added thereafter, and the final database will be locked.
Serious adverse event reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
Data associated with human biological samples
Data associated with human biological samples will be transferred from laboratories internal 
or external to AstraZeneca.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation 
(ICH)/GCP, applicable regulatory requirements, and the AstraZeneca policy on Bioethics and 
Human Biological Samples.  
10.2
Patient 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.
10.3
Ethics and regulatory review
An EC/IRB should approve the final study protocol, including the final version of the ICF and 
any other written information and/or materials to be provided to the patients.  The Investigator 
will ensure the distribution of these documents to the applicable EC/IRB and to the study site 
staff.
The opinion of the EC/IRB should be given in writing.  The Investigator should submit the 
written approval to AstraZeneca before enrolment of any patient into the study. 
The EC/IRB should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the EC/IRB annually.
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the ICF, should be approved by the national regulatory authority or a notification to 
the national regulatory authority should be approved, according to local regulations.
AstraZeneca will handle the distribution of these documents to the national regulatory 
authorities.
AstraZeneca will provide regulatory authorities, ECs/IRBs, and Principal Investigators safety 
updates or reports according to local requirements.
Each Principal Investigator is responsible for providing the EC/IRB with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the IIP.  
AstraZeneca will provide this information to the Principal Investigator so that he/she can meet 
these reporting requirements.
10.4
Informed consent
The Principal Investigator(s) at each center will:

Ensure that each patient is given full and adequate oral and written information 
about the nature, purpose, possible risk, and benefit of the study

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
Ensure that each patient is notified that he or she is free to discontinue from the 
study at any time

Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided

Ensure that each patient provides a signed and dated informed consent before 
conducting any procedure specifically for the study

Ensure that the original, signed ICF(s) is/are stored in the Investigator’s Study File

Ensure that a copy of the signed ICF is given to the patient

Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the ICF that is approved by an EC/IRB.
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and, where required, in a new version of the study 
protocol (revised clinical study protocol).
The amendment is to be approved by the relevant EC/IRB and, if applicable, the national 
regulatory authority, before implementation.  Local requirements are to be followed for 
revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator.  For distribution to EC/IRB, see Section 10.3.
If a protocol amendment requires a change to a center’s ICF, AstraZeneca and the center’s 
EC/IRB are to approve the revised ICF before the revised form is used. 
If required by local regulations, any administrative change will be communicated to or 
approved by each EC/IRB.
10.6
Audits and inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an EC/IRB may perform 
audits or inspections at the center, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and to determine if data 
were recorded, analyzed, and accurately reported according to the protocol, GCPs, ICH 
guidelines, and any applicable regulatory requirements.  The Investigator will contact 
AstraZeneca immediately if contacted by a regulatory agency about an inspection at the 
center.

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11.
LIST OF REFERENCES
Aaronson et al 1993
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst 1993;85(5):365-76.
Alexandrov et al, 2013
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S, Blankin AV, et al. 
Signatures of mutational processes in human cancer. Nature. 2013 Aug 22;500:415-21.
Antonia et al 2014b
Antonia S, Ou SI, Khleif SN, Brahmer J, Blake-Haskins A, Robbins PB, et al. Clinical activity 
and safety of MEDI4736, an anti-programmed cell death ligand-1 (PD-L1) antibody in 
patients with NSCLC. Poster presented at the European Society for Medical Oncology 
(ESMO) Meeting; 2014 Sep 26-30; Madrid, Spain.
Antonia et al 2016
S. Antonia1, S-W. Kim, A. Spira, M-J. Ahn, et al. Safety and Clinical Activity of Durvalumab 
(MEDI4736), an Anti‒PD-L1 Antibody, in Treatment-Naïve Patients with Advanced Non‒
Small Cell Lung Cancer. Poster presented at the American Society of Clinical Oncology 
(ASCO) Annual Meeting; Chicago, IL, USA; June 3–7, 2016
Antonia et al 2018
Antonia SJ, Villegas A, Daniel D1, Vicente D, et al. Overall Survival with Durvalumab after 
Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018 Dec 13;379(24):2342-2350.
Bergman et al 1994
Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M; EORTC Study Group on 
Quality of Life. The EORTC QLQ-LC13: a modular supplement to the EORTC Core Quality 
of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials. Eur J Cancer 
1994;30A(5):635-42.
Bonomi 2010
Bonomi PD. Implications of key trials in advanced nonsmall cell lung cancer. Cancer 
2010;116(5):1155-64.
Brahmer et al, 2012
Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity 
of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 
2012;366(26):2455-65.

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Qin et al 2016
Mechanisms of immune evasion and current status of checkpoint inhibitors in non-small cell 
lung cancer. Cancer Med. 2016 Sep 5; 9:2169–2170
Reck et al 2014
Reck M, Popat S, Reinmuth N, De Ruysscher D, Kerr KM, Peters S; ESMO Guidelines 
Working Group. Metastatic non-small-cell lung cancer (NSCLC): ESMO clinical practice 
guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014;25(Suppl 3):iii27-39.
Rizvi et al 2015
Rizvi N, Brahmer J, Ou S-H, Segal NH, Khleif SN, Hwu WJ. Safety and clinical activity of 
MEDI4736, an anti-programmed cell death-ligand-1 (PD-L1) antibody, in patients with 
nonsmall cell lung cancer (NSCLC). J Clin Oncol 2015;33:Abstract 8032.
Robins & Tsiatis, 1991
James M. Robins and Anastasios A. Tsiatis. Correcting for non-compliance in randomized 
trials using rank preserving structural failure time models. Commun Stat Theory Methods 
1991; 20(8):2609-2631
Robin, 1993
James M. Robin. Information recovery and bias adjustment in proportional hazards regression 
analysis of randomized trials using surrogate markers. Proceedings of the Biopharmaceutical 
Section, American Statistical Association; 1993. p. 24-33.
Sandler et al 2006
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin 
alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 
2006;355(24):2524-50.
Scagliotti et al 2008
Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III 
study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-
naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 
2008;26(21)3543-51.
Schiller et al 2002
Schiller JH, Harringdon D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of 
four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 
2002;10(346):92-8.
Segal et al 2015
Segal NH, Ou S-HI, Balmanoukian AS, Fury MG, Massarelli E, Brahmer JR, et al. Safety and 
efficacy of MEDI4736, an anti-PD-L1 antibody, in patients from a squamous cell carcinoma 
of the head and neck (SCCHN) expansion cohort. J Clin Oncol 2015;33:Abstract 3011.

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Stewart et al 2015
Stewart R, Morrow M, Hammond SA, Mulgrew K, Marcus D, Poon E, et al. Identification 
and characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. Cancer 
Immunol Res 2015;3(9):1052-62.
Sun and Chen 2010
Sun X, Chen C. Comparison of Finkelstein's Method with the conventional approach for 
interval-censored data analysis. Stat Biopharm Res 2010;2(1):97-108.
Topalian et al 2012
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 
2012;366(26):2443-54.
Whitehead and Whitehead 1991
Whitehead A, Whitehead J. A general parametric approach to the meta-analysis of 
randomized clinical trials. Stat Med 1991;10(11):1665-77.
Zhang et al 2008
Zhang C, Wu S, Xue X, Li M, Qin X, Li W, et al. Anti-tumor immunotherapy by blockade of 
the PD-1/PD-L1 pathway with recombinant human PD-1-IgV. Cytotherapy 2008;10(7):711-9.
Zhou 2014
Zhou, Caicun. Lung cancer molecular epidemiology in China: recent trends. Transl Lung 
Cancer Res. 2014 Oct; 3(5): 270–279.
Lin et al 2019
Ray S. Lin, Ji Lin, Satrajit Roychoudhury, Keaven M. Anderson, Tianle Hu, Bo Huang, et al. 
Alternative Analysis Methods for Time to Event Endpoints Under Nonproportional Hazards: 
A Comparative Analysis. Statistics in Biopharmaceutical Research. DOI: 
10.1080/19466315.2019.1697738.

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Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the subject 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 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (e.g., hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., 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 subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
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 subject or may require 
medical intervention 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 (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization.
Development of drug dependency or drug abuse.
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.

Time Course.  Exposure to suspect drug.  Has the subject actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
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
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.

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Appendix B
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.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) 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 e.g., 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 e.g., Hepatitis A, B, C, D, and E viruses,
Human immunodeficiency virus (HIV) 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.

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 
containment standards are encouraged wherever possible when road or rail transport 
is used.

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Appendix C
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
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 the managing liver abnormalities can be 
found in Section 6.9 of the protocol.
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 (IMP). 
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.
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥2xULN 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 ≥3x ULN together with TBL ≥2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, e.g., elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
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 ≥3xULN

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
AST ≥ 3xULN

TBL ≥ 2xULN
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator 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 local laboratory results the Investigator will 
without delay:

Determine whether the patient meets PHL criteria (see Definitions within this 
Dosing Modifications and Toxicity Management or 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 Definitions within this 
Dosing Modifications and Toxicity Management or definition) by reviewing 
laboratory reports from all previous visits.

Promptly enter the laboratory data into the laboratory CRF.
Follow-up
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the patient has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:

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
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Actions Required When Potential Hy’s Law Criteria are Met Before 
and After Starting Study Treatment)

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:

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 etiology 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.
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 3 weeks 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
IMP.  The AstraZeneca Medical Science Director 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 IMP:

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
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.
If, there is an unavoidable delay, of over 3 weeks, 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.
Actions Required When Potential Hy’s Law Criteria are Met Before and After Starting 
Study Treatment 
This section is applicable to patients 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 
Potential Hy’s Law Criteria met of this Appendix.
# 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.
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.

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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:

Was the alternative cause for the previous occurrence of PHL criteria being met 
found to be the disease under study e.g. chronic or progressing malignant disease, 
severe infection or liver disease, or did the patient meet PHL criteria prior to 
starting study treatment and at their first on study treatment visit as described in 
Actions Required When Potential Hy’s Law Criteria are Met Before and After 
Starting Study Treatment?
If No: follow the process described in Potential Hy’s Law Criteria met of this Appendix
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 Potential Hy's Law 
Criteria met of this Appendix.
# 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.
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf

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Appendix D
Guidelines for Evaluation of Objective Tumor Response
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 
(RECIST) 1.1 guidelines (Eisenhauer et al 2009) for the D419AC00002 study with regards to 
Investigator assessment of tumor burden including protocol-specific requirements for this 
study.
Definition 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. 
Tumor lesions selected for screening biopsy should not be selected as target lesions, unless 
imaging occured at least 2 weeks after biopsy, allowing time for healing.
Measurable:
A lesion, not previously irradiated or biopsied per the protocol prior to randomisation, that can 
be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes 
which must have short axis ≥ 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 at baseline1).

Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung and, abdominal masses/abdominal 
                                               
1 The short axis is defined at the longest axis perpendicular to the long axis of the tumor. Nodes with <10 mm 
short axis are considered non-pathological and should not be recorded or followed as non-target lesions 
(NTLs).

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organomegaly identified by physical examination that is not measurable by CT or 
MRI.

Tumor lesions selected for screening biopsy

Previously irradiated lesions2

Skin lesions assessed by clinical examination

Brain metastasis
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 is considered as a single organ.
Non-target lesions:
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.
Methods of assessment
The same method of assessment and the same 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 13, and 
those excluded from tumor assessments for this study are highlighted with the rationale 
provided.
                                               
2 Localised post-radiation changes which affect lesion sizes may occur.  Therefore, lesions that have been 
previously irradiated will not be considered measurable and must be selected as NTL at baseline and followed 
up as part of the NTL assessment.

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Table 13
Summary of methods of assessment
Target lesions 
Non-target lesions
New lesions
CT (preferred)
MRI
CT (preferred)
MRI
Clinical examination 
X-ray, Chest X-ray
CT (preferred)
MRI
Clinical examination 
X-ray, Chest X-ray
Ultrasound
Bone scan
FDG-PET
   CT  Computed tomography; FDG-PET  18-Fluoro-deoxyglucose positron emission tomography; MRI  
Magnetic resonance imaging.
CT and MRI 
CT and MRI, each preferably with intravenous contrast, are generally considered to be the 
best currently available and reproducible methods to measure TL selected for response 
assessment and to assess NTL and identification of any new lesions. 
It is recommended that intravenous contrast-enhanced CT examinations of the chest and 
abdomen (including liver and adrenal glands) are 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 intravenous 
CT contrast, a non-contrast CT examination of the chest and an MRI with intravenous contrast 
of the abdomen and pelvis is appropriate. In patients with severely compromised renal 
function a non-contrast CT examination of the chest, abdomen and pelvis is appropriate. For 
brain lesion assessment, MRI with intravenous contrast is the preferred method over 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 will not be used for assessment of TL.  Clinically detected lesions can be 
selected as TLs if they are assessed by CT or MRI scans.  Clinical examination can be used to 
assess NTL and to identify the presence of new lesions.
X-ray
Chest X-ray
Chest X-ray assessment will not be used for assessment of TL as they will be assessed by CT 
examination or MRI examination.  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. 

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Ultrasound 
Ultrasound examination will not be used for assessment of TL and NTL as it is not a 
reproducible method, does not provide an accurate assessment of tumor size, and it is 
subjective and operator dependent.  Ultrasound examination can, however, be used to identify 
the presence of new lesions.  If new clinical symptoms occur and an ultrasound is performed 
then new lesions should be confirmed by CT or MRI examination.
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 will not be used for tumor response assessments as per RECIST 1.1.
Cytology and histology 
Histology will not be used as part of the tumor response assessment as per RECIST 1.1. 
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumor has met criteria for response or stable 
disease. In such circumstances, the cytology is necessary for the Investigator to differentiate 
between response/stable disease (an effusion may be a side effect of the treatment) and 
progressive disease (if the neoplastic origin of the fluid is confirmed). Where cytology 
findings are not available, any effusion that significantly worsens (from trace to large) or 
appearance of clinically significant effusion (requiring change in drug therapy) during the 
study treatment will be considered to be progression of NTL, or disease progression due to 
new lesions. 
Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray 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 will be recorded where a positive hot-spot that 
was not present on the baseline bone scan assessment is identified on a bone scan performed 
at any time during the study.  The Investigator should consider the positive hot-spot to be a 
significant new site of malignant disease and represent true disease progression in order to 
record the new lesion.  Confirmation by CT, MRI and X-ray is recommended where bone scan 
findings are equivocal.
FDG-PET scan
18-Fluoro-deoxyglucose positron emission tomography (FDG-PET) scans may be used as a 
method for identifying new lesions, according with the following algorithm: New lesions will 

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be recorded where there is positive 18-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 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 confirm new lesions.
At present, low dose or attenuation correction CT portions of a combined FDG-PET/CT 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 
intravenous contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT 
can be used for RECIST measurements. However, this is not recommended because the PET 
portion of the CT 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, e.g., 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 investigational 
product. Efficacy for all patients will be assessed by objective tumor assessments every 
6 weeks for the first 48 weeks (relative to the date of randomization; see Section 3.1 of the 
Clinical Study Protocol), then every 8 weeks thereafter until confirmed objective disease 
progression as defined by RECIST 1.1 (irrespective of the reason for stopping treatment/or 
subsequent therapy). 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 study drug due to toxicity in the absence of confirmed objective 
progression, objective tumor assessments should be continued every 6 weeks for 48 weeks 
(relative to the date of randomization) then every 8 weeks until confirmed objective disease 
progression. 
                                               
3 A positive FDG-PET scan lesion should be reported only when an uptake greater than twice that of the 
surrounding tissue is observed.

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Radiologic progression (PD by RECIST 1.1) requires confirmation; the confirmatory scan 
should occur no earlier than 4 weeks after the prior assessment of PD in the absence of 
clinically significant deterioration.
If progression is not confirmed then the patient should continue on study treatment continue 
with imaging assessments on their regular schedule.
If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits.  This 
schedule is to be followed in order to minimise any unintentional bias caused by some patients 
being assessed at a different frequency than other patients.
Additional assessments will be performed post confirmed objective disease progression for 
patients remaining on IMT treatment, re-treatment, or until subsequent cancer therapy 
according to the clinical study protocol.
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. Target lesions 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.

If a lesion has completely disappeared, the longest diameter should be recorded as 
0 mm.

If a TL splits into two or more parts, then record the sum of the diameters of those 
parts. 

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
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 e.g., radiotherapy, embolization, surgery, 
during the study, the size of the TL should still be provided where possible and the 
intervention recorded in the RECIST case report form.
Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TL (see Table 14).
Table 14
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 were not assessed or not evaluable 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 15).

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Table 15
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 progression. 
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.
The finding of a new lesion should be unequivocal: i.e., 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 new lesion has been confirmed.  If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan.
Symptomatic deterioration
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy.
Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumor 
assessments where possible until objective disease progression is observed.

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Evaluation of overall visit response
The overall visit response will be derived using the algorithm shown in Table 16.
Table 16
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 non-target lesions at baseline)
Confirmation of Progression
Radiologic progression (PD by RECIST 1.1) requires confirmation with a subsequent scan, 
and the confirmatory scan should occur no earlier than 4 weeks after the prior assessment of 
progression of disease (PD) in the absence of clinical deterioration.
Radiologic progression would be considered confirmed if the following criteria are met:

≥20% increase in sum diameters of target lesions compared to the nadir at 
2 consecutive visits (with an absolute increase of at least 5 mm)

And/or significant progression (worsening) of NTLs at the follow-up scan time-point 
compared with the immediate prior time-point

and/or significant progression (worsening) of pre-existing new lesions4 at the follow-
up scan timepoint compared with the immediate prior timepoint (Note: Pre-existing 
                                               
4 A new lesion is considered new only at the visit it was first identified—in all subsequent visits, it will be considered a pre-
existing ‘new’ lesion and will still need to be recorded if present.

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new lesions from earlier time-points are evaluated as NTLs at the confirmatory scan 
time-point)

And/or additional new unequivocal lesions at the confirmatory scan time-point.
In the absence of significant clinical deterioration, the Investigator should continue study 
treatment until radiologic progression is confirmed. 
If radiologic progression is not confirmed, then the patient should continue on study treatment 
and continue with regularly scheduled imaging assessments. 
If a patient discontinues treatment (and/or receives a subsequent cancer therapy) prior to 
progression, then the patient should still continue to be followed until confirmed objective 
disease progression.
Central Review
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed Contract Research Organization (CRO) for quality control 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. If a BICR is 
implemented, 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.
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 E
Patient Reported Outcomes
EORTC QLQ-C30, EORTC QLQ-LC13, AND 
EORTC QLQ-C30 (Version 3)
We are interested in some things about you and your health. Please answer all of the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" 
answers. The information that you provide will remain strictly confidential.
___________________________________________________________________________________
Not 
at All
A 
Little
Quite 
a Bit
Very 
Much
1.
Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase?
1
2
3
4
2.
Do you have any trouble taking a long walk?
1
2
3
4
3.
Do you have any trouble taking a short walk outside of the house?
1
2
3
4
4.
Do you need to stay in bed or a chair during the day?
1
2
3
4
5.
Do you need help with eating, dressing, washing yourself
or using the toilet?
1
2
3
4
During the past week: 
6.
Were you limited in doing either your work or other daily activities?
1
2
3
4
7.
Were you limited in pursuing your hobbies or other
leisure time activities?
1
2
3
4
8.
Were you short of breath?
1
2
3
4
9.
Have you had pain?
1
2
3
4
10. Did you need to rest?
1
2
3
4
11. Have you had trouble sleeping?
1
2
3
4
12. Have you felt weak?
1
2
3
4
13. Have you lacked appetite?
1
2
3
4
14. Have you felt nauseated?
1
2
3
4
CCI

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15. Have you vomited?
1
2
3
4
16. Have you been constipated?
1
2
3
4
During the past week: 
Not at 
All
A 
Little
Quite 
a Bit
Very 
Much
17. Have you had diarrhea?
1
2
3
4
18. Were you tired?
1
2
3
4
19. Did pain interfere with your daily activities?
1
2
3
4
20. Have you had difficulty in concentrating on things,
like reading a newspaper or watching television?
1
2
3
4
21. Did you feel tense?
1
2
3
4
22. Did you worry?
1
2
3
4
23. Did you feel irritable?
1
2
3
4
24. Did you feel depressed?
1
2
3
4
25. Have you had difficulty remembering things?
1
2
3
4
26. Has your physical condition or medical treatment
interfered with your family life?
1
2
3
4
27. Has your physical condition or medical treatment
interfered with your social activities?
1
2
3
4
28. Has your physical condition or medical treatment
caused you financial difficulties?
1
2
3
4
For the following questions please circle the number between 1 and 7 that 
best applies to you
29.
How would you rate your overall health during the past week?
1
2
3
4
5
6
7
Very poor
             Excellent

Clinical Study Protocol
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Study Code D419AC00002
Version 9
Date 18 Jun 2021
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30.
How would you rate your overall quality of life during the past week?
1
2
3
4
5
6
7
Very poor
Excellent

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Study Code D419AC00002
Version 9
Date 18 Jun 2021
177 (183)
EORTC QLQ - LC13
Patients sometimes report that they have the following symptoms or problems. Please indicate 
the extent to which you have experienced these symptoms or problems during the past week. 
Please answer by circling the number that best applies to you.
__________________________________________________________________________________
During the past week :
Not 
at all
A 
little
Quite 
a bit
Very 
much
1.
How much did you cough?
1
2
3
4
2.
Did you cough up blood?
1
2
3
4
3.
Were you short of breath when you rested?
1
2
3
4
4.
Were you short of breath when you walked?
1
2
3
4
5.
Were you short of breath when you climbed stairs?
1
2
3
4
6.
Have you had a sore mouth or tongue?
1
2
3
4
7.
Have you had trouble swallowing?
1
2
3
4
8.
Have you had tingling hands or feet?
1
2
3
4
9.
Have you had hair loss?
1
2
3
4
10.
Have you had pain in your chest?
1
2
3
4
11.
Have you had pain in your arm or shoulder?
1
2
3
4
12.
Have you had pain in other parts of your body?
1
2
3
4
If yes, where 
13.
Did you take any medicine for pain?
1
No
2
Yes
If yes, how much did it help?
1
2
3
4

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736)
Study Code D419AC00002
Version 9
Date 18 Jun 2021
180 (183)
Appendix F
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis, including COVID-19 Outbreak
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (e.g., during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
agreement from the sponsor.
F 1 Reconsent of Study Participants During Study Interruptions 
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, e.g., remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Sections F 2 to F 3. Local and regional regulations and/or guidelines regarding 
reconsent of study participants should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should 
be signed at the participant’s next contact with the study site). Visiting the study sites for the 
sole purpose of obtaining reconsent should be avoided. 
F 2 Telemedicine Visit to Replace On-site Visit (Where Applicable)
In this appendix the term telemedicine visit refers to remote contact with the participants using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow AEs, concomitant medicationadd other information including 
efficacy data where relevant to be collected according to study requirements to be reported 
and documented.
F 3 Data Capture During Telemedicine Visits
Data collected during telemedicine visits will be captured by the qualified HCP from the study 
site in the source documents, or by the participant themselves.

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Study Code D419AC00002
Version 9
Date 18 Jun 2021
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F 4 COVID-19 Risk Assessment 
The safety of participants is of primary importance. Any potential risks of participating in the 
study, particularly with the added challenges due to COVID-19 outbreak, should be weighed 
against the anticipated benefit (see also principle 2.2 of ICH GCP). Investigators are advised 
to use clinical judgment in determining infection prevention precautions for study participants.
The emergence of SARS-CoV-2 presents a potential safety risk for cancer patients. 
Participants enrolling in this study may require more frequent visits to the site for study 
treatment administration and for study assessments compared to participants receiving 
standard of care. Therefore, several risk mitigation factors have been implemented related to 
study conduct during the COVID-19 outbreak, for patient management in an event of 
COVID-19, and actions to be taken on study treatment (see Section F6). With these measures 
in place, it is considered that the anticipated potential benefits for the participants enrolled in 
this study outweigh the potential risks. All implemented measures prioritise trial participant 
safety and data validity; in case these two conflict with each other, trial participant safety 
should always prevail (see also European Medicines Agency Guidance on the management of 
clinical trials during the COVID-19 [coronavirus] pandemic [EMA 2020]). 
F 5 Potential Risks during COVID-19
Every effort should be made to follow the CSP. Section F7 provides a dose modification and 
management plan for participants with confirmed or suspected COVID-19 who are being 
treated with study intervention durvalumab. The risk-benefit assessment should be carefully 
considered for each participant enrolling in the study based on the known safety risks related 
to COVID-19, individual needs, and local guidelines and restrictions. Investigators must 
continue to use their best clinical judgment in determining the most optimal care for 
participants and utmost diligence in determining their eligibility for study participation, 
continued study treatment, and overall assessment of benefit/risk of study treatment or 
participation.
The sponsor must be promptly notified of a site’s inability to perform study activities due to 
COVID-19 outbreak in order to minimise any potential risks.
F 6 Study Treatment Administration
If an AE or SAE is associated with COVID-19, the investigator should determine whether the 
participants’ treatment with investigational product should continue, be interrupted, or be 
discontinued in accordance with the CSP.
AEs, SAEs, cycle delays and/or treatment suspensions associated with COVID-19 along with 

Clinical Study Protocol
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Study Code D419AC00002
Version 9
Date 18 Jun 2021
182 (183)
logistical issues should be reported according to the eCRF Completion Guidelines. 
For dosing discontinuations, where applicable, the dosing discontinuation guidelines should 
be followed, and the End of Treatment Form(s) completed
F 7 Ongoing Participants
Participants receiving study intervention should continue to undergo safety assessments prior 
to dosing in accordance with the CSP. In case it is not feasible to perform safety assessments, 
study intervention should be interrupted until such assessments can be completed.
F7.1 If a Participant has an Event Suspected to be COVID-19
Delay or omit study intervention as appropriate and test for COVID-19 per local health 
authority or institutional guidance. 
-
Signs and symptoms of COVID-19 include but are not limited to new onset of fever, new 
or worsening cough, shortness of breath, difficulty breathing and sometimes abnormal 
chest imaging and may be similar to those of an imAE. 
-
In accordance with the CSP and the TMGs for imAEs, thorough evaluation should be 
performed to accurately identify the underlying pathology in case an AE is encountered 
for a participant. 
-
If COVID-19 is ruled out, study intervention may be resumed per the CSP.
-
If COVID-19 is confirmed or diagnosis still suspected after evaluation, manage 
COVID-19 per local guidance until full recovery. 
F7.2 Participants with Confirmed COVID-19
Participants with confirmed COVID-19 (by local laboratory testing and/or combination of 
key symptoms) should have study intervention withheld and COVID-19 managed per local 
guidance.
In case of confirmed COVID-19 and a simultaneous imAE requiring treatment, investigators 
are advised to apply clinical judgement regarding the use of corticosteroids as per the 
durvalumab TMGs. This includes also the consideration of alternate immunosuppressive 
agents other than corticosteroids for imAE management, depending on the individual 
participant’s presentation (Curigliano et al 2020).
F7.3 Restarting Study Intervention
Study intervention must not be resumed until recovery from COVID-19 (e.g., confirmed by 
imaging, lab testing and/or absence of symptoms) and COVID-19-specific treatment has been 
completed per local guidance.

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Study Code D419AC00002
Version 9
Date 18 Jun 2021
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The study clinical lead should be contacted if any additional guidance or clarification is 
needed.
F7.4 Vaccination Against COVID-19
Protocol restrictions applying to live attenuated vaccines are relevant for live attenuated 
COVID-19 vaccines as well. Investigators should apply their discretion assessing the 
risk-benefit of other types of COVID-19 vaccines for participants in clinical trials. Ideally, 
administration of the vaccine should be done on a different day other than the day of study 
drug administration to differentiate any potential AEs seen from the vaccine and study drug. 
The administration of the vaccine and any potential AEs associated with the vaccine are to be 
documented on the concomitant medication and AE eCRFs, respectively.
F 8 References
Curigliano et al 2020 
Curigliano G, Banerjee S, Cervantes A, Garassino M, Garrido P, Girard N. Managing cancer 
patients during the COVID-19 pandemic: an ESMO multidisciplinary expert consensus. Ann 
Oncol 2020;31(10):1320-35.
EMA 2020
EMA, Clinical Trials Facilitation and Coordination Group, European Commission. Guidance 
on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, 
Version 2, 27 March 2020. Available from: URL: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf. Accessed: 17 December 2020.

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: d419ac00002-csp-v9
Document Title:
D419AC00002 Clinical Study Protocol version 9
Document ID:
Doc ID-004046539
Version Label:
4.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
24-Jun-2021 08:33 UTC
Content Approval
28-Jun-2021 15:47 UTC
Content Approval
14-Jul-2021 01:19 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
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