Conditions: Carcinoma, Non- Small Cell Lung
Keywords: NCSLC Double-blind PD-L1 MEDI4736 Durvalumab DFS OS MRD+ Lung cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
This is a Phase III double-blind, placebo-controlled study of Durvalumab versus Placebo in patients with stage II-III NSCLC who are MRD-positive following curative intent therapy.

Detailed description:
This is a Phase III, randomized, multicenter, double-blind, placebo-controlled, study to evaluate the efficacy and safety of durvalumab adjuvant therapy compared to placebo in patients with completely resected stage II-III NSCLC who have undergone curative intent therapy (complete resection ± neoadjuvant and/or adjuvant therapy), who have no evidence of Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1-defined disease recurrence, and who become MRD+ during surveillance period.

Arms:
arm 1: Intravenous administration of Durvalumab arm 2: Intravenous administration of placebo

Interventions: intervention 1: Durvalumab intervention 2: Placebo
Intervention descriptions: intervention 1: Intravenous administration of Durvalumab intervention 2: Placebo Comparator

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol 
Drug Substance
Durvalumab
Study Code
D910MC00001
Version
2.0
Date
02 August 2022
A Phase III, Randomized, Multicenter, Double-blind, Placebo-controlled 
Study of Durvalumab for the Treatment of Stage II-III NSCLC Patients 
with Minimal Residual Disease Following Surgery and Curative Intent 
Therapy (MERMAID-2)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Local Sponsor in Japan: AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, 
Japan
Regulatory Agency Identifying Number(s): IND 120006; EudraCT 2020-000612-30
Redacted for Public Disclosure
d
A Phase II
Phase
Study of Dur
Study of Du
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th Minima
d f
eca AB, 151 85 
a AB, 151
 AstraZeneca K
 AstraZene
Number(s)
Number(s): IND
:


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1 (Version 2.0)
02 August 2022
Original Protocol (Version 1.0)
05 June 2020
Overall Rationale for the Amendment:
Considering the approval of neoadjuvant and adjuvant immunotherapy options for patients 
with resectable Stage II-III NSCLC, as described in Section 10.1, AstraZeneca has decided 
to close enrollment to MERMAID-2 (D910MC00001) early. This amendment describes 
the procedures required for all patients who have signed informed consent for the study
and ensures that eligible patients have access to open-label durvalumab where appropriate. 
Section 10 serves as the new reference point for the study following amendment 
implementation (CSP v2.0) at site.
Section # and name
Description of change
Brief rationale
Section 1.2, Synopsis; 
Section 3, Objectives and 
Endpoints; Section 8.7.2.3, 
Collection of stools for 
microbiome testing 
(OPTIONAL); Section 8.8, 
Medical resource 
utilization and health 
economics
Text added and changes made to 
some objectives and endpoints and 
their analyses; objectives and 
endpoints have been reordered
Following AstraZeneca’s decision to 
close enrollment, study objectives 
and endpoints have been updated as 
all analyses of the objectives and 
endpoints will be descriptive only 
and considered exploratory; medical 
resource utilization and health 
economics will no longer be 
analyzed
Section 4.3, End of study 
definition
End of study definition has been
updated in Section 10.3.3
End of study definition is now 
defined as when the last subject has 
received their last dose of open-label 
durvalumab
Section 5, Study 
Population
Note added to clarify that enrolment 
is closed and there will be no 
randomizations after CSP v2.0 
implementation
AstraZeneca decided to close 
enrolment; no patients will be 
randomized after CSP v2.0
implementation
Section 6, Study 
Treatments
Clarified that placebo will no longer 
be administered 
Patients and Investigators will be 
unblinded to study treatment; 
placebo will no longer be 
administered
Section 6.3, Treatment 
compliance
Clarified that IP administration
following signature of informed 
consent (ICF3) should be recorded 
in source documents rather than the 
eCRF 
To clarify where IP administration 
should be recorded after CSP v2.0
amendment implementation and 
patient signature of informed 
consent (ICF3)


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IP  investigational product; CSP  Clinical Study Protocol.
Section 6.4, Concomitant 
therapy
Section updated throughout to 
reflect concomitant therapy 
restrictions for CSP v2.0; removal of 
rescue medication section
To update concomitant therapy text; 
removed section regarding rescue 
medication as it will no longer be 
centrally supplied and sites are to 
follow toxicity management 
guidelines
Section 6.5, Dose 
modification; 
Section 8.3.12, Adverse 
events of special interest; 
Section 8.3.13 Safety data 
to be collected following 
the final DCO of the study; 
Section 8.4.5, Specific 
toxicity management and 
dose modification 
information – Durvalumab
Deletion of Dosing Modification 
and Toxicity Management 
Guidelines link 
Removal of Toxicity Management 
Guidelines web portal as web portal 
has been decommissioned. 
Guidelines are distributed directly to 
the sites
Section 7.1, 
Discontinuation of study 
treatment
Text updated for patients receiving 
durvalumab
To remove duration of study 
treatment (26 cycles) that is no 
longer applicable for patient 
receiving open-label durvalumab
Section 8.4.5, Specific 
toxicity management and 
dose modification 
information – Durvalumab 
Removed language not relevant for 
CSP amendment
Removal of reference to study-
specific assessments (imaging and 
ePRO) and relation to dose delay
Section 9, Statistical 
Considerations
Clarified that all analyses of the 
objectives and endpoints will be 
descriptive only and considered 
exploratory and that interim analysis 
and medical resource use analysis 
will not be performed
Aligns with the considerations 
added in Section 10.4
New Section 10, Rationale 
and Procedures Following 
CSP v2.0 Approval
Addition of guidance for patient 
eligibility for open-label 
durvalumab and discontinuation of 
patients from study 
To clarify the next steps for patients, 
including the option to receive 
open-label durvalumab (where 
appropriate) or discontinuation from 
the study 
Throughout
Notations indicating which
sections/text that are applicable/no 
longer applicable following CSP 
v2.0 implementation and to 
cross-reference to Section 10 and its 
subsections
To clearly present which 
sections/text are 
applicable/redundant
Throughout
Minor editorial and formatting 
revisions, and minor changes to 
ensure the consistency between 
sections or clarifications
To ensure consistency throughout 
the protocol


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This Clinical Study Protocol (CSP) has been subject to a peer review according to 
AstraZeneca Standard procedures. The CSP is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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TABLE OF CONTENTS
TITLE PAGE...............................................................................................................1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE...........................2
TABLE OF CONTENTS.............................................................................................5
1
PROTOCOL SUMMARY.......................................................................11
1.1
Schedule of activities (SoA).....................................................................11
1.2
Synopsis ..................................................................................................25
1.3
Schema....................................................................................................36
2
INTRODUCTION...................................................................................43
2.1
Study rationale.........................................................................................43
2.2
Background .............................................................................................44
2.2.1
Immunotherapies .....................................................................................44
2.2.2
Durvalumab.............................................................................................45
2.2.3
Non-small cell lung cancer and unmet need .............................................45
2.2.3.1
Value of anti-PD-1 and anti-PD-L1 monotherapy in NSCLC ...................46
2.2.3.2
Minimal residual disease detection in NSCLC .........................................47
2.2.3.3
Rationale for early interception studies predicated on MRD.....................47
2.2.3.4
MRD monitoring following surgery and other curative therapy................48
2.3
Benefit/risk assessment............................................................................49
2.3.1
Potential benefits of durvalumab..............................................................49
2.3.2
Overall risks ............................................................................................49
2.3.2.1
Durvalumab.............................................................................................49
2.3.3
Overall benefit/risk ..................................................................................50
3
OBJECTIVES AND ENDPOINTS..........................................................51
4
STUDY DESIGN ....................................................................................53
4.1
Overall design..........................................................................................53
4.1.1
Overall rationale and study population.....................................................56
4.1.2
Study design ............................................................................................57
4.1.3
Primary and secondary outcome measures ...............................................57
4.1.3.1
Rationale for exploratory endpoints .........................................................57
4.2
Justification for durvalumab dose.............................................................58
4.2.1
Durvalumab monotherapy dose................................................................58
4.2.1.1
PK/Pharmacodynamic data ......................................................................58
4.2.1.2
Clinical data.............................................................................................59
4.2.1.3
Rationale for fixed dosing........................................................................59
4.3
End of study definition.............................................................................60
5
STUDY POPULATION ..........................................................................60
5.1
Inclusion criteria......................................................................................61
5.1.1
Inclusion criteria assessed during the first screening period......................62
5.1.2
Inclusion criteria assessed during the second screening period .................64
5.1.3
Inclusion criteria assessed prior to entering the observation period...........65
5.2
Exclusion criteria.....................................................................................65


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5.3
Lifestyle restrictions (to be observed up to 90 days after last dose of 
durvalumab).............................................................................................68
5.4
Information regarding patients previously enrolled in MERMAID-1 
(D910LC00001).......................................................................................68
5.5
Screen failures .........................................................................................69
6
STUDY TREATMENTS.........................................................................69
6.1
Treatments administered..........................................................................70
6.1.1
Investigational products...........................................................................70
6.1.2
Dosage and treatment regimens................................................................72
6.1.2.1
Durvalumab or placebo............................................................................72
6.1.3
Duration of treatment...............................................................................72
6.1.4
Storage ....................................................................................................74
6.2
Measures to minimize bias: randomization and blinding ..........................74
6.2.1
Patient enrollment and randomization ......................................................74
6.2.2
Procedures for handling incorrectly enrolled or randomized patients........76
6.2.3
Methods for assigning treatment groups...................................................76
6.2.4
Methods for ensuring blinding .................................................................76
6.2.5
Methods for unblinding the study.............................................................77
6.3
Treatment compliance..............................................................................77
6.4
Concomitant therapy................................................................................78
6.4.1
Restrictions for patients during the first screening and surveillance 
periods.....................................................................................................78
6.4.2
Restrictions for patients during the second screening and treatment .........78
6.4.3
Other concomitant treatment....................................................................80
6.4.4
Durvalumab drug-drug interactions..........................................................80
6.5
Dose modification....................................................................................80
6.6
Treatment after the primary DFS analysis ................................................80
7
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL .....................................................................................81
7.1
Discontinuation of study treatment...........................................................81
7.1.1
Procedures for discontinuation of study treatment....................................81
7.2
Lost to follow-up .....................................................................................82
7.3
Withdrawal from the study.......................................................................84
7.3.1
All patients ..............................................................................................84
7.3.2
MRD- patients who are withdrawn from surveillance by the Sponsor.......84
8
STUDY ASSESSMENTS AND PROCEDURES ....................................85
8.1
Efficacy assessments................................................................................86
8.1.1
Disease-free survival................................................................................86
8.1.1.1
Evidence of disease recurrence ................................................................87
8.1.1.2
Dating of recurrence ................................................................................88
8.1.1.3
Post-recurrence........................................................................................88
8.1.2
Computed tomography and magnetic resonance imaging .........................89
8.1.2.1
Central reading of scans...........................................................................89
8.1.3
Survival assessments................................................................................89
8.1.4
Clinical outcome assessments ..................................................................89
8.1.4.1
EORTC QLQ-C30 and EORTC QLQ-LC13............................................90






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9.6
Interim analyses.....................................................................................129
9.6.1
Data monitoring committee (DMC) .......................................................130
10
RATIONALE FOR AND PROCEDURES FOLLOWING CSP V2.0 
IMPLEMENTATION............................................................................131
10.1
Overall rationale ....................................................................................131
10.2
Next steps for patients............................................................................132
10.2.1
Patients in first screening, surveillance, or follow-up .............................134
10.2.1.1
Patients in first screening or surveillance ...............................................134
10.2.1.2
Randomized patients in study-specific follow-up ...................................134
10.2.1.3
Discontinuation of patients from the study.............................................134
10.2.2
Patients in second screening or randomized and receiving study 
treatment................................................................................................135
10.3
End of study/study closure.....................................................................136
10.3.1
Treatment with open-label durvalumab..................................................136
10.3.2
Safety data to be collected......................................................................136
10.3.3
End of study definition...........................................................................136
10.4
Statistical considerations........................................................................136
11
REFERENCES......................................................................................137
12
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.............................................................................147
LIST OF TABLES
Table 1
Schedule of assessments for first screening and surveillance (initiated 
by the signing of ICF1)...................................................................13
Table 2
Schedule of assessments for second screening and 24-month 
durvalumab/placebo treatment period (initiated by the signing of 
ICF2a) ............................................................................................16
Table 3
Schedule of assessments for patients who have completed or 
discontinued treatment....................................................................21
Table 4
Schedule of assessments for observation period (initiated by the 
signing of ICF2b)............................................................................24
Table 5
Inclusion criteria assessment relative to first and second screening 
periods............................................................................................40
Table 6
Exclusion criteria assessment relative to first and second screening 
periods............................................................................................42
Table 7
Study objectives and endpoints/variables ........................................51
Table 8
Study treatments .............................................................................70
Table 9
Prohibited concomitant medications................................................78
Table 10
Supportive medications...................................................................79
Table 11
Clinical chemistry...........................................................................93
Table 12
Hematology....................................................................................93


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Table 13
Urinalysis .......................................................................................93
Table 14
Summary of outcome variables and analysis populations ..............116
Table 15
Visit responses for symptoms and health-related quality of life.....121
Table 16
Pre-planned statistical and sensitivity analyses to be conducted ....124
Table 17
Required data entry for patients in first screening or surveillance..134
Table 18
Summary of imaging modalities for tumor assessment..................173
Table 19
RECIST 1.1 evaluation of target lesions........................................181
Table 20
RECIST 1.1 evaluation of non-target lesions.................................181
Table 21
RECIST 1.1 overall visit response ................................................182
Table 22
Highly Effective Methods of Contraception (<1% Failure Rate) ...187
LIST OF FIGURES
Figure 1
Study design...................................................................................37
Figure 2
Potential scenarios for permissible curative intent therapy ..............39
Figure 3
Dosing scheme ...............................................................................72
Figure 4
Multiple testing procedure for controlling the type 1 error rate......129
Figure 5
Patients with opportunity to receive open-label durvalumab following 
CSP v2.0 implementation at site ...................................................133
LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations..................148
Appendix B
Adverse event definitions and additional safety information .........153
Appendix C
Handling of Human Biological Samples .......................................158
Appendix D
Genetics (for Optional Genetic Research Study) ...........................161
Appendix E
Mandatory Genetic analysis for Minimal Residual Disease...........165
Appendix F
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law.................................................................167
Appendix G
Guidelines for evaluation of objective tumor response using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumors).........173
Appendix H
Contraception Requirements.........................................................185
Appendix I
.............................................................188
Appendix J
Abbreviations ...............................................................................198
CCI


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1
PROTOCOL SUMMARY
From CSP v2.0 implementation at site, please use Section 10 as a reference point for the 
study. This study has closed enrolment early and patients will either start open-label
durvalumab or be discontinued from the study.
The protocol summary below refers to the original study design.
1.1
Schedule of activities (SoA)
This study will employ a multi-tiered consent and screening process for patients with 
histologically confirmed resectable non-small cell lung cancer (NSCLC) (World Health 
Organization [WHO] 2015 classification) (Stage IIA to select [ie, T3N2 or T4N2] 
Stage IIIB; according to Version 8.0 of the International Association for the Study of Lung 
Cancer Staging Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic 
Oncology v8.0]).
Table 1 includes the procedures conducted during the first screening period (initiated by 
the signing of Informed Consent Form 1 [ICF1]). The primary purpose of this screening 
period is to determine the minimal residual disease (MRD) status of the patient. This is 
done by whole exome sequencing (WES) of the patient’s resected tumor tissue and 
germline blood sample to identify tumor-specific DNA variants. A personalized panel 
comprised of the patient’s tumor variants is then created and used to identify circulating 
tumor DNA (ctDNA) extracted from the patient’s plasma. The patient is considered 
MRD-positive (MRD+) if the panel detects ctDNA. This assay requires mandatory genetic 
testing.
Following this first screening, eligible patients will be enrolled in a 96-week surveillance 
period and monitored for the emergence of MRD. Surveillance will begin the day the 
plasma sample used to determine a patient’s MRD status post-curative intent therapy is 
collected. During this surveillance period, the patient may or may not become eligible for 
randomization into the study. Patients who are MRD+ at the start of surveillance or 
become MRD+ during the 96-week surveillance period may be eligible for the second 
screening (see Section 5.1.2). The procedures for the second screening and treatment 
period are presented in Table 2 and initiated with the signing of ICF2a. The primary 
purpose of the second screening is to ensure that all eligibility criteria are met prior to 
randomization. Patients who successfully complete the second screening are eligible for 
randomization into the study, where patients may receive up to a total of 24 months 
(26 cycles) of treatment with investigational product (IP).
Table 3 includes the procedures for the follow-up period for patients who discontinue 
treatment with IP due to toxicity or Response Evaluation Criteria in Solid Tumors 
(RECIST) Version 1.1-defined disease recurrence or who complete the full 24 months 
(26 cycles) of IP treatment.


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Up to 142 MRD- patients who complete their 96-week surveillance period without 
becoming MRD+ or experiencing disease recurrence may be eligible for entry into an 
observation period initiated by the signing of ICF2b. Patients in the observation group will 
be followed up for disease-free survival (DFS) for an additional 24 months or until 
primary DFS analysis (whichever occurs first), after which these patients will be followed 
for overall survival (OS) until the end of the study. Table 4 includes the procedures for this 
observation period.
Whenever vital signs and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: vital signs and then blood draws. The 
timing of the vital signs assessments should be such that it allows the blood draw to occur 
at the timepoints indicated in the SoAs. Whenever electrocardiograms (ECGs), vital signs, 
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. The timing of the first 2 
assessments should be such that it allows the blood draw to occur at the timepoints 
indicated in the SoAs.
For durvalumab or placebo monotherapy:
!
Patients may delay dosing under certain circumstances.
Dosing may be delayed per the Dosing Modification and Toxicity Management 
Guidelines (See Section 8.4.5), due to either an immune or a non-immune-related 
adverse event (AE).
If dosing must be delayed for reasons other than treatment-related toxicity, dosing will 
resume as soon as feasible.
Dosing intervals of subsequent cycles may be shortened as clinically feasible in order 
to gradually align treatment cycles with the schedule of disease (RECIST) and 
Patient-reported Outcome (PRO) assessments. Subsequent time between 
2 consecutive doses cannot be less than 21 days, based on the half-life of 
durvalumab (see current Investigator Brochure [IB] for durvalumab).


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Table 1
Schedule of assessments for first screening and surveillance (initiated by the signing of ICF1)
First screening perioda
Surveillance 
Prior to start of 
surveillance
Start of surveillanceb
8w ± 1w after completion of 
adjuvant therapy or 12w ± 1w 
post-surgery
Up to 96 weeks or until 
emergence of MRD or disease 
recurrence
For details, 
see Section
ICF1a.c
X
5.1
Eligibility, including complete information 
on curative intent therapyd
X
X
5.1, 5.2
Table 5, 
Table 6
Demography, including disease 
characteristics (at diagnosis) and tobacco use
X
5.1
Whole blood sample for WES/development 
of personalized panel
X
8.7.1.2
Resected tumor tissue sample for 
WES/development of personalized panele
X
8.7.1.2
Resected tumor tissue sample for central 
EGFR/ALK testinge,f
X
8.7.1.1
Resected tumor tissue sample sent for 
prospective PD-L1 testinge,g
X
8.7.1.3
Resected tumor tissue collected for 
exploratory analysese
X
8.7.2.2
Plasma sample collection for MRD 
evaluation and exploratory analyses
Xh
Start of surveillance is the date 
of this plasma collection
q6w ± 3di,j
5.1.1
8.7.2.1
Pre-surgical plasma sample collection for 
exploratory analyses (if ICF1 is signed prior 
to surgery)
X
8.7.2.1
Pregnancy testk
X
X
q12w ± 1w
8.2.1


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Table 1
Schedule of assessments for first screening and surveillance (initiated by the signing of ICF1)
First screening perioda
Surveillance 
Prior to start of 
surveillance
Start of surveillanceb
8w ± 1w after completion of 
adjuvant therapy or 12w ± 1w 
post-surgery
Up to 96 weeks or until 
emergence of MRD or disease 
recurrence
For details, 
see Section
SAE assessmentsl
X
X
X
8.3
Concomitant medications/medical historyl
X
X
X
6.4, 8.2.2
Concomitant proceduresl
X
X
X
5.1, 5.2
Disease assessments (RECIST 1.1)
Xm,n
q12w ± 1wj,n,o,p
8.1, 
Appendix G
Tumor biopsy (optional)q
At recurrence
8.7.2.2
a
The first screening period will be initiated with the signing of ICF1. Patients should sign and date ICF1 before surgery or as soon as possible post-surgery 
(including during adjuvant therapy, if administered) to allow resected tumor tissue and whole blood samples to be sent to the diagnostic lab and enable 
development of the personalized panel for MRD detection. In order for the personalized panel to be ready for prior to the start of surveillance, these samples 
must be sent as soon as possible after ICF1 is signed but no later than 1-2 weeks post-completion of adjuvant therapy or 3-5 weeks post-surgery. Patients 
who are screen failures of MERMAID-1 (D910LC00001) and subsequently enroll in this study (MERMAID-2; D910MC00001) may be allowed to use a 
previously developed personalized panel for MRD detection, as well as results of previous PD-L1 and/or EGFR/ALK testing (see section 5.4 for details).
b
Start of surveillance is defined as the day the first post-curative intent therapy plasma sample is collected in order to determine a patient’s MRD status (ie, 
8w ± 1w after completion of adjuvant therapy or 12w ± 1w post-surgery).
c
Written informed consent and any locally required privacy act document authorization must be obtained prior to performing any protocol-specific 
procedures, including first screening evaluations and start of surveillance. ICF1 will be signed either prior to surveillance or at the start of surveillance.
d
Curative intent therapy (complete resection ± neoadjuvant and/or adjuvant therapy) are SoC and not considered study procedures. However, information 
pertaining to curative intent therapy must be made available during the first screening period for evaluation of study eligibility. Eligibility must also be 
reviewed at the start of surveillance to ensure the patient is able to participate in this study.
e
The indicated tumor tissue samples come from the tumor which was removed during surgery. Separate rows indicate that portions of this singular surgical 
sample will undergo different tests or analyses performed at different locations. FFPE samples of resected tumor tissue will be collected.
f
Results from local EGFR/ALK testing of either a pre-surgery biopsy or the resected tumor tissue may be used for this study, provided testing was performed 
using a well-validated, local regulatory-approved kit. If local testing will be done on either the pre-surgery biopsy (if available) or resected tumor tissue, 
EGFR/ALK testing does not need to be repeated by the central lab.
g
PD-L1 testing will be done prospectively for screened patients using resected tumor tissue as this information is required prior to randomization for 
stratification.


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h
A patient determined to be MRD- at the start of surveillance (based on the plasma sample collected 8w ± 1w post-completion of adjuvant therapy [if 
administered] or 12w± 1w post-surgery [if adjuvant therapy is not given]) will continue in surveillance. If testing of this first plasma sample returns an 
MRD+ result, the patient may be eligible to continue to the second screening (initiated with the signing of ICF2a). The plasma sample at the start of 
surveillance should be collected as indicated in the schedule, even if creation of the personalized panel for MRD detection is delayed. Note: a patient who 
received prior neoadjuvant immunotherapy must be MRD- based on analysis of this first plasma sample in order to continue in the study.
i
If a plasma sample taken during surveillance returns as MRD+, the patient may be eligible to sign ICF2a and continue to the second screening period (see 
Table 2).
j
In order to minimize any delay in randomization in the event that a patient is determined to be MRD+, the Investigator should proactively schedule CT 
and/or MRI scans of the chest/abdomen and brain to coincide within the weeks following q6w plasma collection visits that are not aligned with the q12w 
CT scan schedule (ie, Week 6, 18, 30, etc, relative to the start of surveillance). A CT or MRI scan of the brain should also be proactively scheduled to occur 
within the week following the q12w CT scan.
k
For women of childbearing potential only. A urine or serum pregnancy test is acceptable. Women of childbearing potential are required to have a pregnancy 
test within 7 days prior to the start of surveillance and then every 12w ± 1w. Pregnancy test results should be reviewed by the treating physician or 
Investigator prior to a visit where a surveillance scan will be performed.
l
Any SAEs reported after ICF1 has been signed (ie, during first screening and surveillance) should be recorded in the eCRF. Medical history should only be 
recorded in the eCRF if an SAE is reported. All prior anti-cancer medications or prior radiotherapy should be recorded for all patients after ICF1 is signed; 
all other concomitant medications should only be recorded in the eCRF if an SAE is reported.
m
After the completion of curative intent therapy, a CT scan of the chest and abdomen (including liver and adrenal glands) and a brain MRI (preferred) or 
brain CT with IV contrast should be performed per local clinical practice with timing according to Investigator discretion. If a post-therapy scan is 
unavailable, these scans must be performed prior to the start of surveillance.
n
Contrast-enhanced CT scan of the chest and abdomen (including liver and adrenal glands) is required. Brain MRI (preferred) or brain CT with IV contrast 
may be performed only if clinically indicated. Brain MRI (preferred) or brain CT with IV contrast may be performed if clinically indicated.
o
If scans conducted during the first screening or during surveillance demonstrates evidence of RECIST 1.1-defined disease recurrence and/or metastatic 
disease, the patient is considered a screen failure (section 5.5) and is no longer eligible to participate in the study. In this case, the final scans along with the 
date of disease recurrence or metastatic disease should be captured in the eCRF.
p
Before an MRD+ patient can be randomized, a contrast-enhanced CT scan of the chest and abdomen (including liver and adrenal glands) and a brain MRI 
(preferred) or brain CT with IV contrast needs to be performed to confirm no evidence of RECIST 1.1-defined disease recurrence and/or metastasis. These 
scans do not need to be repeated during the second screening period if the post-curative intent therapy scans were conducted within 28 days ± 7 days prior 
to randomization. If a patient becomes MRD+ during surveillance, the CT scan of the chest and abdomen conducted during surveillance may be used as the 
baseline scan, provided it was performed within 28 days ± 7 days prior to randomization. A brain MRI (preferred) or brain CT with IV contrast must also 
be performed prior to randomization. If the previously performed scans fall outside of this window, additional scans of the chest, abdomen, and brain must 
be performed before the patient is randomized to confirm no evidence of disease recurrence and/or metastasis.
q
FFPE samples of recurrent tumor biopsy will be collected from consenting patients.
ALK Anaplastic lymphoma kinase; CT Computed tomography; D Day; eCRF Electronic case report form; EGFR Epidermal growth factor receptor; 
FFPE Formalin-fixed paraffin-embedded; ICF1 Informed consent form 1; IV intravenous; MRD Minimal residual disease; MRI Magnetic resonance imaging; 
PD-L1 Programmed cell death ligand-1; q6w Every 6 weeks; q12w Every 12 weeks; RECIST Response Evaluation Criteria in Solid Tumors; SAE Serious 
adverse event; SoC Standard of care; w Week; WES Whole exome sequencing.


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Table 2
Schedule of assessments for second screening and 24-month durvalumab/placebo treatment period (initiated 
by the signing of ICF2a)
Second 
screening 
perioda
C1
C2
C3 
C4
C5 
C6
C7 to C26 or 
until RECIST 
1.1-defined 
disease 
recurrence
For details, 
see Section
Week
-4 to -1
0
q4w ± 3d unless dosing needs to be held for toxicity reasons
Day
-28 to -1
1b
q28d ± 3d unless dosing needs to be held for toxicity reasons
ICF2ac
X
5.1
Informed consent for optional
genetic analysis (Gx)
X
5.1.2
Study procedures
Medical history
X
8.2.2
Physical exam (full)
X
8.2.3
Targeted physical exam (based 
on symptoms)
X
X
X
X
X
X
X
8.2.3
Vital signsd
X
X
X
X
X
X
X
X
8.2.4
ECGe
X
As clinically indicated
8.2.5
Concomitant medications
<-------------------------------------------------------------------------------------------------------------------------->
6.4
Eligibility criteria
X
5.1, 5.2
Table 5
Table 6
Laboratory Assessments
Clinical chemistryf
X
Xf
X
X
X
X
X
X
Table 11
Hematologyf
X
Xf
X
X
X
X
X
X
Table 12
TSH (reflex free T3 or free 
T4g)
X
Xh
X
X
X
X
X
X
Table 11


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Table 2
Schedule of assessments for second screening and 24-month durvalumab/placebo treatment period (initiated 
by the signing of ICF2a)
Second 
screening 
perioda
C1
C2
C3 
C4
C5 
C6
C7 to C26 or 
until RECIST 
1.1-defined 
disease 
recurrence
For details, 
see Section
Week
-4 to -1
0
q4w ± 3d unless dosing needs to be held for toxicity reasons
Day
-28 to -1
1b
q28d ± 3d unless dosing needs to be held for toxicity reasons
Urinalysis
X
As clinically indicated
8.2.1
Hepatitis B and C and HIV
X
8.2.8
Pregnancy testi
X
X
X
X
X
X
X
X
8.2.1
Monitoring
WHO/ECOG performance 
status
X
X
X
X
X
X
X
X
8.2.7
AE/SAE assessmentj
<------------------------------------------------------------------------------------------------------------>
8.3
Patient follow-up contact / 
Patient review for safety
Recommended phone contact 
midway through Cycles 1, 2, and 
3: Days 14 of C1, 2, and 3
8.2.6
IP administration
Durvalumab/placebok,l
X
X
X
X
X
X
X
6
Other assessments and assays
Plasma sample for exploratory 
analysesm
Sample collected pre-dose on Day 1 of each treatment cycle
8.7.1.2
Whole blood for gene 
expression (PaxGene mRNA)
Xn
Xn
C26 or 
recurrenceo
8.7.2
Serum for soluble biomarkers
Xn
X
C26 or 
recurrenceo
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Table 2
Schedule of assessments for second screening and 24-month durvalumab/placebo treatment period (initiated 
by the signing of ICF2a)
Second 
screening 
perioda
C1
C2
C3 
C4
C5 
C6
C7 to C26 or 
until RECIST 
1.1-defined 
disease 
recurrence
For details, 
see Section
Week
-4 to -1
0
q4w ± 3d unless dosing needs to be held for toxicity reasons
Day
-28 to -1
1b
q28d ± 3d unless dosing needs to be held for toxicity reasons
Stool sample collection for 
microbiome analysis (optional)p
X
X
C26 or 
recurrenceo
8.7
, 
 
, 
, 
, 
, 
X
X
X
X
X
X
q4w
8.1.4
Health resource use (HOSPAD 
module)r
To be completed at each hospitalization
Optional Gx sample (DNA 
element for long-term 
storage/future use)s
X
8.6.2
Efficacy evaluations
Disease assessments 
(RECIST 1.1)
Xt
Disease assessments occur q8w ± 1w until Week 48, then q12w ± 1w (relative to the date of 
randomization) until appearance of RECIST 1.1-defined disease recurrence or completion of 
the study.u,v,w
Upon detection of RECIST 1.1-defined disease recurrence, an additional follow-up CT scan 
should be performed 4-8w laterx and evaluated using post-progression radiological criteria.
8.1
Appendix G
Tumor biopsy (optional)x,y
At recurrence
8.7.2.2
a
In order to minimize the time an MRD+ patient is in second screening (ie, the time from receiving an MRD+ result to being randomized and starting 
treatment), a patient may sign ICF2a as soon as MRD+ test results are received. In addition, the Investigator should proactively schedule CT and/or MRI 
scans of the chest/abdomen and brain to coincide within the weeks following q6w plasma collection visits that are not aligned with the q12w CT scan 
schedule (ie, Week 6, 18, 30, etc, relative to the start of surveillance). A CT or MRI scan of the brain should also be proactively scheduled to occur within 
the week following the q12w CT scan.
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Table 3
Schedule of assessments for patients who have completed or discontinued treatment 
Evaluation
Time since last dose of IP
Weeks
4 (± 3d)a
12 (± 1w)
q12w ± 1w until primary DFS 
analysisb or until disease 
recurrence
For details, 
see Section
Physical examination (full)
X
8.2.3
Vital signs (temperature, respiratory rate, blood 
pressure, and pulse)
X
8.2.4
Pregnancy testc
X
X
X
8.2.1
AE/SAE assessment
Xd
8.3
Concomitant medications
X
6.4
WHO/ECOG performance status
At timepoints consistent with tumor assessments; at 30 and 90 days; and then at initiation 
of subsequent anticancer therapye
8.2.7
Subsequent anticancer therapyf and progression 
assessmentg
<-------------------------------------------------------------------------------------------------------->
8.1
Survival status
X
Xh
8.1.3
Hematology 
X
X
Table 12
Clinical chemistry
X
X
Table 11
TSH (reflex free T3 or free T4i)
X
X
Table 11
Plasma samples for exploratory analyses
q12w ± 1w (preferably to coincide with time of scan)
Sample at time of RECIST 1.1-defined disease recurrence (if applicable)j
8.7.2.1
, 
, 
, 
k
To be completed q4w until PFS event following disease recurrence (ie, a DFS event), 
study discontinuation, or death (whichever occurs first)
PRO data collection will stop at the time of primary DFS analysis
8.1.4
Health resource use (HOSPAD)l
To be completed at each hospitalization until PFS event following disease recurrence (ie, 
a DFS event), initiation of subsequent therapy, study discontinuation, or death 
(whichever occurs first)
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Table 3
Schedule of assessments for patients who have completed or discontinued treatment 
Evaluation
Time since last dose of IP
Weeks
4 (± 3d)a
12 (± 1w)
q12w ± 1w until primary DFS 
analysisb or until disease 
recurrence
For details, 
see Section
Disease assessment (RECIST 1.1)
Disease assessments occur q8w ± 1w until Week 48, then q12w ± 1w (relative to the date 
of randomization) until appearance of RECIST 1.1-defined disease recurrence or 
completion of the study.m,n Upon detection of RECIST 1.1-defined disease recurrence, an 
additional follow-up CT scan should be performed 4-8w later and evaluated using post-
progression radiological criteria.o
8.1
Appendix G
Tumor biopsy sample (optional)p
At recurrencej
8.7.2.2
a
Patients who discontinue treatment due to disease recurrence will continue to be followed for OS and subsequent therapy until the end of the study. See 
footnote k for details regarding the timing of final sample collection.
b
After database lock for primary DFS analysis, all patients remaining on study will continue for OS follow-up including collection of data on safety and 
subsequent therapies. Plasma samples for exploratory analyses will no longer be collected. Efficacy scans will be collected in accordance with local clinical 
practice. See Section 6.1.3 for details.
c
For women of childbearing potential only. A urine or serum pregnancy test is acceptable.
d
SAEs that occur after the 90-day safety follow-up period and that the Principal Investigator deems to be significant or related to IP should be reported.
e
WHO/ECOG performance status should also be collected at other site visits that the patient attends, if appropriate site staff are available to collect such 
information. In addition, WHO/ECOG performance status should be provided when information on subsequent anticancer therapy is provided, where 
possible.
f
Details of any treatment for NSCLC (including surgery and radiotherapy) post the last dose of IP must be recorded in the eCRF through the completion of 
the study.
g
Post-recurrence progression (PFS) will be assessed by the Investigator per local clinical practice (See section 8.1.1.3).
h
Patients may be contacted in the week following data cut-offs to confirm survival status.
i
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
j
For patients who discontinued treatment due to disease recurrence, the last plasma sample should be collected with the optional biopsy of recurrent tumor (if 
provided) at the visit 4 weeks post-last dose of IP. For patients who complete treatment, but who later experience disease recurrence, these plasma and 
tumor biopsy samples should be collected as close to the time of disease recurrence as possible (ie, at the time the additional follow-up scan is performed 
approximately 4-8 weeks after the first radiographic evidence of RECIST 1.1-defined disease recurrence).
k
l
HOSPAD module should be completed by site staff whenever the patient has attended or been admitted in to the hospital. A reminder will be provided at 
each clinic visit.
m
On-study schedule of q12w ± 1w (relative to the date of randomization) must be followed.
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n
Contrast-enhanced CT scan of the chest and abdomen (including liver and adrenal glands) is required. Brain MRI (preferred) or brain CT with IV contrast 
may be performed only if clinically indicated.
o
Post-progression scans will be performed per local clinical practice.
p
FFPE sample of recurrent tumor biopsy will be collected from consenting patients.
d Day; DFS disease-free survival; ECOG Eastern Cooperative Oncology Group; eCRF Case report form; 
 
; 
; FFPE Formalin-fixed paraffin-embedded; HOSPAD Hospital 
resource use module; IP investigational product; NSCLC non-small cell lung cancer; OS Overall survival; 
; q8w Every 
8 weeks; q12w Every 12 weeks; RECIST Response Evaluation Criteria in Solid Tumors; SAE Serious adverse event; T3 Triiodothyronine; T4 Thyroxine; 
TSH Thyroid-stimulating hormone; WHO World Health Organization; w Week.
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Table 4
Schedule of assessments for observation period (initiated by the signing of ICF2b)
Up to 24 months or until RECIST 1.1-defined disease recurrence or primary DFS analysis 
(whichever occurs first)a
For details, 
see Section
ICF2bb
X
5.1
Medical history
To be collected on or by the first observation visit
8.2.2
Pregnancy testc
X
SAEs
<------------------------------------------------------------------------------->
8.3
Subsequent anticancer therapy
<------------------------------------------------------------------------------->
8.1.3
Survival status
q12w ± 1w
8.1.3
Plasma sample for exploratory 
analysesc
q12w ± 1w coinciding with scans and at time of disease recurrence, or until discontinuation from 
the study
8.7.2.1
Disease assessment (RECIST 1.1)d
Follow-up disease assessments occur q12w ± 1w (relative to the date of surveillance completion) 
until appearance of RECIST 1.1-defined disease recurrence or end of the studye,f . Upon detection 
of disease recurrence, an additional follow-up scan should be performed 4-8w later and evaluated 
using post-progression radiological criteriag
8.1
Appendix G
Tumor biopsy sample (optional)h
At recurrence
8.7.2.2
a
Patients in observation will adhere to this schedule of assessments until (1) completion of 24 months in observation; (2) disease recurrence; or (3) until 
primary DFS analysis; after which, these patients will be followed for OS (including subsequent therapy) until the end of the study.
b
Written informed consent and any locally required privacy act document authorization must be obtained prior to performing any protocol-specific 
procedures. The procedures outlined in this table will be initiated by the signing of ICF2b.
c
For women of childbearing potential only. A urine or serum pregnancy test is acceptable.
d
After database lock for primary DFS analysis (See Section 6.1.3), plasma samples for exploratory analyses will no longer be collected. Scans will be 
collected in accordance with local practice.
e
Scan schedule of q12w ± 1w (relative to the date of randomization) must be followed while a patient is in observation.
f
Contrast-enhanced CT scan of the chest and abdomen (including liver and adrenal glands) is required. Brain MRI (preferred) or brain CT with IV contrast 
may be performed only if clinically indicated.
g
Post-progression scans will be performed per local clinical practice.
h
FFPE samples of recurrent tumor biopsy will be collected from consenting patients.
CT computed tomography; DFS disease-free survival; ICF2b Informed consent form 2b; IV intravenous; MRI magnetic resonance imaging; OS Overall 
survival; q12w Every 12 weeks; RECIST Response Evaluation Criteria in Solid Tumors; SAE Serious adverse event; w Week(s).


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1.2
Synopsis
From CSP v2.0 implementation at site, please use to Section 10 as a reference point for the 
study. This study has closed enrolment early and patients will either start open-label 
durvalumab or be discontinued from the study.
The synopsis below refers to the original study design. The objectives and endpoints have 
been updated for CSP v2.0. All analyses of the objectives and endpoints will be descriptive 
only and considered exploratory.
International Coordinating Investigator
David Spigel
Sarah Cannon Research Institute
250 25th Avenue North
Nashville, Tennessee 37203
USA
Charles Swanton
The Francis Crick Institute,
Cancer Evolution and Genome Instability Laboratory
3rd Floor South West
Midland Road
London,
NW1 1AT
Protocol Title: A Phase III, Randomized, Multicenter, Double-blind, Placebo-controlled, 
Study of Durvalumab for the Treatment of Stage II-III NSCLC Patients with Minimal 
Residual Disease Following Surgery and Curative Intent Therapy
Short Title: MERMAID-2
Rationale:
Up to 30% of patients with non-small cell lung cancer (NSCLC) present with surgically 
resectable disease (Molina et al 2008). For patients with stage II-IIIA and select stage IIIB 
disease, surgery and adjuvant standard of care (SoC) chemotherapy results in 5-year 
disease-free survival (DFS) rates of only ~40% (Wakelee et al 2017). Long-term survival is 
improved through administration of chemotherapy in the immediate post-operative setting 
(Pignon et al 2008), yet chemotherapy in the first-line metastatic setting results in no long-
term survival benefit and progression-free survival (PFS) benefits of only a small number of 
months (Cochrane Review 2000). In contrast, immunotherapy agents have transformed the 
treatment landscape in the first-line setting (Garon et al 2019) and provides a rationale to 
conduct studies to intercept relapsing NSCLC with immunotherapy prior to the emergence of 
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There is evidence that detection of minimal residual disease (MRD) through detection of 
circulating tumor DNA (ctDNA) post-surgery can accurately predict recurrence (Abbosh et al 
2017, Chaudhuri et al 2017). In the TRACERx study, the presence or absence of MRD was 
evaluated via ctDNA detection in plasma samples taken from patients who had undergone 
surgery for stage III NSCLC. In 13 of 14 patients who underwent surgical resection of their 
tumors and subsequently suffered post-operative relapse of their disease, MRD was detected 
via ctDNA before or at the point of clinically evident disease recurrence (through SoC 
imaging or presentation of symptoms) (Abbosh et al 2017). In all 12 patients who did not 
experience post-operative disease recurrence, MRD was not detected following surgery 
(Abbosh et al 2017). Detection of MRD at a time when there is no radiologic evidence of 
disease provides an opportunity for earlier therapeutic intervention (Abbosh et al 2018). 
Patients with MRD (MRD-positive [MRD+]) experience inferior recurrence-free survival 
compared to patients without detectable MRD (MRD-negative [MRD-]). Therefore, MRD+ 
patients could benefit from earlier intervention and escalation of additional adjuvant therapy 
(including immunotherapy); furthermore, MRD- patients (the majority of whom are cured by 
surgery alone) could be spared from additional treatment and the resulting unnecessary 
toxicity.
Immunotherapy has changed the landscape of advanced NSCLC (Martinez et al 2019). First-
line treatment of metastatic NSCLC with anti-programmed cell death-1 (anti-PD-1) or anti-
programmed cell death ligand 1 (anti-PD-L1) monotherapy has demonstrated an overall 
survival (OS) benefit compared with chemotherapy alone in patients whose tumors expressed 
PD-L1 (Garon et al 2019, Mok et al 2019, Reck et al 2016, Spigel et al 2019). In the second-
or third-line metastatic setting, it has further been established that immune-oncologic (IO) 
therapy can provide clinical benefit irrespective of PD-L1 status (Rittmeyer et al 2017). 
However, even with these improvements, most patients will experience disease progression 
and ultimately die.
Durvalumab can be effective in situations of residual cancer as evidenced by improved PFS 
and OS observed with durvalumab versus placebo following definitive concurrent 
chemoradiation in the PACIFIC study (Antonia et al 2018, Gray et al 2019). Moreover, 
intervention with combination chemotherapy and immunotherapy versus chemotherapy alone 
improves PFS and OS in advanced NSCLC (Gandhi et al 2018, Gadgeel et al 2019, Paz-Ares 
et al 2018). These data suggest that earlier intervention with immunotherapy as adjuvant 
therapy following curative intent treatment could improve outcomes in early-stage NSCLC, 
prevent progression, and circumvent the need to expose patients to potentially more toxic 
chemotherapy regimens in the metastatic setting.
This study is being conducted to evaluate the efficacy and safety of durvalumab adjuvant 
therapy compared to placebo in patients with completely resected stage II-III NSCLC who 


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have undergone curative intent therapy (complete resection ± neoadjuvant and/or adjuvant 
therapy), and who become MRD+ during a 96-week surveillance period.
Objectives and Endpoints
Primary objective:
Endpoint/variable:
To assess the efficacy of durvalumab compared to 
placebo as measured by DFS in all randomized 
patients
DFS in FAS (using Investigator assessments 
according to RECIST 1.1)
Secondary/Safety objective:
Endpoint/variable:
To assess the safety and tolerability profile of 
durvalumab monotherapy compared with placebo
AEs, physical examinations, vital signs, and 
laboratory findings
Exploratory objectives:
Endpoint/variable:
To assess the efficacy of durvalumab compared to 
placebo as measured by DFS in the PD-L1 TC≥1% 
analysis set
DFS in PD-L1 TC≥1% (using Investigator 
assessments according to RECIST 1.1)
To assess the efficacy of durvalumab compared to 
placebo on post-recurrence outcomes
PFS (using local standard practice)
To assess the efficacy of durvalumab compared to 
placebo as measured by OS in the PD-L1 TC≥1% 
analysis set and in all randomized patients
OS in PD-L1 TC≥1% and in FAS
To assess patient-reported symptoms, functioning, 
and HRQoL in patients treated with durvalumab 
compared to placebo
Change from baseline and time to deterioration in 
EORTC QLQ-C30 and EORTC QLQ-LC13
To investigate the relationship between a patient’s 
baseline PD-L1 TC expression and efficacy of study 
treatments
IHC analysis of PD-L1 TC expression and spatial 
distribution within the tumor microenvironment 
relative to efficacy outcomes (ie, DFS, OS)
To assess the efficacy of durvalumab monotherapy to 
clear ctDNA compared to placebo
ctDNA endpoints, as defined by:
•
Best overall clearance rate (number converted at 
any time)
•
Best confirmed clearance rate (as above but 
confirmed at subsequent visit)
•
Time to ctDNA clearance
•
Duration of ctDNA clearance
•
Time to ctDNA recurrence
•
Time to confirmed ctDNA recurrence
•
Changes in variant allele frequencies (VAF) 
following treatment
To assess the relationship between treatment effect 
on DFS and treatment effect on ctDNA endpoints
ctDNA endpoints (as defined above) and DFS
To assess the association of TMB with efficacy of 
durvalumab compared with placebo, and other 
biomarker subpopulations
DFS, OS, and other efficacy endpoints in patients 
according to TMB in subpopulations including, but 
not limited to, PD-L1 TC≥1%, ctDNA endpoints, etc.
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The study will screen approximately 
 patients and randomize approximately 
 MRD+ 
patients with stage II-III NSCLC (according to IASLC Staging Manual in Thoracic Oncology 
v8.0) (select stage IIIB [ie, T3N2 or T4N2] patients) whose tumors are epidermal growth 
factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild type, and who have 
completed curative intent therapy. Randomized patients will include approximately 
 
PD-L1 TC≥1% and 
 PD-L1 TC<1% patients. The study will be conducted in 
approximately 250 centers globally.
This study will employ a multi-tiered consent and screening process. Table 1 includes the 
procedures for the first screening (initiated by the signing of Informed Consent Form 1 
[ICF1]) and surveillance of eligible patients. Table 2 includes the procedures for the second 
screening (initiated by the signing of Informed Consent Form 2a [ICF2a]) and randomization 
to treatment with investigational product (IP). Table 3 includes the procedures for the 
follow-up period, which is for randomized patients who discontinue treatment with IP due to 
toxicity or RECIST 1.1-defined disease recurrence or who have completed 24 months (26 
cycles) of treatment with IP.
Resected tumor tissue collected during the first screening will be evaluated for EGFR/ALK 
and programmed death ligand-1 (PD-L1) tumor cell (TC) expression by a central reference 
laboratory. Patients whose tumor tissue tests positive for EGFR mutations and/or ALK 
translocations will be excluded from the study. In addition, PD-L1 status must be known prior 
to, and is required for, randomization.
!
Note: Results from local EGFR/ALK testing of either a pre-surgery biopsy or the resected 
tumor tissue performed as part of standard care may be used for this study, provided 
testing was performed using a well-validated, local regulatory-approved kit.
This study requires mandatory genetic testing. During the first screening period (Table 1), 
whole exome sequencing (WES) of the patient’s tumor is performed on the resected tumor 
tissue and derived tumor-specific DNA variants are identified by removing background 
germline variants, determined by WES of the patient’s whole blood sample. A personalized 
panel is then created, comprised of up to 50 of the patient’s tumor variants expressed at high 
frequency. This panel is then used to identify the presence of these tumor-specific variants on 
DNA extracted from a patient’s plasma. The patient is considered MRD+ if the panel detects 
patient-specific tumor variants.
!
Note: In order to initiate surveillance within the appropriate timeframe, samples of 
resected tumor tissue and whole blood should be sent to the diagnostic laboratory as soon 
as possible. These samples are critical for WES and the creation of the personalized panel 
for MRD detection. These samples must be sent no later than to 1-2 weeks after 
completion of adjuvant therapy (including post-operative radiotherapy (PORT), if 
administered) or 3-5 weeks after surgery (if no adjuvant therapy is administered).
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A plasma sample will be collected approximately 8 weeks after completion of adjuvant 
therapy (including PORT, if administered) or approximately 12 weeks after surgery (if no 
adjuvant therapy is given), marking the start of surveillance. This sample will be used to 
determine a patient’s MRD status and must be collected at the indicated timepoint, even if 
creation of the personalized panel for MRD detection and/or results from PD-L1 testing are 
delayed.
Eligible patients will be enrolled and monitored for the emergence of MRD during a 96-week 
surveillance period. During surveillance, the patient will be evaluated for MRD every 6 weeks 
(q6w) and will receive computed tomography (CT) scans every 12 weeks [q12w] for up to 
96 weeks (Table 1). The duration of the surveillance period was selected based on 5-year DFS 
data across historic adjuvant studies (ANITA [Douillard et al 2006], BLT [Waller et al 2004], 
E1505 [Wakelee et al 2017], IALT Wakelee et al 2017], JBR.10 [Winton et al 2005]) in which 
DFS events were observed to be highest in years 1 and 2 and then plateaued. The 96-week 
surveillance strategy is expected to capture approximately 82% of NSCLC patients who suffer 
clinical relapse post-surgical resection, based on historical adjuvant studies. The predicted 
prevalence of patients with MRD is approximately 22% with 96-week surveillance. Tumor 
doubling times in metastatic solid tumors can be as low as 47 days (reported in colorectal liver 
metastases; Wiggans et al 2016). Data internally available to the Sponsor demonstrated that 
plasma sampling q6w to assess MRD status should capture approximately 
 of tumors with 
an estimated tumor burden 
. This assumption is based on an estimated 
 tumor 
doubling time in relapsing NSCLC and the observation that 1 cm3 of tumor burden results in 
an estimated ctDNA fraction in blood of ~0.01% (Abbosh et al 2017), close to the 
limit of detection of the MRD assay.
The premise of the MERMAID-2 study is to identify patients with the lowest possible tumor 
burden through detection of MRD and to provide treatment to these patients at an earlier 
timepoint. The window between detection of MRD and clinical relapse is short. Therefore, it 
is critical to minimize the time between the receipt of an MRD+ test result and randomization 
of a patient.
Patients who become MRD+ during surveillance (including cases where analysis of the first 
plasma sample collected [marking the start of surveillance] returns an MRD+ status) will 
undergo a second screening period, initiated by the signing of ICF2a (Table 2). Note: Patients 
who received prior neoadjuvant immunotherapy must be MRD- based on analysis of the first 
plasma sample collected (which marks the start of surveillance).
Patients should sign ICF2a as soon as their MRD+ result is available to immediately enter the 
second screening period. To ensure the duration of the second screening period is as short as 
possible, and to prevent any unforeseen delays in scheduling necessary scans, Investigator 
should proactively schedule CT and/or magnetic resonance imaging (MRI) scans of the 
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chest/abdomen and brain within 2 weeks following each q6w plasma collection. Thus, the 
baseline scans necessary to confirm eligibility will already be scheduled if testing of the 
plasma sample returns an MRD+ status. 
Once all additional inclusion and none of the exclusion criteria are met, patients will be 
eligible for randomization. Patients must be randomized as soon as possible after eligibility 
criteria are confirmed, and treatment must begin within 3 days of randomization (Table 2).
Approximately 284 MRD+ patients will be randomized 1:1 to treatment with durvalumab 
monotherapy 1500 mg or placebo every 4 weeks (q4w) intravenously (IV). Patients will be 
treated for up to a total of 24 months (26 cycles), until disease recurrence, or until other 
specific treatment discontinuation criteria are met (whichever comes first). The study will be 
fully blinded.
Based on internal Sponsor data from stage II-III resected patients, it is estimated that 
 of 
randomized patients will be PD-L1 TC≥1%. To ensure that the target of 
 PD-L1 TC≥1% 
patients are randomized in the study, enrollment of PD-L1 TC<1% patients into surveillance 
will end once 
 PD-L1 TC<1% patients have been randomized. The remaining PD-L1 
TC<1% patients will be immediately withdrawn from surveillance. Additional data will not be 
collected on these patients. Patients who are determined to be PD-L1 TC<1% during the first 
screening will not be eligible to continue to surveillance and will be considered screen failures 
(see Section 5.5). Please note that any PD-L1 TC <1% patient who is already in the 
observation arm will remain in the study.
Similarly, enrollment into the study will end once 284 MRD+ patients are randomized. 
Patients in surveillance will be immediately withdrawn from the study and additional data will 
not be collected on these patients. Please note that patients already in the observation arm will 
remain in the study.
Note: In the event the Sponsor withdraws patients from surveillance because the applicable 
cohort(s) have been filled, these patients may continue to receive CT scans every 12 weeks 
until 96 weeks have elapsed (relative to the start of surveillance) to honor the patient’s consent 
to q12w scans or until disease recurrence or primary DFS analysis (whichever occurs first). 
No additional data will be collected on these patients.
Up to 142 of the patients who complete their 96-week surveillance period, remain MRD-, and 
have no evidence of RECIST 1.1-defined disease recurrence may be eligible for entry into an 
observation period initiated by the signing of a separate informed consent (ICF2b; Table 4). 
These patients will be followed for serious adverse events (SAEs), DFS, OS, subsequent 
anticancer therapy, and MRD assessments for 24 months or until primary DFS analysis 
(whichever occurs first) after which patients will be followed for OS until the end of the study. 
Data from this cohort of patients will be compared to the patients randomized to placebo to 
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support the hypothesis that MRD can be used as a prognostic biomarker to identify patients at 
high risk of disease recurrence prior to radiologic evidence of disease.
Patients with evidence of RECIST 1.1-defined disease recurrence using Investigator 
assessments during the surveillance period will not be eligible for randomization and will no 
longer be followed as part of the study; however, data pertaining to their recurrence must be 
captured (see section 5.5).
Study period:
Estimated date of first patient randomized: Q1 2021
Estimated date of last patient completed: Q4 2025
Number of patients:
The study will plan to enroll approximately 1500 patients into surveillance and randomize 
approximately 284 MRD+ patients to treatment with durvalumab or placebo. The approximate 
number of enrolled patients is based on the anticipated emergence of MRD+ patients over the 
96-week surveillance period based on previously published data (Abbosh et al 2017) and data 
internal to the Sponsor, combined with published historic data (see above). Eligible MRD+ 
patients will be randomized in a 1:1 ratio to receive durvalumab monotherapy or placebo. 
Patients will be stratified by PD-L1 status (TC <1% vs TC ≥1%), time from start of 
surveillance to emergence of MRD (≤6 months vs >6 months), and prior neoadjuvant 
immunotherapy (Yes vs No). It is required that 170 randomized patients will be PD-L1 
TC≥1%. Therefore, once 114 PD-L1 TC<1% patients are randomized, the Sponsor will 
immediately withdraw all remaining PD-L1 TC<1% patients from surveillance and patients 
who are determined to be PD-L1 TC<1% during the first screening will not be allowed to 
enter surveillance.
In addition to the 284 MRD+ patients that will be treated with durvalumab or placebo, up to 
142 MRD- patients who have no evidence of RECIST 1.1-defined disease recurrence will 
enter an observation period for exploratory purposes after completion of their 96-week 
surveillance period.
Treatments and treatment duration
Durvalumab 1500 mg or placebo by IV infusion once q4w starting at Week 0 for up to a 
maximum of 24 months of treatment (up to 26 doses/cycles).
(Please note, if a patient’s weight falls to 30 kg or below [≤30 kg] during the treatment period, 
then the patient should receive weight-based dosing equivalent to 20 mg/kg of durvalumab or 
placebo q4w after consultation between Investigator and Study Physician, until the weight 


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improves to above 30 kg [>30 kg], at which point the patient should start receiving the fixed 
dosing of durvalumab or placebo 1500 mg q4w).
Duration of treatment
This study will use a 24-month treatment period (26 cycles of treatment). This study has 
selected a high-risk MRD+ population where prolonged adjuvant therapy is indicated. 
Treatment for 24 months is supported by early results from CheckMate 153, demonstrating 
that prolongation of nivolumab treatment beyond 12 months is beneficial in previously treated 
advanced NSCLC (Spigel et al 2017). In addition, 2 pembrolizumab studies (KEYNOTE-024 
and -042) evaluated treatment over 24 months in the front-line setting (Mok et al 2019, Reck 
et al 2016). Targeted agents have also been developed using a 24-month treatment regimen in 
the adjuvant setting (Zhong et al 2018).
Unless specific treatment discontinuation criteria are met, patients will be treated q4w with 
durvalumab or placebo for a total of 24 months (26 cycles) or until RECIST 1.1-defined 
disease recurrence (whichever comes first).
During the treatment period, patients who are clinically stable at an initial 
RECIST 1.1-defined disease recurrence may continue to receive study treatment at the 
discretion of the Investigator until the confirmatory, follow-up scan.
Post-treatment follow-up period
After completion of durvalumab or placebo treatment, patients will be followed for safety, 
MRD status, patient-reported outcomes (PROs), health economics, RECIST 1.1-defined 
disease recurrence, subsequent anticancer therapy, and survival status at specified intervals 
until the primary DFS analysis. Patients will be followed for safety and long-term survival 
until the end of the study.
Patients will not be eligible for retreatment at any time.
Follow-up of patients post discontinuation of investigational product
Patients who have discontinued treatment due to toxicity or symptomatic deterioration, 
clinical progression, or who have commenced subsequent anticancer therapy will be followed 
up with disease assessments until RECIST 1.1-defined disease recurrence plus an additional 
follow-up scan or until death (whichever comes first) and followed for survival until the end 
of the study. These patients are not eligible for retreatment at any time.
Survival assessments
All randomized patients and patients in observation should be followed up for survival until 
study completion. If OS data has not reached the required maturity per the timelines of the 
study, continued OS data collection and analysis may be performed in a roll-over study.


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Disease assessments
Efficacy assessments of the primary endpoint of DFS will be derived using Investigator 
assessments according to RECIST 1.1 and pre-specified definitions of disease recurrence (ie, 
local or regional recurrence, distant recurrence, second primary NSCLC) and by survival 
assessments. All patients will be followed for disease recurrence until the primary DFS 
analysis and followed for survival until the completion of the study. PFS and OS are 
secondary endpoints of the study.
Tumor evaluations utilize images from CT (preferred) or MRI, each preferably with IV 
contrast of the chest and abdomen (including liver and adrenal glands) collected during 
screening, at the start of surveillance, and at selected timepoints during the study duration. 
Any other areas of disease involvement should be additionally imaged based on the signs and 
symptoms of individual patients.
Data Monitoring Committee
An independent data monitoring committee (IDMC) comprised of independent experts will 
meet approximately 12 months after the first patient has been dosed with IP or after 
approximately 50 patients have received at least 1 dose of IP (whichever occurs first) to assess 
the safety and tolerability of durvalumab. The IDMC will review unblinded safety data and 
make recommendations to continue, amend, or stop the study based on safety findings. The 
timing of subsequent reviews will be determined by the IDMC but will not occur more 
frequently than every 6 months. The IDMC safety reviews will be conducted in an unblinded 
manner.
Full details of the IDMC procedures and processes can be found in the IDMC Charter.
Statistical methods:
The primary objective of the study is to compare the efficacy of durvalumab to placebo in 
terms of DFS, defined as time from the date of randomization until the date of disease 
recurrence (using Investigator assessments according to RECIST 1.1) or date of death due to 
any cause (whichever occurs first) in the PD-L1 TC≥1% analysis set. DFS in the full analysis 
set (FAS) is a secondary endpoint.
The FAS will include all randomized patients. The PD-L1 TC≥1% analysis set will include all 
patients in the FAS who are PD-L1 TC≥1% at baseline.
DFS will be analyzed using a stratified log-rank test. The treatment effect will be estimated in 
terms of the hazard ratio (HR) together with the corresponding 95% confidence interval (CI) 
from the Cox proportional hazard model stratified by PD-L1 status (TC<1% vs TC ≥1%), time 
from the start of surveillance (ie, the date the plasma sample used to determine a patient’s 
MRD status post-curative intent therapy is collected) to emergence of MRD (≤6 months vs 


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>6 months), and prior neoadjuvant immunotherapy (Yes vs No). For the primary analysis in 
the PD-L1 TC≥1% analysis set, the PD-L1 status (TC<1% vs TC ≥1%) stratification factor 
will not be included. The stratification factor covariates in the statistical modeling will be 
based on the values entered into interactive web response system (IWRS) at randomization, 
even if it is subsequently discovered that these values were incorrect. For the purpose of 
statistical analysis of the primary and relevant secondary endpoints, a plan for reducing the 
number of strata cells will be included in the statistical analysis plan (SAP) in case there are 
insufficient events in one level of any strata. Descriptive summaries and Kaplan-Meier curves 
and estimates will also be produced.
The study will plan to enroll approximately 1500 patients and randomize approximately
284 patients with stage II-III NSCLC and are MRD+, including at least 170 patients with 
PD-L1 TC≥1%. Patients will be randomized 1:1 to durvalumab or placebo. Randomization 
will be stratified by PD-L1 status (TC <1% vs TC≥1%), time from the start of surveillance to 
emergence of MRD (≤6 months vs >6 months), and prior neoadjuvant immunotherapy (Yes vs 
No).
The study is sized for the primary endpoint of DFS in the PD-L1 TC≥1% analysis set and for 
the secondary endpoint of DFS in the FAS.
The analysis of the primary endpoint (DFS) will occur when approximately 118 DFS events 
have occurred (69% maturity) in the PD-L1 TC≥1% analysis set. If the true DFS HR is 0.55 in 
the PD-L1 TC≥1% analysis set, the study will provide at least 90% power to demonstrate a 
statistically significant difference for DFS with overall 2-sided significance level of 5%; this 
translates to 3.2-month benefit in median DFS over 4 months on placebo, or 8.4% difference 
in 24-month DFS rate over 1.5% on placebo, if DFS is exponentially distributed. The smallest 
treatment difference that would be statistically significant is an HR of 0.7.
The study is also sized to provide at least 90% power for the DFS endpoint in the FAS. The 
analysis will be performed at the same time as the primary analysis, when it is expected that 
approximately 197 DFS events have occurred (69% maturity) in the FAS. If the true DFS HR 
is 0.63 in this population, this will provide at least 90% power to demonstrate a statistically 
significant difference for DFS, assuming overall 5% 2-sided significance level; this translates 
to a 2.3-month benefit in median DFS over 4 months on placebo, or 5.6% difference in 
24-month DFS rate over 1.5% on placebo, if DFS is exponentially distributed. The smallest 
treatment difference that would be statistically significant is an HR of 0.76.
It is estimated that the primary analysis for DFS will occur approximately 38 months after the 
first patient has been randomized assuming a 34-month recruitment period and allowing for 
patients to have a minimum follow-up of 4 months.


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In order to provide strong control of the type I error rate, α=5% (2-sided), a multiple testing 
procedure with gatekeeping strategy will be used across the primary endpoint of DFS in the 
PD-L1 TC≥1% analysis set and the secondary endpoint of DFS in the FAS, starting with 
testing the primary endpoint on the PD-L1 TC≥1% analysis set. The overall 5% alpha will be 
allocated to the analysis of DFS in the PD-L1 TC≥1% analysis set. If that analysis is 
significant, the 5% alpha will be recycled to the DFS endpoint in the FAS.
OS will be a secondary efficacy endpoint, 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. OS 
will analyzed at the time of the DFS analysis. In the PD-L1 TC≥1% analysis set if the true HR 
is 0.79 then it is anticipated that approximately 59 events (35% maturity) will have occurred. 
This translates to a 4.3 month benefit in median OS over 16 months on placebo. In the FAS if 
the true HR is 0.89 then it is anticipated that approximately 102 events (36% maturity) will 
have occurred. This translates to a 2 month benefit in median OS over 16 months on placebo. 
OS will be analyzed similarly to DFS.
A further analysis of OS will be performed at approximately 127 events (75% maturity) in the 
PD-L1 TC≥1% analysis set. At this time there is also expected to be approximately 218 events 
(77% maturity) in the FAS. It is anticipated this analysis will occur approximately 60 months 
after first patient is randomized. If events are accruing slower than expected then the data cut-
off (DCO) may occur 60 months after first patient is randomized regardless of number of 
events accrued.
Safety data will be summarized descriptively and will not be formally analyzed.
1.3
Schema
The general study design is summarized in Figure 1.


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Figure 1
Study design
a
Results from local EGFR/ALK testing of either a pre-surgery biopsy or the resected tumor tissue performed as part of standard care may be used for this 
study, provided testing was performed using a well-validated, local regulatory-approved kit. EGFR/ALK status can also be assessed by the central laboratory 
using either a pre-surgical biopsy or on resected tumor tissue from surgery if local testing is not available. Patients whose tumors are positive for EGFR 
mutations and/or ALK translocations will be excluded from the study. Only patients with wild-type status should provide a plasma sample for MRD 
assessment at the start of surveillance (see footnote f).
b
Patients will receive curative intent therapy (complete resection ± neoadjuvant and/or adjuvant therapy) as SoC within the clinics. Details of surgery and 
prior therapy will be captured in the appropriate section of the eCRF and will be included as a subgroup analysis. Please note that PORT can be included as 
part of adjuvant therapy and must be completed before starting surveillance. See Figure 2 for potential scenarios for permissible curative therapy in this 
study.


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c
ICF1 can be signed during or immediately following the completion of curative intent therapy and should be signed as soon as possible to allow the Sponsor 
access to the biosamples required for creation of the personalized panel for MRD detection (see footnote d) and for central testing of EGFR/ALK and/or 
PD-L1 (if required, see footnotes a and e).
d
The whole blood and resected tumor tissue samples must be sent as soon as possible after ICF1 is signed but no later than 1-2 weeks after completion of 
adjuvant therapy or 3-5 weeks after surgery (if no adjuvant therapy is given) to enable creation of the personalized panel for MRD detection.
e
PD-L1 status must be known prior to and is required for randomization.
f
Surveillance is initiated once the first plasma sample used to determine MRD status is collected (approximately 8±1 weeks after completion of adjuvant 
therapy or up to 12±1 weeks post-surgery [if no adjuvant therapy is given; See Figure 2]).
g
If scans conducted during the first screening or during surveillance demonstrates evidence of RECIST 1.1-defined disease recurrence and/or metastatic 
disease, the patient is considered a screen failure (section 5.5) and is no longer eligible to participate in the study
h
Before an MRD+ patient can be randomized, a CT scan of the chest and abdomen (including liver and adrenal glands) and a brain MRI (preferred) or brain 
CT with IV contrast must be performed to confirm no evidence of disease recurrence and/or metastatic disease.
i
During surveillance, patient visits will occur q6w±3d for plasma collection and q12w±1w for CT scans.
ALK Anaplastic lymphoma kinase; DFS Disease-free survival; EGFR Epidermal growth factor receptor; ICF Informed consent form; MRD Minimal residual 
disease; N number; NSCLC Non-small cell lung cancer; OS Overall survival; PD-L1 Programmed cell death ligand-1; q4w Every 4 weeks; R Randomization; 
WES whole exome sequencing.


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Potential scenarios for permissible curative intent therapy are shown in Figure 2. Please note that 
only one course of standard of care (SoC) chemotherapy (eg, 4 cycles of platinum-based 
chemotherapy) is allowed in the adjuvant setting. In addition, adjuvant therapy may include 
post-operative radiotherapy (PORT).
All patients should be consented as soon as possible after surgery (Scenarios 1 and 2) but may be 
consented during adjuvant therapy (Scenarios 3 and 4) to ensure that the creation of the 
personalized panel for MRD detection and epidermal growth factor receptor (EGFR), anaplastic 
lymphoma kinase (ALK), and PD-L1 testing are not rate-limiting and patients are able to enter 
surveillance within the appropriate timeframe.
The 96-week surveillance period must begin within 8 ± 1 weeks of completion of adjuvant 
therapy or within 12 ± 1 weeks post-surgery (if no adjuvant therapy is administered).
Figure 2
Potential scenarios for permissible curative intent therapy
*Adjuvant therapy may include post-operative radiotherapy (PORT).
The resected tumor tissue and whole blood samples should be sent to the diagnostic laboratory as soon as possible, 
as they are critical for the development of the personalized panel for MRD detection. The white arrow indicates 
latest time these samples can be sent to the diagnostic laboratory (ie, 3-5 weeks after surgery [Scenario 1 or 2] or 1-2 
weeks after the completion of adjuvant therapy [Scenario 3 or 4]). 
The black arrow indicates when the first surveillance plasma sample should be collected and marks the start of 
surveillance. Surveillance should start by 12 ± 1 weeks for Scenario 1 or 2 by 8 ± 1 weeks for Scenario 3 or 4.


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Table 5
Inclusion criteria assessment relative to first and second screening 
periods
First screening (initiated by the signing of ICF1)
(Section 5.1.1)
Second screening (initiated by MRD+ status and 
the signing of ICF2a)
(Section 5.1.2)
Criteria for surgical planning
Imaging of chest/abdomen and brain within 6 
weeks prior to surgery
Criteria for curative intent therapy
•
Complete resection
•
Undergone (or be undergoing) curative intent 
therapy (which may include neoadjuvant ± 
adjuvant therapy)a
Criteria for entering surveillance
•
ICF1 signed prior to initiation of screening 
and surveillance activities
•
Age ≥18 years
•
Male and/or female
•
Diagnosis of histologically confirmed NSCLC 
with resectable (Stage IIA to select [ie, T3N2 
or T4N2] Stage IIIB) diseaseb
•
Confirmation of resected tumor tissue and 
whole blood sample appropriate for WES for 
creation of the personalized panel required for 
the MRD assayc
•
Plasma sample marking start of surveillance 
collected 8±1w after completion of adjuvant 
therapy or 12±1w post-surgery for patients not 
receiving adjuvant therapy.
Patient who is MRD- at start of surveillance 
and remains MRD- based on subsequent 
MRD tests continues in surveillance.
Patient who is MRD+ at start of surveillance 
may be eligible to enter second 
screening (initiated by the signing of 
ICF2a). If a patient has not received any 
adjuvant therapy (scenario 2, Figure 2), 
these patients are ideal candidates for 
the MERMAID-1 (D910LC00001) 
companion study. Investigators are 
asked to consider these patients for 
MERMAID-1. If the Investigator feels 
that the best course of action is to 
proceed with screening into MERMAID-
2, the Investigator is asked to consult 
with the study physician on the study.

Note: Patient who received prior 
neoadjuvant immunotherapy must be 
MRD- based on analysis of the first 
plasma sample collected (which 
marks the start of surveillance) in 
order to continue in the study
Criteria for randomization (must be met within 
28 days ± 7 days prior to randomization)
•
ICF2a signed after determination of MRD+ 
status but prior to final screening and 
randomization
•
Known PD-L1 status as determined by central 
laboratoryd
•
No evidence of RECIST 1.1-defined disease 
recurrence confirmed by CT and/or MRIe
•
WHO/ECOG PS 0 or 1
•
If no adjuvant therapy administered: 
Completed postoperative wound healing
•
If adjuvant therapy administered: Must have 
recovered from all acute, reversible toxic 
effects from chemotherapy that could 
potentially adversely impact further 
administration of durvalumab or placebo 
according to the Investigator’s judgment
•
Adequate organ and marrow function based 
on specified criteria
•
Life expectancy >12 weeks
•
Body weight >30 kg


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Table 5
Inclusion criteria assessment relative to first and second screening 
periods
First screening (initiated by the signing of ICF1)
(Section 5.1.1)
Second screening (initiated by MRD+ status and 
the signing of ICF2a)
(Section 5.1.2)
Patient who becomes MRD+ during any 
MRD test conducted during surveillance 
may be eligible to enter second 
screening (initiated by the signing of 
ICF2a)
•
No evidence of RECIST 1.1-defined disease 
recurrence confirmed by CT and/or MRIc
•
Consents to be accessible for q6w±3d plasma 
collection and for q12w±1w scans during the 
96-week surveillance period
a
Patients who discontinue chemotherapy for toxicity prior to completion of all planned chemotherapy 
are eligible. Patients who have not received any neoadjuvant and/or adjuvant therapy, and meet all other 
eligibility criteria, may be eligible under protocol-specified circumstances (see Section 5.1.1).
b
Select stage IIIB (ie, T3N2 or T4N2) patients will be eligible, provided they are upstaged to T3N2 or 
T4N2 based on confirmed pathology after surgery. Patients who are staged as T3N2 or T4N2 prior to 
surgery are not eligible.
c
If a CT scan of the chest and abdomen (including liver and adrenal glands) conducted either prior to the 
start of surveillance or during surveillance shows evidence of RECIST 1.1-defined disease recurrence, 
the patient is a screen fail and is no longer eligible to participate in the study (see section 5.5).
d
Patients entering MERMAID-2 (D910MC00001) after participating and subsequently screen-failing 
MERMAID-1 (D910LC00001) may be able to use their personalized panel for MRD detection and 
associated data as well as their previously determined PD-L1 status for this study. See section 5.4 for 
details.
e
Before an MRD+ patient can be randomized, a contrast-enhanced CT scan of the chest and abdomen 
(including liver and adrenal glands) and a brain MRI (preferred) or brain CT with IV contrast must be 
performed to confirm no evidence of disease recurrence and/or metastasis. For a patient who is MRD+ 
at the start of surveillance scans do not need to be repeated during the second screening period if the 
post-curative intent therapy scans (ie, the scans conducted prior to the start of surveillance [Table 1]) 
was conducted within 28 days ± 7 days prior to randomization. If a patient becomes MRD+ during 
surveillance, a CT scan of the chest and abdomen conducted during surveillance may be used as the 
baseline scan, provided it was performed within 28 days ± 7 days prior to randomization. A brain MRI 
or brain CT with IV contrast must performed prior to randomization. If the previously performed scans 
fall outside of this window, additional scans of the chest, abdomen, and brain must be performed before
the patient is randomized to confirm no evidence of disease recurrence and/or metastasis.
For details on each criterion, refer to the full list of inclusion criteria in Sections 5.1.1 (first screening) and 
5.1.2 (second screening).
CT Computed tomography; d Day; ECOG Eastern Cooperative Oncology Group; ICF1 Informed consent 
form 1; ICF2a Informed consent form 2a; IV Intravenous; MRD Minimal residual disease; MRD+ MRD-
positive; MRD- MRD-negative; MRI Magnetic resonance imaging; NSCLC Non-small cell lung cancer; 
PD-L1 Programmed cell death ligand 1; PS Performance status; q6w Every 6 weeks; q12w Every 
12 weeks; RECIST Response Evaluation Criteria in Solid Tumors; WES Whole exome sequencing; w 
Week; WHO World Health Organization


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Table 6
Exclusion criteria assessment relative to first and second screening 
periods
First screening
Second screening
•
EGFR and/or ALK mutant on pre-surgical 
biopsy or resected tumor tissuea
•
Mixed small cell and NSCLC pathology
•
Require re-resection or are deemed to have 
unresectable NSCLC
•
History of allogeneic organ or bone marrow 
transplantation
•
Non-leukocyte-depleted whole blood 
transfusion in 120 days of genetic sample 
collection
•
Active or prior documented autoimmune or 
inflammatory disorders
•
Uncontrolled intercurrent illness
•
History of another primary malignancy (with 
specified exceptions)
•
Received any radiotherapy in the neoadjuvant 
setting
•
Received any IO therapy in adjuvant setting
•
Prior exposure to durvalumab
•
Any concurrent chemotherapy, IP, biologic, or 
hormonal therapy for cancer treatment
•
Previous IP assignment in the present study
•
Active or prior documented autoimmune or 
inflammatory disorders
•
Baseline imaging demonstrating RECIST 1.1-
defined disease recurrence or other evidence 
of clinical recurrence
•
Uncontrolled intercurrent illness
•
History of active, primary immunodeficiency
•
Active infection including tuberculosis, HBV, 
HCV, HIV
•
Brain metastases or spinal cord compression
•
Known allergy or hypersensitivity to any of 
the IPs
•
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 IP
•
Receipt of live attenuated vaccine within 30 
days prior to the first dose of IP
•
Major surgical procedure (as defined by the 
Investigator) within 28 days prior to the first 
dose of IP
•
Current or prior use of immunosuppressive 
medication within 14 days before the first 
dose of IP
•
Previous IP assignment in the present study
•
Concurrent enrollment in another clinical 
study, unless observational (non-
interventional) or follow-up period of an 
interventional study
•
Prior randomization/treatment in previous 
durvalumab clinical study regardless of 
treatment arm assignment
•
Female who is pregnant or breastfeeding or 
male or female patients of reproductive 
potential who are not willing to employ 
effective birth control from second screening 
to 90 days after the last dose of IP
•
Judgment by Investigator that the patient 
should not participate in the study
a
Patients entering MERMAID-2 (D910MC00001) after participating and subsequently screen-failing 
MERMAID-1 (D910LC00001) may be able to use the results from prior EGFR/ALK testing for this 
study. See section 5.4 for details.
For details, see the full list of exclusion criteria in Section 5.2. Some criteria must be checked during both 
screening periods and therefore appear twice in this table.
ALK Anaplastic lymphoma kinase; EGFR Epidermal growth factor receptor; HBV Hepatitis B virus; 
HCV Hepatitis C virus; HIV Human immunodeficiency virus; IO Immuno-oncologic; IP Investigational 
product; NSCLC Non-small cell lung cancer; RECIST Response Evaluation Criteria in Solid Tumors.


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2
INTRODUCTION
2.1
Study rationale
Up to 30% of patients with NSCLC present with surgically resectable disease (Molina et al 
2008). For patients with stage II-III disease, surgery and adjuvant SoC chemotherapy 
results in 5-year DFS rates of only ~40% (Wakelee et al 2017). Adjuvant chemotherapy 
following resection of NSCLC is standard practice to reduce risk of disease recurrence. 
Further benefit has been obtained with immune-oncologic (IO) therapy, including 
durvalumab (Antonia et al 2018). However, even with these improvements, most patients 
will experience disease recurrence and ultimately die. There is evidence that detection of 
MRD by measurement of ctDNA post-surgery can accurately predict disease recurrence 
(Abbosh et al 2017, Chaudhuri et al 2017). Determination of MRD in lung cancer through 
ctDNA detection has been investigated in 2 studies. In TRACERx, the presence or absence 
of ctDNA was evaluated in plasma samples taken from patients who had undergone 
surgical resection for stage I-III NSCLC. In 13 of 14 patients who experienced disease 
recurrence following surgical resection, MRD was detected using ctDNA before or at 
clinical detection of disease recurrence diagnosed through follow-up assessments (Abbosh 
et al 2017). An additional study of lung cancer patients (the majority of whom had 
undergone curative intent therapy including a complete resection) post-intervention ctDNA 
was detectable in 20 of 37 patients; all 20 patients ultimately recurred and MRD was 
detectable earlier using ctDNA than when using SoC radiological imaging (Chaudhuri et al 
2017).
Durvalumab can be effective in situations of residual cancer as evidenced by improved 
PFS and OS observed with durvalumab versus placebo following definitive concurrent 
chemoradiation in the PACIFIC study (Antonia et al 2018, Gray et al 2019). Moreover, 
intervention with combination chemotherapy and immunotherapy versus chemotherapy 
alone improves PFS and OS in advanced NSCLC (Gandhi et al 2018, Gadgeel et al 2019, 
Paz-Ares et al 2018). These data suggest that earlier intervention with immunotherapy as 
adjuvant therapy following curative intent treatment could improve outcomes in early-
stage NSCLC, prevent progression, and circumvent the need to expose patients to 
potentially more toxic chemotherapy regimens in the metastatic setting.
This study is designed to assess whether detection of MRD via ctDNA isolation after 
complete resection ± neoadjuvant and/or adjuvant therapy (Figure 2) for stage II-III 
NSCLC identifies a high risk patient population that would receive benefit from additional 
adjuvant therapy. In addition, this study tests the research hypothesis that adjuvant 
durvalumab monotherapy will be more effective than placebo in treating this patient 
population.
From CSP v2.0 implementation at site, please use Section 10 as a reference point for the 
study. This study has closed enrolment early and patients will either start durvalumab 
(as open-label treatment) or be discontinued from the study.


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2.2
Background
A detailed description of the chemistry, pharmacology, efficacy, and safety of durvalumab 
is provided in the IB.
2.2.1
Immunotherapies
It is increasingly understood that cancers are recognized by the immune system, and under 
some circumstances, the immune system may control or even eliminate tumors (Dunn et al 
2004).
Programmed cell death ligand-1 (PD-L1) is part of a complex system of receptors and 
ligands that are involved in controlling T-cell activation. The programmed cell death-1 
(PD-1) receptor (cluster of differentiation [CD]279) is expressed on the surface of 
activated T cells (Keir et al 2008). It has 2 known ligands: PD-L1 (B7-H1; CD274) and 
programmed cell death ligand-2 (PD-L2) (B7-DC; CD273) (Okazaki and Honjo 2007). 
PD-1 and PD-L1/PD-L2 belong to a 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 antitumor activity.
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a 
way of evading immune detection and elimination. The binding of an anti-PD-L1 agent to 
the PD-L1 receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors 
expressed on immune cells. This activity overcomes PD-L1-mediated inhibition of 
antitumor immunity. While functional blockade of PD-L1 results in T-cell reactivation, 
this mechanism of action is different from direct agonism of a stimulatory receptor such as 
CD28.
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti-PD-L1 
antibody could be used therapeutically to enhance antitumor immune responses in patients 
with cancer. Results of pre-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, 


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Zhong et al 2018, 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 (eg, in bladder carcinoma; Alexandrov et al 
2013) may contribute to the responses seen with immune therapy.
Pre-clinical data has now been added to a wealth of clinical data showing that blockade of 
negative regulatory signals to T cells such as cytotoxic T-lymphocyte-associated antigen 4 
(CTLA-4) and PD-L1 has promising clinical activity. Ipilimumab was first granted United 
States (US) FDA approval for the treatment of metastatic melanoma and is currently under 
investigation for several other malignancies. Nivolumab and pembrolizumab, 2 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 NSCLC, squamous cell carcinoma of the head and neck, and 
urothelial carcinoma. In addition, there are data from agents in the anti-PD-1/PD-L1 class 
showing clinical activity in a wide range of tumor types.
2.2.2
Durvalumab
Durvalumab is a human mAb of the immunoglobulin G (IgG) 1 kappa subclass that blocks 
the interaction of PD-L1 (but not programmed cell death ligand-2) with PD-1 on T cells 
and CD80 (B7.1) on immune cells (IC). It is being developed by AstraZeneca. The 
proposed mechanism of action for durvalumab is interference in the interaction of PD-L1 
with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions 
releases the inhibition of immune responses, including those that may result in tumor 
elimination. In vitro studies demonstrate that durvalumab antagonizes the inhibitory effect 
of PD-L1 on primary human T cells resulting in the restored proliferation of 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
 patients as part of completed and 
ongoing studies either as monotherapy or in combination with other anticancer agents. 
Details on the safety profile of durvalumab monotherapy are summarized in Section 4.2.1
and Section 8.3.12. Refer to the current durvalumab IB for a complete summary of 
pre-clinical and clinical information including safety, efficacy, and pharmacokinetics (PK).
2.2.3
Non-small cell lung cancer and unmet need
Lung cancer is the most common cancer and the most common cause of death from cancer 
in the world, with an estimated 2.1 million new cases (11.6% of all new cancers) and 
1.8 million deaths (18.4% of cancer deaths) in 2018 (GLOBOCAN 2018). NSCLC 
represents 80% to 85% of all lung cancers (Pisters and LeChevalier 2005) and up to 30% 
of these patients present with surgically resectable disease (Molina et al 2008).
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Despite presentation with resectable disease, surgery and adjuvant SoC chemotherapy 
results in a 5-year DFS rate of only ~40% in stage II and III NSCLC (Wakelee et al 2017). 
Following disease recurrence, long-term survivorship is rare, ranging from 2% to 13% at 
5 years (Wong et al 2016, Sekihara et al 2017, McMurry et al 2018). Adjuvant 
chemotherapy following resection of NSCLC is standard practice to reduce risk of disease 
recurrence. In stage III disease, a 5-year OS benefit of up to 15% has been observed with 
adjuvant cisplatin and vinorelbine (Pignon et al 2008). Additional adjuvant chemotherapy 
regimens have shown similar benefits, as reflected in national guidelines (NCCN 2019). 
However, although adjuvant chemotherapy following resection of NSCLC provides 
important benefits, most patients will experience disease recurrence and ultimately die. 
Identifying patients who would benefit from additional treatment in the adjuvant setting 
represents an important unmet need.
2.2.3.1
Value of anti-PD-1 and anti-PD-L1 monotherapy in NSCLC
Immunotherapy has changed the landscape of advanced NSCLC treatment (Martinez et al 
2019). Randomized controlled studies of mAbs targeting PD-1 first demonstrated benefit 
in second or later line metastatic NSCLC setting in 2015, with nivolumab improving 
survival versus docetaxel in patients with both squamous and non-squamous NSCLC 
(Brahmer et al 2015, Borghaei et al 2015, Horn et al 2017). Subsequent clinical trials 
reported that first-line treatment of metastatic NSCLC with anti-PD-1 monotherapy 
demonstrated an OS benefit compared with chemotherapy alone in patients whose tumors 
expressed PD-L1 (Spigel et al 2019, Mok et al 2019, Reck et al 2016, Reck et al 2019). 
However, CheckMate 026 did not demonstrate a benefit of nivolumab versus
platinum-based chemotherapy in patients with advanced untreated NSCLC and PD-L1 
tumor proportion score (TPS)≥1%, analyses in PD-L1 TPS>5% and TPS>50% populations 
also failed to show a benefit of intervention with nivolumab over platinum-based 
chemotherapy (Carbone et al 2017).
The PACIFIC study randomized unresectable stage III patients to receive durvalumab or 
placebo following definitive radiotherapy, irrespective of primary tumor PD-L1 status 
(Antonia et al 2018). Patients randomized to durvalumab consolidation therapy 
experienced improved PFS (HR 0.52 [95% CI 0.42, 0.65], p<0.001, 16.8 months versus 
5.8 months) and OS (HR 0.68 [95% CI 0.53, 0.87], p=0.00251 (Antonia et al 2018). 
Updated analyses revealed that 3-year OS rate in the durvalumab-treated patients was 57% 
versus 43.5% in the placebo group (Gray et al 2019). The results from PACIFIC provide a 
rationale for anti-PD-L1 as a consolidation therapy following definitive treatment of 
NSCLC capable of improving long-term OS outcomes by effectively treating patients with 
low tumor burden. Moreover, anti-PD-(L)1 agents have demonstrated clinically 
meaningful responses in metastatic NSCLC, with some patients exhibiting durable 
responses even after discontinuing therapy (Martinez et al 2019). Ongoing studies are 
assessing the efficacy of adjuvant immunotherapy in NSCLC (eg, IMpower-10, 
KEYNOTE-091, BR.31, ANVIL, and MERMAID-1 [D910LC00001]).


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2.2.3.2
Minimal residual disease detection in NSCLC
Detection of MRD, as indicated by the presence of ctDNA, may reveal the existence of 
clinically indiscernible residual tumor following curative intent therapy (completed 
resection ± neoadjuvant and/or adjuvant therapy). Detection of MRD at a time when there 
is no radiologic evidence of disease provides an opportunity for earlier therapeutic 
intervention (Abbosh et al 2018). MRD+ patients experience inferior recurrence-free 
survival compared to MRD- patients. Therefore, MRD+ patients may benefit from earlier 
intervention and escalation of treatment, including immunotherapy alone or in combination 
with chemotherapy; furthermore, MRD- patients (the majority of whom are cured by 
surgery alone) could be spared from more intensive therapy and the resulting unnecessary 
toxicity. This MRD-driven treatment hypothesis is currently under investigation in 
MERMAID-1 (D910LC00001) in stage II-III NSCLC patients who are determined to be 
MRD+ post-surgery (landmark MRD+).
MRD detection in lung cancer via isolation of ctDNA has been investigated in 2 studies. In 
the TRACERx study, the presence or absence of ctDNA was evaluated in plasma samples 
taken from patients who had undergone surgery for stage I-III NSCLC. In 13 of 14 patients 
who underwent surgical resection of their tumors and subsequently suffered post-operative 
relapse of their disease, MRD was detected either before or at the point of clinically 
evident disease recurrence (through SoC imaging or presentation of symptoms). In all 
12 patients who did not experience post-operative disease recurrence, MRD was not 
detected following surgery (Abbosh et al 2017). In the other study, MRD was detectable in 
20 of 37 lung cancer patients, the majority of whom had undergone curative intent therapy 
with chemotherapy and/or radiotherapy. All 20 MRD+ patients ultimately recurred, 
whereas the 17 MRD- patients did not experience a progression event (Chaudhuri et al 
2017). Detection of MRD preceded radiographic progression in 72% of patients by a 
median of 5.2 months (Chaudhuri et al 2017). These studies demonstrate the potential 
utility of MRD detection for identifying patients who are at high risk of experiencing 
disease recurrence.
Technically, MRD detection is challenging due to the ultra-low frequency of ctDNA 
molecules in cell-free DNA (Abbosh et al 2018). In this study, the Sponsor will leverage 
an advanced, sensitive, personalized assay predicated on sequencing excised primary 
tumor alongside a whole blood sample to derive a patient-specific MRD signature. This 
approach will lead to optimal capture of MRD+ patients during surveillance after SoC 
curative intent therapy.
2.2.3.3
Rationale for early interception studies predicated on MRD
Long-term survival can be improved through administration of chemotherapy in the 
immediate post-operative setting (Pignon et al 2008), yet chemotherapy in the first-line 
metastatic setting results in no long-term survival benefit and PFS benefits of only a small 
number of months (Cochrane Review 2000). Intervention with consolidation durvalumab 
following definitive chemoradiation in unresectable stage III NSCLC resulted in improved 
OS outcomes in an all-comers PD-L1 TPS population (Antonia et al 2018). Together, these 


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data highlight that the residual disease left after curative intent therapy is vulnerable to 
additional adjuvant therapy and thereby provide rationale to escalate this consolidation 
therapy in these patients in order to intercept relapsing NSCLC when tumor burden is low.
In metastatic NSCLC, the combination of chemotherapy and IO therapy is an established 
treatment option, particularly in patients whose tumors exhibit PD-L1 TPS <50% and who 
lack targetable driver mutations (Gandhi et al 2018, Paz-Ares et al 2018). However, this 
combination leads to an increased rate of treatment discontinuation due to toxicity. For 
example, in KEYNOTE-407 study, 13.3% of patients treated with chemotherapy and IO 
therapy discontinued treatment due to toxicity, compared to only 6.4% in the 
chemotherapy-only arm (Paz-Ares et al 2018). Interception of relapsing NSCLC with 
maintenance anti-PD-(L)1 monotherapy could improve DFS while sparing patients the 
toxicity associated with combination treatment for recurrent disease. MRD detection 
provides a solution to these challenges by facilitating adjuvant studies in smaller, more 
relevant MRD+ patient populations where adjuvant treatment can be escalated due to the 
high probability of disease recurrence. Two studies conducted in patients with either 
NSCLC or urothelial cancer showed that patients treated with durvalumab had a reduction 
in ctDNA at 6 weeks that was associated with tumor shrinkage and improved PFS and OS 
(Raja et al 2018). Similar correlation between ctDNA and outcomes have been reported in 
other studies of agents that target EGFR (Friends of Cancer Research White Paper 2018). 
These findings suggest that on-treatment ctDNA clearance could be established as a 
surrogate endpoint of therapeutic response to adjuvant intervention, thereby facilitating 
accelerated clinical adoption of novel treatment options that prove to be efficacious in this 
setting.
2.2.3.4
MRD monitoring following surgery and other curative therapy
In this study, patients will be monitored for MRD over a 96-week surveillance period 
beginning post-surgery and completion of other curative therapy (complete resection ± 
neoadjuvant and/or adjuvant therapy). Historic NSCLC adjuvant trials demonstrate that 
~75% of the total number of 5-year DFS events occur within the first 2 years following 
surgery (Wakelee et al 2017, Douillard et al 2006, Waller et al 2004, Arriagada et al 2004). 
This provides a rationale for 96-week MRD surveillance which should theoretically 
capture the majority of NSCLC recurrence events.
Tumor doubling times in metastatic solid tumors can be as low as 47 days (reported in 
colorectal liver metastases) (Wiggans et al 2016). A study of NSCLC brain metastases 
demonstrated tumor doubling times of 58.5 days (Yoo et al 2008). Since NSCLC tumor 
burden correlates with concentration of ctDNA in blood (Abbosh et al 2017), it was 
determined that tumor burden and consequently ctDNA could rise quickly in a relapse 
setting. Therefore, in order to capture disease recurrence at the lowest possible tumor 
volume to intervene with durvalumab adjuvant therapy, q6w monitoring using the 
Sponsor-approved panel for MRD detection will be used.


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2.3
Benefit/risk assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of durvalumab monotherapy may be found in the IB.
See Section 9.6.1 and Appendix A for information regarding the IDMC.
2.3.1
Potential benefits of durvalumab
The majority of the safety and efficacy data currently available for durvalumab are based 
on the first-in-human, single-agent study 
 
in patients with advanced solid tumors, the study of durvalumab monotherapy in NSCLC 
, 
, 
 
 and the study of durvalumab monotherapy in NSCLC 
following completion of platinum-based chemotherapy concurrent with radiation therapy 
. Data from these studies have demonstrated clinical 
activity of durvalumab therapy in patients with NSCLC. Details pertaining to these studies 
are provided in the durvalumab IB. Additionally, recent data from D419MC00004 
(POSEIDON) show a benefit of durvalumab plus platinum-based chemotherapy in 
metastatic NSCLC when administered in the first-line setting (AstraZeneca press release 
2019; Johnson et al 2021).
2.3.2
Overall risks
Monoclonal antibodies directed against immune checkpoint proteins, such as PD-L1 as 
well as those directed against PD-1 or CTLA-4, aim to boost endogenous immune 
responses directed against tumor cells. By stimulating the immune system, however, there 
is the potential for adverse effects on normal 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 that 
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 diarrhea, pneumonitis/interstitial lung disease (ILD), hepatic AEs such as liver 
enzyme elevations, skin events such as rash and dermatitis, and endocrinopathies including 
hypo- and hyper-thyroidism.
2.3.2.1
Durvalumab
Risks with durvalumab include, but are not limited to, diarrhea/colitis, pneumonitis/ILD, 
endocrinopathies (ie, 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, myocarditis, 
myositis/polymyositis, infusion-related reactions, hypersensitivity reactions, pancreatitis, 
serious infections, and other rare or less frequent inflammatory events including 
neuromuscular toxicities (eg, Guillain-Barre syndrome, myasthenia gravis).
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For information on all identified and potential risks with durvalumab, please always refer 
to the current version of the durvalumab IB.
In monotherapy clinical studies, including a study in unresectable NSCLC in which 
patients received durvalumab following concurrent SoC platinum-based 
chemoradiotherapy (PACIFIC), 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 Common Terminology 
Criteria for Adverse Events (CTCAE) Grade 3 to 5 events reported across the durvalumab 
program.
The majority of treatment-related AEs were manageable, with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of 
established treatment guidelines for immune-mediated toxicity (see Section 8.4.5).
A detailed summary of durvalumab monotherapy AE data can be found in the current 
version of the durvalumab IB.
2.3.3
Overall benefit/risk
Recent progress in immunotherapy for NSCLC has been a substantive advance, although 
further improvement is needed. However, up to 60% of patients will still experience 
disease recurrence. Novel treatment approaches are needed to improve the long-term 
prognosis for patients with early-stage NSCLC. Identification of patients who will benefit 
from immunotherapy in the adjuvant setting following curative intent therapy could lead to 
improved outcomes. Early studies of immunotherapy in the neoadjuvant setting in patients 
with resected NSCLC have shown promising clinical activity as well as acceptable safety 
profiles (Forde et al 2018; Shu et al 2018). Data from PACIFIC demonstrated the efficacy 
and tolerability of durvalumab administered after completion of platinum-based adjuvant 
chemotherapy (Antonia et al 2018). Therefore, in this Phase III study, the administration of 
durvalumab monotherapy compared to placebo will be investigated in patients with stage 
II-III NSCLC who are or become MRD+ following curative intent therapy.
The study design aims to minimize potential risks. For example, a safety evaluation by an 
IDMC will take place to assess whether durvalumab may adversely impact post-operative 
or post-treatment outcomes; the IDMC will report back to the Sponsor.
Therefore, based upon the available nonclinical and clinical safety data and the mitigations 
designed for this study, the investigation of the potential therapeutic efficacy and safety of 
durvalumab monotherapy following completion of curative intent therapy is acceptable in 
patients with completely resected NSCLC and the overall benefit/risk assessment supports 
the proposed study design.
Note for CSP v2.0: There is no change to the overall benefit/risk assessment of the 
study.


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3
OBJECTIVES AND ENDPOINTS
From CSP v2.0 implementation at site, please use Section 10 as a reference point for the 
study. This study has closed enrolment early and patients will either start open-label 
durvalumab or be discontinued from the study.
The objectives and endpoints have been updated for CSP v2.0. All analyses of the 
objectives and endpoints will be descriptive only and considered exploratory. Please see 
Section 10.4 for additional information.
Table 7
Study objectives and endpoints/variables
Primary objective:
Endpoint/variable:
To assess the efficacy of durvalumab compared to 
placebo as measured by DFS in all randomized 
patients
DFS in FAS (using Investigator assessments 
according to RECIST 1.1)
Secondary/safety objective:
Endpoint/variable:
To assess the safety and tolerability profile of 
durvalumab monotherapy compared with placebo
AEs, physical examinations, vital signs, and 
laboratory findings
Exploratory objectives:
Endpoint/variable:
To assess the efficacy of durvalumab compared to 
placebo as measured by DFS in the PD-L1 TC≥1% 
analysis set
DFS in PD-L1 TC≥1% (using Investigator 
assessments according to RECIST 1.1)
To assess the efficacy of durvalumab compared to 
placebo on post-recurrence outcomes
PFS (using local standard practice)
To assess the efficacy of durvalumab compared to 
placebo as measured by OS in the PD-L1 TC≥1% 
analysis set and in all randomized patients
OS in PD-L1 TC≥1% and in FAS
To assess patient-reported symptoms, functioning, 
and HRQoL in patients treated with durvalumab 
compared to placebo
Change from baseline and time to deterioration in 
EORTC QLQ-C30 and EORTC QLQ-LC13
To investigate the relationship between a patient’s 
baseline PD-L1 TC expression and efficacy of 
study treatments
IHC analysis of PD-L1 TC expression and spatial 
distribution within the tumor microenvironment 
relative to efficacy outcomes (ie, DFS, OS)
To assess the efficacy of durvalumab monotherapy 
to clear ctDNA compared to placebo
ctDNA endpoints, as defined by:
•
Best overall clearance rate (number converted 
at any time)
•
Best confirmed clearance rate (as above but 
confirmed at subsequent visit)
•
Time to ctDNA clearance
•
Duration of ctDNA clearance
•
Time to ctDNA recurrence
•
Time to confirmed ctDNA recurrence
•
Changes in variant allele frequencies (VAF) 
following treatment
To assess the relationship between treatment effect 
on DFS and treatment effect on ctDNA endpoints
ctDNA endpoints (as defined above) and DFS
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4
STUDY DESIGN
From CSP v2.0 implementation at site, please use Section 10 as a reference point for the 
study. This study has closed enrolment early (with a total of 416 patients having signed 
informed consent) and patients will either start open-label durvalumab or be 
discontinued from the study.
The section below refers to the original study design. Microbiome analysis has been 
removed and the end of study definition section has been amended. Refer to Section 10.1
for the rationale for changes under CSP v2.0.
4.1
Overall design
For an overview of the study design see Figure 1, Section 1.3. For details on treatments 
given during the study, see Section 6.1.
For details on what is included in the efficacy and safety endpoints, see Section 3
Objectives and Endpoints.
This is a Phase III, randomized, multicenter, double-blind, placebo-controlled study to
evaluate the efficacy and safety of durvalumab adjuvant therapy compared to placebo in 
patients with stage II-III NSCLC who have undergone curative intent therapy (complete 
resection ± neoadjuvant and/or adjuvant therapy), who have no evidence of RECIST 1.1-
defined disease recurrence, and who become MRD+ during a 96-week surveillance period.
The study will screen approximately 1500 patients and randomize approximately 284 
MRD+ patients with stage II-III NSCLC (according to IASLC Staging Manual in Thoracic 
Oncology v8.0) (select Stage IIIB [T3N2 or T4N2] patients) whose tumors are EGFR and 
ALK wild type, and who have completed curative intent therapy. The study will be 
conducted in approximately 250 centers globally.
This study requires mandatory genetic testing. During the first screening, WES is 
performed on the patient’s resected tumor tissue and derived tumor-specific DNA variants 
are identified by removing background germline variants, determined by WES of the 
patient’s whole blood sample. A personalized panel is then created, comprised of up to 50 
of the patient’s tumor variants present at a high frequency. This panel is then used to 
identify the presence of these tumor-specific variants on DNA extracted from the patient’s 
plasma. The patient is considered MRD+ if the panel detects patient-specific tumor 
variants.
Resected tumor tissue collected during the first screening will be evaluated for EGFR/ALK 
and programmed death ligand-1 (PD-L1) expression by a central reference laboratory. 
Patients whose tumor tissue tests positive for EGFR mutations and/or ALK translocations 
will be excluded from the study. In addition, PD-L1 status must be known prior to, and is 
required for, randomization.


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!
Note: Results from local EGFR/ALK testing of either a pre-surgery biopsy or the 
resected tumor tissue performed as part of SoC may be used for this study, provided 
testing was performed using a well-validated, local regulatory-approved kit.
Eligible patients will be enrolled in a 96-week surveillance period during which they will 
be monitored for the emergence of MRD. During surveillance, the patient will be assessed 
for MRD by plasma sampling every 6 weeks (q6w±3d) and will receive CT scans every 
12 weeks (q12w±1w) for up to 96 weeks.
Patients with evidence of RECIST 1.1-defined disease recurrence using Investigator 
assessments during the surveillance period will not be eligible for randomization and will 
no longer be followed as part of the study; however, data pertaining to their recurrence 
must be captured.
Patients who become MRD+ during surveillance (including cases where analysis of the 
first plasma sample collected [marking the start of surveillance] returns an MRD+ status) 
will undergo a second screening period, initiated by the signing of ICF2a (Table 2). Note: 
Patients who received prior neoadjuvant immunotherapy must be MRD- based on analysis 
of the first plasma sample collected (which marks the start of surveillance).
Patients should sign ICF2a as soon as their MRD+ result is available and immediately 
enter the second screening period. To ensure the duration of the second screening period is 
as short as possible, and to prevent any unforeseen delays in scheduling necessary scans, 
the Investigator should proactively schedule CT and/or MRI scans of the chest/abdomen 
and brain within 2 weeks following each q6w plasma collection. Thus, the baseline scans 
necessary to confirm eligibility will already be scheduled if testing of the plasma sample 
returns an MRD+ status.
Once all additional inclusion and none of the exclusion criteria are met, patients will be 
eligible for randomization. Patients must be randomized as soon as possible after eligibility 
criteria are confirmed, and treatment must begin within 3 days of randomization (Table 2).
Approximately 284 MRD+ patients will be randomized 1:1 to treatment with durvalumab 
monotherapy 1500 mg or placebo every 4 weeks (q4w) intravenously (IV). Patients will be 
treated for up to a total of 24 months (26 cycles), until disease recurrence, or until other 
specific treatment discontinuation criteria are met (whichever comes first). This study will 
be fully blinded.
Based on internal Sponsor data from stage II-III resected patients, it is estimated that 
 
of randomized patients will be PD-L1 TC≥1%. To ensure that the target of 
 PD-L1 
TC≥1% patients are randomized in the study, enrollment of PD-L1 TC<1% patients into 
surveillance will end once 
 PD-L1 TC<1% patients have been randomized. The 
remaining PD-L1 TC<1% patients will be immediately withdrawn from surveillance. 
Additional data will not be collected on these patients. Patients who are determined to be 
PD-L1 TC<1% during the first screening will not be eligible to continue to surveillance 
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and will be considered screen failures (see Section 5.5). Please note that any PD-L1 TC 
<1% patient who is already in the observation arm will remain in the study.
Similarly, enrollment into the study will end once 284 MRD+ patients are randomized.
Patients in surveillance will be immediately withdrawn from the study and additional data 
will not be collected on these patients. Please note that patients already in the observation 
arm will remain in the study.
Note: In the event the Sponsor withdraws patients from surveillance because the 
applicable cohort(s) have been filled, these patients may continue to receive CT scans 
every 12 weeks until 96 weeks have elapsed (relative to the start of surveillance) to honor 
the patient’s consent to q12w scans or until disease recurrence or primary DFS analysis 
(whichever occurs first). No additional data will be collected on these patients.
Up to 142 of the patients who complete their 96-week surveillance period, remain MRD-, 
and have no evidence of RECIST 1.1-defined disease recurrence may be eligible for entry 
into an observation period initiated by the signing of a separate informed consent (ICF2b; 
Table 4). These patients will be followed for SAEs, DFS, OS, subsequent anticancer 
therapy, and MRD assessments for 24 months or until completion of the study (whichever 
occurs first). Patients who complete 24 months of observation will be followed for OS 
until the end of the study. Data from this cohort of patients will be compared to the 
patients randomized to placebo to support the hypothesis that MRD can be used as a 
prognostic biomarker to identify patients at high risk of disease recurrence prior to 
radiologic evidence of disease.
Efficacy assessments of the primary endpoint of DFS will be derived using Investigator 
assessments according to RECIST 1.1 and pre-specified definitions of disease recurrence 
(ie, local or regional recurrence, distant recurrence, second primary NSCLC) and by 
survival assessments. All randomized patients and patients in the observation arm will be 
followed for disease recurrence until the primary DFS analysis and followed for safety and 
survival until the completion of the study. Disease evaluations utilize images from CT 
(preferred) or MRI, each preferably with IV contrast, of the chest and abdomen (including 
liver and adrenal glands) collected during screening/baseline and at selected timepoints 
during the study duration. Any other areas of disease involvement should be additionally 
imaged based on the signs and symptoms of individual patients
An IDMC comprised of independent experts will meet approximately 12 months after the 
first patient has been dosed with IP or after approximately 50 patients have received at 
least 1 dose of IP (whichever occurs first) to assess the safety and tolerability of 
durvalumab, and will report back to the Sponsor. The timing of subsequent reviews will be 
determined by the IDMC but will not occur more frequently than every 6 months. Full 
details of the IDMC procedures will be specified within the IDMC Charter. The IDMC 
safety reviews will be conducted in an unblinded manner. Scientific rationale for study 
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4.1.1
Overall rationale and study population
For patients with stage II-III disease, surgery and adjuvant SoC chemotherapy per National 
Comprehensive Cancer Network and European Society for Medical Oncology guidelines 
results in 5-year DFS rates of only ~40% (Wakelee et al 2017). Improvement in clinical 
outcomes may be achieved through the early identification of patients at high risk for 
recurrence and combined treatment of immunotherapy and SoC chemotherapy. 
Identification of high-risk patients may be achieved by monitoring patients for MRD for 
96 weeks after completion of curative intent therapy.
The 96-week surveillance period was selected based on 5-year DFS data across historic 
adjuvant studies (ANITA [Douillard et al 2006], BLT [Waller et al 2004], E1505 [Wakelee 
et al 2017], IALT [Arriagada et al 2004], JBR.10 [Winton et al 2005]) in which DFS 
events were observed to be highest in years 1 and 2 and then plateaued. Data available to 
the Sponsor estimates a lead-time of 
 days from MRD detection to measurable disease 
in an untreated patient population (
 unpublished data). Taken together, these 
data suggest a 96-week surveillance strategy would be expected to capture ~82% of 
patients who suffer NSCLC recurrence post-operatively. Based on an estimated 
 
tumor doubling time at NSCLC recurrence, q6w plasma sampling for MRD assessments 
should capture approximately 
 of tumors at a volume of 
, the approximate 
volume limit-of-detection associated with the personalized MRD assay being leveraged in 
this study.
The stratification factors of PD-L1 status (TC <1% vs TC ≥1%), time from start of 
surveillance to emergence of MRD (≤6 months vs >6 months), and prior neoadjuvant 
immunotherapy (Yes vs No) were chosen to mitigate the risk of imbalance of known or 
potential prognostic factors across treatment arms. PD-L1 status was chosen based on the 
established prognostic differences of PD-L1 expression with IO monotherapy agents 
(Spigel et al 2019, Mok et al 2019, Reck et al 2016, Reck et al 2019). A previous study in 
NSCLC demonstrated that PFS was significantly improved for patients treated 
continuously with immunotherapy versus those whose treatment was interrupted and re-
started (Spigel et al 2017). Therefore, prior neoadjuvant immunotherapy was selected as a 
stratification factor as patients who receive neoadjuvant immunotherapy may be less likely 
to respond to additional immunotherapy in the adjuvant setting. Data internally available to 
the Sponsor suggest that emergence of MRD following curative therapy follows an 
exponential distribution. Assuming an exponential distribution, the median time from 
surgery to becoming MRD+ would be approximately 
. Based on these data and 
taking into account the typical 3-month duration of adjuvant therapy, the length of time 
from the start of the surveillance period to becoming MRD+ will be stratified using a ≤6 
months vs >6 months cut-off. Phenotypic differences may also be elucidated between 
patients who become MRD+ shortly after completing curative intent therapy (ie, those 
with residual disease refractory to SoC curative therapy) compared to patients who become 
MRD+ many months after (ie, those who initially responded to SoC curative therapy and 
then develop recurrent disease).
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4.1.2
Study design
In order to avoid bias, the study will be randomized and double-blind.
4.1.3
Primary and secondary outcome measures
The primary efficacy endpoint of this study is DFS in the PD-L1 TC≥1% analysis set. DFS 
(see Section 9.4.1.1 for full definition), which represents a direct measure of the IP’s 
efficacy. Historical data have shown that the DFS benefit seen with the use of adjuvant 
chemotherapy in this disease setting was consistent with an improvement in the OS 
outcome, which suggests an association between these 2 endpoints in this setting 
(Mauguen et al 2013). DFS has been the primary basis of approval for adjuvant breast 
cancer hormonal therapy, adjuvant colon cancer therapy, and adjuvant cytotoxic breast 
cancer therapy. The study is sized for the PD-L1 TC≥1% population, as PD-L1 is the most 
established predictive biomarker for immune checkpoint inhibitors (see Section 2.2.3.1). 
However, DFS in all patients will be evaluated as a secondary outcome.
OS, which also represents a direct measure of efficacy, is routinely used on oncology trials 
and will also be evaluated as a non-powered, secondary outcome.
The secondary objective of disease-related symptoms and overall health-related quality of 
life (HRQoL), assessed using the European Organisation for Research and Treatment of 
Cancer (EORTC) 30-item Core Quality of Life Questionnaire (QLQ-C30), version 3 
(QLQ-C30 v3), and the complementary 13-item Lung Cancer Quality of Life 
Questionnaire (QLQ-LC13). These PRO questionnaires are well established instruments 
that have been previously included in cancer clinical studies.
The safety and tolerability of each study treatment will be assessed by the standard safety 
endpoints including AEs, SAEs, laboratory abnormalities, and vital signs.
4.1.3.1
Rationale for exploratory endpoints
Biomarkers to be assessed are justified on the basis that they may identify subpopulations 
most likely to derive clinical benefit from therapy (predictive biomarkers); to rapidly 
identify subjects most likely to experience clinical benefit after treatment has started (early 
efficacy biomarkers); and to assess target engagement and/or mechanism of action 
(pharmacodynamic biomarkers) to support dosing, understanding of the therapeutic index, 
and/or potential future combination therapies. Biomarkers may include, but are not limited 
to, PD-L1 TC expression; tumor, immune, and stromal cell gene and protein expression 
profiles; and genomic analyses such as tumor mutational burden (TMB).
Although ctDNA is an emerging biomarker, the endpoint has significant capability for 
diagnosis and has already demonstrated utility at various levels of disease staging and 
management (De Rubis et al 2018, Wills et al 2018). Limitations in using ctDNA as an 
endpoint include detection sensitivity in early cancers, predictability in diseased 
individuals versus healthy individuals, and quality aspects due to processing time (De 
Rubis et al 2018). However, given the supporting literature and regulatory landscape, the 


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proposed primary and secondary endpoints are aligned with existing clinical trials and 
justified by the expected clinical benefits, and ctDNA clearance will be assessed as an 
exploratory outcome.
 
 
Patients who remain MRD- through their 96-week surveillance period and have no 
evidence of RECIST 1.1-defined disease recurrence may be eligible for entry into an 
observation period initiated by the signing of a separate informed consent (ICF2b; 
Table 4). Data from this observation cohort will be compared to data from randomized 
placebo-treated patients to support the hypothesis that MRD can be used as a prognostic 
biomarker to identify patients at high risk of disease recurrence prior to radiologic 
evidence of disease.
4.2
Justification for durvalumab dose
4.2.1
Durvalumab monotherapy dose
A durvalumab dose of 20 mg/kg q4w is supported by in vitro data, pre-clinical activity, 
clinical PK/pharmacodynamics, biomarkers, and activity data from Study CD-ON-
MEDI4736-1108 (hereafter referred to as Study 1108) in patients with advanced solid 
tumors and from a Phase I study performed in Japanese patients with advanced solid tumor 
(D4190C00002).
4.2.1.1
PK/Pharmacodynamic data
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses 
ranging from 0.1 to 10 mg/kg q2w or 15 mg/kg every 3 weeks (q3w), durvalumab 
exhibited non-linear (dose-dependent) PK consistent with target-mediated drug 
disposition. The PK approached linearity at ≥3 mg/kg q2w, suggesting near complete 
target saturation (membrane-bound and soluble PD-L1 [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 ≥3 mg/kg q2w 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 durvalumab IB).
A population PK model was developed using the data from Study 1108 (doses=0.1 to 
10 mg/kg q2w or 15 mg/kg q3w; Fairman et al 2014). Multiple simulations indicate that a 
similar overall exposure is expected following both 10 mg/kg q2w and 20 mg/kg q4w 
regimens, as represented by AUCss (4 weeks). Median Cmax,ss is expected to be higher with 
20 mg/kg q4w (~1.5 fold) and median Ctrough,ss is expected to be higher with 10 mg/kg q2w 
(~1.25 fold). Clinical activity with the 20 mg/kg q4w dosing regimen is anticipated to be 
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consistent with 10 mg/kg q2w with the proposed similar dose of 20 mg/kg q4w 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 anti-drug antibody impact; and (d) achieve 
PK exposure that yielded maximal antitumor activity in animal models.
Given the similar area under the serum drug concentration-time curve 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 20 mg/kg q4w and 10 mg/kg q2w regimens are expected to have similar efficacy and 
safety profiles, supporting further development with a dose of 20 mg/kg q4w. This dose 
has been used in multiple studies previously with no safety concern.
4.2.1.2
Clinical data
Refer to the current durvalumab IB for a complete summary of clinical information 
including safety, efficacy, and PK at the 20 mg/kg q4w regimen.
4.2.1.3
Rationale for fixed dosing
A population PK model was developed for durvalumab using monotherapy data Study 
1108 (N=292; doses= 0.1 to 10 mg/kg q2w or 15 mg/kg q3w; solid tumors). Population 
PK analysis indicated only minor impact of body weight on the PK of durvalumab 
(coefficient of ≤0.5). The impact of body weight-based (10 mg/kg q2w) and fixed dosing 
(750 mg q2w) of durvalumab was evaluated by comparing predicted steady state PK 
concentrations (5th, median, and 95th percentiles) using the population PK model. A fixed 
dose of 750 mg was selected to approximate 10 mg/kg (based on median body weight of 
~75 kg). A total of 1000 patients were simulated using body weight distribution of 40 to 
120 kg. Simulation results demonstrate that body weight-based and fixed dosing regimens 
yield similar median steady state PK concentrations with slightly less overall between-
patient variability with fixed dosing regimen.
Similar findings have been reported by others (Narwal et al 2013, Wang et al 2009, Zhang 
et al 2012). Wang and colleagues investigated 12 mAbs and found that fixed and body 
size-based dosing perform similarly, with fixed dosing being better for 7 of 12 antibodies 
(Wang et al 2009). In addition, they investigated 18 therapeutic proteins and peptides and 
showed that fixed dosing performed better for 12 of 18 in terms of reducing the 
between-patient variability in PK/pharmacodynamic parameters (Zhang et al 2012).
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar PK exposure and variability, 
AstraZeneca considered it feasible to switch to fixed dosing regimens. Based on average 
body weight of 75 kg, a fixed dose of 1500 mg q4w durvalumab (equivalent to 20 mg/kg 
q4w) is included in the current study.


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4.3
End of study definition
From CSP v2.0 implementation at site, please use Section 10 as the reference point for 
the study. Refer to Section 10.3.3 for the updated end of study definition for CSP v2.0.
Patients may be withdrawn from the study if the study itself is stopped. The study may be 
stopped if, in the judgment of AstraZeneca, study patients are placed at undue risk because 
of clinically significant findings or for any other reason.
In the event that a roll-over or safety extension study is available at the time of the final 
DCO and database closure, randomized patients (including those currently receiving 
treatment with durvalumab and those in follow-up) may be transitioned to such a study, 
and the current study would reach its end. The roll-over or safety extension study would 
ensure treatment continuation and/or follow-up with visit assessments per its protocol. Any 
patient who would be proposed to move to such a study would be given a new Informed 
Consent form.
See Sections 8.3.13 and 10.3 for details regarding data collection on randomized patients.
See Appendix A 6 for guidelines for the dissemination of study results.
5
STUDY POPULATION
Note for CSP v2.0: Enrolment is closed as of 25May2022 and no patients will be 
randomized following implementation of this amendment at site.
Section 5.3 remains in effect for the patients who receive durvalumab during open-label 
or double-blind treatment and up to 90 days after the last dose.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for 
this study in order to be randomized to a study intervention. Under no circumstances can 
there be exceptions to this rule. Subjects who do not meet the entry requirements are 
screen failures, refer to Section 5.5.
In this protocol:
!
“Enrolled” patients are defined as those who sign ICF1.
!
“Patients in surveillance” are defined as those who have successfully completed the 
first screening and have had at least one plasma sample collected for MRD testing but 
are not randomized nor in observation.
!
“Randomized” patients are defined as those who sign ICF2a, complete the second 
screening period, undergo randomization, and receive a randomization number.


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!
“Patients in observation” are MRD- patients who remain MRD- during their
96-week surveillance period and who have no evidence of RECIST 1.1-defined 
disease recurrence. These patients have signed ICF2b and entered the observation 
cohort.
For procedures for withdrawal of incorrectly enrolled subjects see Section 6.2.2 and 
Section 7.3.
5.1
Inclusion criteria
This study will employ a tiered informed consent and screening process.
Table 1 summarizes the study procedures and assessment during the first screening period 
and surveillance. Sites should review the appropriate inclusion and exclusion criteria 
summarized in Table 5 and Table 6 to confirm the patient’s eligibility prior to signing 
ICF1 and entering surveillance.
Patients who are MRD+ at the start of surveillance or become MRD+ during their 96-week 
surveillance period may be eligible to enter the second screening period. If all additional 
inclusion and none of the exclusion criteria are met, these MRD+ patients may be 
randomized to treatment with IP. Table 2 includes the study procedures and assessment 
during the second screening period and randomization, and Table 5 and Table 6
summarize the inclusion and exclusion criteria, respectively, that are applicable to this 
period.
Up to 142 of the patients who remain MRD- during their 96-week surveillance period and 
have no evidence of RECIST 1.1-defined disease recurrence may be eligible to sign a 
separate ICF (ICF2b) and enter an observation period. Table 4 outlines the assessments 
during observation.
Some criteria will need to be checked during both screening periods and/or prior to
entering observation. Subjects are eligible to be included in the study only if all of the 
following inclusion criteria at the indicated times and none of the exclusion criteria apply:
Informed consent
1
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICFs and in this protocol.
2
Provision of signed and dated, written informed consent form prior to any mandatory 
study-specific procedures, sampling, and analyses.
ICF1 must be signed and dated prior to initiation of the first screening and 
surveillance activities outlined in Table 1.
ICF2a must be signed and dated prior to initiation of the second screening activities 
and randomization outlined in Table 2.


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ICF2b must be signed and dated prior to initiation of the study-specific observation 
period and procedures outlined in Table 4.
3
Provision of signed and dated written optional genetic informed consent prior to 
collection of the optional sample for genetic analysis. This consent should be signed at 
the time of second screening. This optional sample and analyses are separate from the 
mandatory genetic testing consent included in ICF1.
The ICF process is described in Appendix A 3.
5.1.1
Inclusion criteria assessed during the first screening period
The following criteria must have been met at the time of surgery or at the time of the 
curative intent therapy (first screening):
Age
4
Age ≥18 years at the time of screening (ICF1).
Sex
5
Male and/or female.
Type of subject and disease characteristics
6
Histologically confirmed NSCLC with resectable stage II-III disease (according to 
IASLC Staging Manual in Thoracic Oncology v8.0) who have undergone curative 
intent therapy (complete resection of the primary tumor ± neoadjuvant and/or adjuvant 
therapy) per SoC.
Select stage IIIB (ie, T3N2 or T4N2) patients will be eligible, provided they are 
upstaged to T3N2 or T4N2 based on confirmed pathology after surgery. Patients who 
are staged as T3N2 or T4N2 prior to surgery are not eligible.
7
A contrast-enhanced CT/MRI scan of the chest and abdomen (including liver and 
adrenal glands) along with brain MRI (preferred) or brain CT with IV contrast must 
have been done for surgical planning prior to surgery. It is recommended that patients 
undergo combined FDG-PET (18F-Fluoro-deoxyglucose positron emission 
tomography) and CT scan (computerized tomography) within the 6 weeks prior to 
surgery in order to rule out detectable extrathoracic, extracranial metastasis and to 
assess for potential mediastinal lymph node involvement prior to surgery. If the 
positron emission tomography (PET) scan was not performed, or data from a PET is 
not available, patients may still be enrolled into the study provided appropriate 
imaging (CT/MRI) is performed prior to randomization.
8
Complete resection of the primary NSCLC is mandatory. Invasive (pre-operative or 
intra-operative) exploration of hilar and mediastinal lymph nodes must have been 
performed to confirm primary tumor nodal status (prior to or after surgery). Surgical 
resection of the primary NSCLC can occur by open thoracotomy or by video-assisted 
thoracic surgery (VATs) and resection can be achieved by segmentectomy, 
lobectomy, sleeve resection, bilobectomy or pneumonectomy. Patients undergoing 
wedge resection are not eligible for this study.


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Note: Where a resection has been extended by means of a wedge resection of an 
adjacent lobe to ensure complete resection of a tumor at or crossing a fissure 
between lobes, this is acceptable if surgical margins are clear of disease. Where 
the resection of a second tumor nodule (eg, a T4 lesion) is undertaken by means 
of a wedge resection of a separate lobe, then the patient is not eligible.
Note: Carcinoma-in-situ can be present at the bronchial margin.
Criteria for prior systemic chemotherapy/radiotherapy:
9
Patients should have completed (or be undergoing) curative intent therapy (surgery ± 
neoadjuvant and/or adjuvant therapy; adjuvant therapy can include PORT) with 
exceptions noted below:
Patients who discontinue chemotherapy and/or PORT for toxicity prior to completion 
of all planned therapy are eligible.
Patients who have not received any neoadjuvant and/or adjuvant chemotherapy, and 
meet all other eligibility criteria, may be eligible under the following 
circumstances:
o
All patients who are eligible for adjuvant chemotherapy MUST be offered 
adjuvant chemotherapy.
o
The patient has declined adjuvant chemotherapy, and in the opinion of the 
Investigator, this is the patient’s final decision after receiving appropriate 
information and adequate time to make the decision. The patient’s refusal of 
adjuvant chemotherapy must be documented.
o
If in the view of the Investigator, adjuvant chemotherapy is contraindicated 
due to an underlying intercurrent illness/laboratory abnormality, which is not 
considered reversible within a reasonable timeframe for the patient to be 
eligible for adjuvant therapy, which must be documented.
Criteria assessed prior to and at the start of surveillance:
10 Confirmation of suitable biosamples for WES and central PD-L1 testing. Resected 
tumor tissue and whole blood samples must be provided to the diagnostic laboratory 
for WES of tumor and germline DNA, respectively as soon as possible following 
pathology confirmation. Samples must be sent no later than 1-2 weeks after 
completion of adjuvant therapy or 3-5 weeks after surgery (if no adjuvant therapy is 
given) for development of the Sponsor-approved personalized panel for MRD 
detection at a central reference laboratory. Germline sequencing of whole blood is 
mandatory. Resected tumor tissue must also be provided for PD-L1 testing at a 
central reference laboratory (see inclusion criteria 15).
11 Post-adjuvant therapy or post-surgery (if no adjuvant therapy is given) CT scan of the 
chest and abdomen (including liver and adrenal glands) and brain MRI [preferred] or 
brain CT with IV contrast should be available to confirm no evidence of metastasis. If 


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scans were not performed post-curative intent therapy, additional scans must be done 
prior to start of surveillance.
12 Consents to be accessible for q6w±3d plasma sample collection for MRD evaluation 
and for q12w±1w CT scans during the 96-week surveillance period.
13 The plasma sample that marks the start of surveillance must be collected 8±1 weeks 
after completion of adjuvant therapy (if administered) or 12±1 weeks after surgery 
(where adjuvant therapy is not given).
−
A patient who is determined to be MRD- based on analysis of this plasma sample 
(ie, MRD- at the start of surveillance) may continue in surveillance provided all 
other eligibility criteria are met.
−
A patient who is determined to be MRD+ based on analysis of this plasma sample 
(ie, MRD+ at the start of surveillance) may be eligible for immediate 
randomization provided all other eligibility criteria are met.
o
Note: In order for a patient who received prior neoadjuvant IO 
immunotherapy to continue in the study, they must be MRD- based on 
analysis of this plasma sample (ie, must be MRD- at the start of 
surveillance).
A patient who becomes MRD+ during surveillance is eligible to enter the second 
screening period and may be randomized in the study if all other eligibility 
criteria are met.
5.1.2
Inclusion criteria assessed during the second screening period
Criteria for second screening prior to randomization to treatment:
14 CT scan of the chest and abdomen (including liver and adrenal glands) and brain MRI 
[preferred] or brain CT with IV contrast performed within the 28 days ± 7 days prior 
to randomization to confirm no evidence of RECIST 1.1-defined disease recurrence 
and/or metastasis.
15 Known tumor PD-L1 status determined at a central reference laboratory testing 
service using a validated Ventana SP263 PD-L1 immunohistochemistry (IHC) assay 
prior randomization. Patients with unknown PD-L1 status are not eligible for the 
study.
16 WHO/Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
17 Complete post-operative wound healing must have occurred prior to randomization; 
patients must have recovered from all acute, reversible toxic effects from prior 
treatments (excluding alopecia) that could potentially adversely impact further 
administration of durvalumab/placebo according to the Investigator’s judgment.
18 Must have recovered from all acute, reversible toxic effects from chemotherapy that 
could potentially adversely impact further administration of durvalumab or placebo 
according to the Investigator’s judgment
19 Adequate organ and marrow function as defined below:


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Hemoglobin ≥9.0 g/dL
Absolute neutrophil count ≥1.5 × 109/L
Platelet count ≥100 × 109/L
Serum bilirubin ≤1.5 × the upper limit of normal (ULN). This will not apply to 
patients with confirmed Gilbert’s syndrome, who will be allowed in consultation 
with their physician.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN
Measured creatinine clearance (CL) ≥30 mL/min or Calculated CL >30 mL/min as 
determined by Cockcroft-Gault (using actual body weight)
Males:
Creatinine CL = Weight (kg) × (140 - Age)
(mL/min)
72 × serum creatinine (mg/dL)
Females:
Creatinine CL = Weight (kg) × (140 - Age) 
× 0.85
(mL/min)
72 × serum creatinine (mg/dL)
20 Must have a life expectancy of at least 12 weeks
Weight
21 Body weight >30 kg
5.1.3
Inclusion criteria assessed prior to entering the observation period
22 No evidence of RECIST 1.1-defined disease recurrence or metastasis confirmed by 
CT scan of the chest and abdomen (including liver and adrenal glands) and a brain 
MRI (preferred) or brain CT with IV contrast.
23 MRD- status, as determined by testing the last plasma sample collected during the 96-
week surveillance period.
5.2
Exclusion criteria
These exclusion criteria must be checked during first and/or second screening periods, as 
summarized in Table 6. If a patient meets an exclusion criterion at one of these timepoints, 
the patient is ineligible to continue in the study.
Diagnostic assessments
1
EGFR and/or ALK mutant as assessed either from the tumor biopsy taken prior to 
surgery or the resected tumor tissue. Testing must be performed using a well-
validated, local regulatory-approved test. EGFR/ALK may be tested centrally if local 
testing is unavailable.
2
Mixed small cell and NSCLC histology.


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3
Require re-resection or are deemed to have unresectable NSCLC by a 
multidisciplinary evaluation that must include a thoracic surgeon who performs lung 
cancer surgery as a significant part of their practice.
4
Baseline imaging demonstrating unequivocal evidence of RECIST 1.1-defined disease 
recurrence or evidence of clinical recurrence outside of imaging prior to 
randomization. In the event of lymphadenopathy on imaging that would lead to 
exclusion, histopathological confirmation of lymph node metastasis should be 
obtained prior to excluding a patient from the study. If pathological confirmation of 
lymph node metastasis is not technically feasible and imaging appearance are deemed 
unequivocal for relapse, the patient will be excluded.
Medical conditions
5
History of allogeneic organ or bone marrow transplantation.
6
Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample 
collection
7
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
Patients with vitiligo or alopecia
Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone 
replacement
Any chronic skin condition that does not require systemic therapy
Patients without active disease in the last 5 years may be included but only after 
consultation with the Study Physician
Patients with celiac disease controlled by diet alone
8
Uncontrolled intercurrent illness, including but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, uncontrolled cardiac arrhythmia, active ILD, serious chronic 
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social 
situations that would limit compliance with study requirement, substantially increase 
risk of incurring AEs or compromise the ability of the patient to give written informed 
consent.
9
History of another primary malignancy except for
Malignancy treated with curative intent and with no known active disease ≥5 years 
before the first dose of IP and of low potential risk for recurrence
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease
Adequately treated carcinoma in-situ without evidence of disease
10 History of active primary immunodeficiency


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11 Active infection including tuberculosis (clinical evaluation that includes clinical 
history, physical examination and radiographic findings, and tuberculosis testing in 
line with local practice), hepatitis B virus (HBV) (known positive HBV surface 
antigen (HBsAg) result), hepatitis C virus (HCV), or human immunodeficiency 
virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection 
(defined as the presence of hepatitis B core antibody [anti-HBc] and absence of 
HBsAg) are eligible. Patients positive for HCV antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA.
12 Known allergy or hypersensitivity to any of the IPs or any of the IP excipients
Prior/concomitant therapy
13 Received any IO therapy in the adjuvant setting or any prior exposure to durvalumab.
14 Received any radiotherapy in the neoadjuvant setting.
15 Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. 
Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone 
replacement therapy) is acceptable.
16 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 IP.
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 while receiving IP 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.
19 Current or prior use of immunosuppressive medication within 14 days before the first 
dose of IP. The following are exceptions to this criterion:
Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection)
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or its equivalent
Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
Prior/concurrent clinical study experience
20 Previous IP assignment in the present study
21 Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study or during the follow-up period of an interventional 
study
22 Prior randomization or treatment in a previous durvalumab clinical study regardless of 
treatment arm assignment.
Other exclusions
23 Female patients who are pregnant or breastfeeding.
−
Female patients who become pregnant during the study will be withdrawn from 
surveillance and are not eligible for randomization.


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24 Male or female patients of reproductive potential who are not willing to employ 
effective birth control at the time of entry into second screening (initiated with the 
signing of ICF2a) until 90 days after the last dose of IP (See Appendix H).
25 Judgment by the Investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions, and requirements.
5.3
Lifestyle restrictions (to be observed up to 90 days after last 
dose of durvalumab)
Note for CSP v2.0: these restrictions remain for patients who start or continue
durvalumab treatment.
The following restrictions apply while the patient is receiving IP and for the specified 
times before and after. These restrictions do not apply to patients during the 
surveillance or observation periods.
1
Female participants must be 1 year post-menopausal, surgically sterile, or using one 
highly effective form of birth control (a highly effective method of contraception is 
defined as one that can achieve a failure rate of less than 1% per year when used 
consistently and correctly.) Women of childbearing potential must agree to use one 
highly effective method of birth control. They should have been stable on their chosen 
method of birth control for a minimum of 3 months before randomization to 90 days 
the last dose (see Appendix H for complete list of highly effective birth control 
methods). Non-sterilized male partners of a woman of childbearing potential must use 
a male condom plus spermicide (condom alone in countries where spermicides are not 
approved) throughout this period.
2
Non-sterilized male participants who intend to be sexually active with a female 
partner of childbearing potential must be surgically sterile or using an acceptable 
method of contraception (see Appendix H) from the time of screening throughout the 
total duration of the study and the drug washout period (90 days after the last dose of 
study intervention) to prevent pregnancy in a partner. Male participants must not 
donate or bank sperm during this same time period.
3
All patients: Patients should not donate blood or blood components while participating 
in this study and through 90 days after receipt of the final dose of durvalumab or until 
alternate anticancer therapy is started.
4
Restrictions relating to concomitant medications are described in Section 6.4.
5.4
Information regarding patients previously enrolled in 
MERMAID-1 (D910LC00001)
Patients may be entering this study (MERMAID-2; D910MC00001) after they were screen 
failed for another durvalumab study (ie, MERMAID-1; D910LC00001). These patients 
may have received chemotherapy in the time between screen-failing MERMAID-1 and 
enrolling in MERMAID-2.


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Samples and data collected during the first screening for MERMAID-1 may be used for 
MERMAID-2 if the patient provides consent.
If a patient’s personalized panel for MRD detection has already been created during 
screening for MERMAID-1, it may be possible for that panel to be used for this study. A 
patient with an existing Sponsor-approved personalized panel for MRD detection must 
sign ICF1 for MERMAID-2 (D910MC00001) prior to the use of their panel and associated 
MRD data in this study.
If a patient’s EGFR/ALK status was determined during screening for MERMAID-1, those 
results may be used for this study provided a well-validated, local regulatory-approved kit 
was used. Similarly, if a patient’s PD-L1 status was previously determined at a central 
reference laboratory during screening for MERMAID-1, that test does not need to be 
repeated, provided a validated SP263 assay was used. Patients must sign ICF1 for 
MERMAID-2 to allow the Sponsor retrospective access to these results.
5.5
Screen failures
Screen failures are patients who do not fulfill the eligibility criteria for the study, and 
therefore must not enter the surveillance period (if eligibility during the first screening is 
not met) or must not be randomized (if eligibility during the second screening is not met). 
These patients should have the reason for study withdrawal recorded as “eligibility criteria 
not fulfilled” (ie, patient does not meet the required inclusion/exclusion criteria). This 
reason for study withdrawal is only valid for screen failures (ie, not randomized patients). 
Patients may not be rescreened or re-randomized in this study. The reason for screen 
failures will be captured in the appropriate section of the electronic case report form 
(eCRF).
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure patients to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAE. In addition, surgical history, scans and imaging data, and the date of 
disease recurrence will also be collected on screen failed patients.
See Table 1 in the SoAs and Section 8.2.2 for additional details on information that should 
be collected for patients who participate in the first screening period and surveillance of 
this study (initiated by signing ICF1).
6
STUDY TREATMENTS
Study treatment is defined as any IP(s) (including marketed product comparator and 
placebo) or medical device(s) intended to be administered to a study participant according 
to the study protocol. Study treatment in this study refers to durvalumab (supplied as either 
double-blind or open-label) or placebo.


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Note for CSP v2.0: Placebo will no longer be administered to patients following
implementation of this amendment at the study site.
From implementation of CSP v2.0 at site, preparation, storage, and administration of 
open-label durvalumab should occur as per durvalumab instructions in Sections 6.1, 
6.3, and 6.4 (unless otherwise indicated in Section 10). Refer to Section 10 regarding the 
eligibility and duration of open-label durvalumab treatment, as well as required 
assessments during the treatment.
6.1
Treatments administered
6.1.1
Investigational products
From implementation of CSP v2.0 at site, AstraZeneca will supply open-label
durvalumab only.
The original study treatments are described in Table 8.
Table 8
Study treatments
Study treatment name:
Durvalumab
Placebo
Dosage formulation:
500 mg vial solution for infusion 
after dilution, 50 mg/mL
Vial solution for infusion after 
dilution 
Route of administration 
IV
IV
Dosing instructions:
1500 mg infusion over 60 min 
q4w.a,b
See Section 6.1.1 for specific 
instructions for preparing and 
storing IP.
Infusion over 60 min q4w.a,b
See Section 6.1.1 for specific 
instructions for preparing IP.
Packaging and labeling
Study treatment will be provided 
in 500 mg vials. Each 500 mg 
vial will be labeled in accordance 
with GMP Annex 13 and per 
country regulatory requirement.c
Study treatment will be provided in 
vials. Each vial will be labeled in 
accordance with GMP Annex 13 
and per country regulatory 
requirement.
Provider
AstraZeneca
AstraZeneca
a
If a patient’s weight falls to 30 kg or below while on treatment, the patient should receive weight-based 
dosing equivalent to 20 mg/kg of durvalumab or placebo q4w after consultation between Investigator 
and Study Physician until the weight improves to >30 kg, at which point the patient should start 
receiving the fixed dosing of durvalumab or placebo 1500 mg q4w.
b
See Section 6.1.1 for specific instructions for preparing and storing durvalumab and placebo
c
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.
GMP Good Manufacturing Practice; IP Investigational product; IV Intravenous; q4w Every 4 weeks.
Durvalumab and placebo will be supplied by AstraZeneca as vial solutions for infusion 
after dilution. Durvalumab will be supplied as a 500 mg vial containing 50 mg/mL 
durvalumab, 26 mM histidine/histidine hydrochloride, 275 mM trehalose dihydrate, and 
0.02% weight/volume (w/v) polysorbate 80; it has a pH of 6.0 and density of 1.054 g/mL. 


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Placebo will be supplied as a vial containing 
 histidine/histidine hydrochloride, 
 trehalose dihydrate, and 
 polysorbate 80; it has a pH of 6.0. The 
nominal fill volume for durvalumab and placebo is 10.0 mL.
Durvalumab is a sterile, clear to opalescent, colorless to slightly yellow solution, free
from visible particles.
Durvalumab and placebo vials are stored at 2°C to 8°C (36°F to 46°F) and must not be 
frozen. Durvalumab and placebo should be kept in original packaging until use to prevent 
prolonged light exposure.
Preparation of investigational product doses for administration with an IV bag
The dose of durvalumab or placebo 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 or placebo 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
!
If the final product is stored at both refrigerated and ambient temperatures, the total 
time should not exceed 24 hours.
A dose of 1500 mg (for participants >30 kg in weight) will be administered using an IV 
bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab 
concentration ranging from 1 to 15 mg/mL and delivered through an IV administration set 
with a 0.2- or 0.22-μm filter. Add 30 mL (ie, 1500 mg) of investigational product to the IV 
bag. The IV bag size should be selected such that the final concentration is within 1 to 15 
mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag.
If participant weight falls to ≤30 kg weight-based dosing at 20 mg/kg will be administered 
using an IV bag size selected such that the final concentration is within 1 to 15 mg/mL.
Standard infusion time is one hour, however if there are interruptions, the total allowed 
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 according to local practices to ensure the full dose is 
administered. Infusion time does not include the final flush time.
If either preparation time or infusion time exceeds the time limits, a new dose must be 
prepared from new vials. Durvalumab and placebo do not contain preservatives, and any 
unused portion must be discarded.
CCI
CCI
CCI


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6.1.2
Dosage and treatment regimens
The full dosing scheme by treatment arm throughout the 24-month treatment period is 
shown in Figure 3 and described in the following sections.
Figure 3
Dosing scheme
q4w Every 4 weeks.
6.1.2.1
Durvalumab or placebo
Patients will receive 1500 mg durvalumab or placebo via IV infusion q4w unless there is 
unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. 
See Figure 3. (Please note, if a patient’s weight falls to 30 kg or below (≤30 kg) during the 
treatment period the patient should receive weight-based dosing equivalent to 20 mg/kg of 
durvalumab or placebo q4w after consultation between Investigator and Study Physician, 
until the weight improves to >30 kg, at which point the patient should start receiving the 
fixed dosing of durvalumab or placebo 1500 mg q4w).
6.1.3
Duration of treatment
Note for CSP v2.0: See Section 10.3.1 for the duration of open-label durvalumab 
treatment.
All treatment will be administered beginning on Day 1 for up to 26 cycles (up to a total of 
24 months) of durvalumab or placebo q4w, unless there is unacceptable toxicity, 
withdrawal of consent, or another discontinuation criterion is met.
Treatment will be stopped when a patient has received a total of 24 months of therapy 
(26 cycles of treatment) or upon evidence of RECIST 1.1-defined disease recurrence using 
Investigator’s assessments, whichever occurs first.
During the treatment period, patients who are clinically stable at an initial 
RECIST 1.1-defined disease recurrence may continue to receive study treatment at the 
discretion of the Investigator until the follow-up scan.
Patients with rapid tumor progression or with symptomatic progression that requires 
urgent medical intervention (eg, central nervous system metastasis, respiratory failure due 


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to tumor compression, or spinal cord compression) will not be eligible for continuing 
durvalumab or placebo.
Patients who AstraZeneca and/or the Investigator determine may not continue treatment 
after RECIST 1.1-defined disease recurrence will be followed up for survival until the
completion of the study. Patients who have discontinued treatment due to toxicity or 
symptomatic deterioration, or who have commenced subsequent anticancer therapy, will 
be followed up with tumor assessments until RECIST 1.1-defined disease recurrence plus 
an additional follow-up scan or until death (whichever comes first) and followed for 
survival.
Patients may not receive retreatment in this study.
Post data cut-off
This section is no longer applicable following implementation of CSP v2.0 at site.
After the primary DFS analysis, the study will be unblinded and AstraZeneca will continue 
to supply open-label drug to patients receiving durvalumab monotherapy up to completion 
of a patient’s 24-month treatment period (26 cycles of treatment). Investigators should 
continue to monitor and document data for all study patients in the database after 
scheduled DCO and database lock (DBL) for the primary DFS analysis. Scheduled visits 
as described in Table 2, Table 3, and Table 4 should be followed and data will be collected 
on all randomized patients (including patients in follow-up) and patients in observation 
until final DCO. Depending on the analysis results, a decision may be made to continue 
further data collection for a longer period with intent to analyze long-term DFS and safety 
data to fulfill any other potential Health Authority requirements.
Following DBL for primary DFS analysis, efficacy scans will be collected in accordance 
with local practice.
In the event that a roll-over or safety extension study is available at the time of the DCO 
for primary DFS analysis, randomized patients (including those currently receiving 
treatment with durvalumab and those in follow-up) and patients in observation may be 
transitioned to such a study, and the current study would reach its end. The roll-over or 
safety extension study would ensure treatment continuation and/or follow-up with visit 
assessments per its protocol. Any patient who would be proposed to move to such a study 
would be given a new Informed Consent form.
Safety, subsequent therapy, and survival data will continue to be collected after the final 
DCO until any of following conditions are met:
!
Remaining patients have been transferred into a roll-over study OR
!
All patients receiving durvalumab monotherapy have completed their 24-month 
treatment period (26 cycles of treatment).


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6.1.4
Storage
The Investigator, or an approved representative (eg, pharmacist), will ensure that all IP is 
stored 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.
6.2
Measures to minimize bias: randomization and blinding
This section is not applicable following implementation of CSP v2.0 at site. Refer to
Section 10 for updated unblinding instructions for CSP v2.0.
6.2.1
Patient enrollment and randomization
All patients will be centrally assigned to randomized study treatment using an IWRS. 
Before the study is initiated, the log-in information and directions for the IWRS will be 
provided to each site.
If a patient withdraws from the study, then his/her enrollment/randomization code cannot 
be reused. Withdrawn subjects will not be replaced.
Investigators should keep a record (ie, the patient screening log) of patients who entered 
screening.
This study will use a tiered consent process. The signing of ICF1 will initiate the first 
screening, which includes mandatory genetic testing and development of the personalized 
panel for MRD detection, as well as procedures conducted during the surveillance period 
(Table 1). The signing of ICF2a will initiate the second screening procedures (which 
includes confirmation of final eligibility) followed by the treatment and follow-up periods 
(Table 2). ICF2b will cover the observation period for patients who remain MRD-
throughout their 96-week surveillance period; study procedures and assessments for the 
observation period are outlined in Table 4.
!
Note: The time between signing ICF1 and either ICF2a or ICF2b may be up to 96 
weeks.
At the first screening period and prior to start of surveillance, the Investigators or suitably 
trained delegate will:
!
Obtain signed ICF1 before any study-specific procedures (outlined in Table 1) are 
performed.
!
Obtain a unique 7-digit enrollment number (E-code), through the IWRS in the 
following format (ECCNNXXX: CC being the country code, NN being the center 


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number, and XXX being the patient enrollment code at the center). This number is the 
patient’s unique identifier and is used to identify the patient on the eCRFs.
!
Determine patient eligibility for entry into the surveillance period based on the criteria 
outlines in Table 1, Table 5, and Table 6 and Sections 5.1 and 5.2.
NOTE: Surgery and any neoadjuvant and/or adjuvant therapy will not be considered 
study-specific procedures. However, patients will need to sign ICF1 to give the 
Sponsor access to all information related to prior therapy (including surgery) and 
to obtain resected tumor tissue for this study.
If a patient is determined to be MRD+ at the start of surveillance (Refer to inclusion 
criterion 13 [Section 5.1.1]) or during the surveillance period, they may enter the second 
screening period (Days -28 to -1 relative to randomization). During this second screening 
period, the Investigator or suitably trained delegate will:
!
Obtain signed ICF2a before any study-specific procedures (outlined in Table 2) are 
performed. 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 second screening laboratory and imaging results required for 
final eligibility (specified in Table 2) must have been obtained within 28 days ± 7 days 
prior to randomization.
!
Determine patient eligibility for randomization based on the criteria outlines in 
Table 2, Table 5, and Table 6, and Sections 5.1 and 5.2.
!
Obtain signed informed consent for the optional genetic research study (optional).
At randomization, once the patient is confirmed to be eligible, the Investigator or suitably 
trained delegate will:
!
Randomize the patient in IWRS. Numbers will be assigned strictly sequentially by 
IWRS as patients are eligible for entry into the study. The system will randomize the 
eligible patient to 1 of the 2 treatment groups.
If the patient is ineligible and not randomized, the IWRS should be contacted to terminate 
the patient in the system.
Patients will begin treatment on Day 1. Treatment should start no more than 3 days after 
being randomized. Patients must not be randomized and treated unless all eligibility 
criteria have been met.
If a patient withdraws from participation in the study, then his or her 
enrollment/randomization code cannot be reused. Withdrawn patients will not be replaced.
For details regarding MRD- patients who are withdrawn from surveillance once the study 
is fully randomized, refer to section 7.3.2.


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6.2.2
Procedures for handling incorrectly enrolled or randomized patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Patients who 
are enrolled, but subsequently found to not meet all the eligibility criteria must not be 
randomized or initiated on treatment, and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca Study 
Physician immediately, and a discussion should occur between the AstraZeneca Study 
Physician and the Investigator regarding whether to continue or discontinue the patient 
from treatment. The AstraZeneca Study Physician must ensure all decisions are 
appropriately documented and that the potential benefit:risk profile remains positive for 
the patient.
6.2.3
Methods for assigning treatment groups
The actual treatment given to patients will be determined by the randomization scheme in 
the 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 IWRS per country regulations. Randomization codes will 
be assigned strictly sequentially, within each stratum, as patients become eligible for 
randomization. The IWRS will provide the kit identification number to be allocated to the 
patient at the randomization visit and subsequent treatment visits.
6.2.4
Methods for ensuring blinding
The study is being conducted in a double-blind fashion. Investigator and all study staff, 
study team, and Sponsor will be fully blinded to all treatment.
The IWRS will provide to the Investigator(s) or pharmacists (or a trained delegate) the kit 
identification number to be allocated to the patient at the dispensing visit.
Routines for this will be described in the IWRS user manual that will be provided to each 
center.
The randomization code should not be broken except in medical emergencies and/or when 
the appropriate management of the subject requires knowledge of the treatment 
randomization. The Investigator documents and reports the action to AstraZeneca, without 
revealing the treatment given to subject to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities. Randomization codes will not be broken for the planned analyses of 


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data until all decisions on the evaluability of the data from each individual subject have 
been made and documented.
The IWRS will provide to the Investigator and pharmacists or a trained delegate the kit 
identification number to be allocated to the patient at the dispensing visit. Blinded access 
and notifications will be controlled using the IWRS. Investigators will remain blinded to 
each subject’s assigned study treatment throughout the course of the study.
In the event that the treatment allocation for a subject becomes known to the Investigator 
or other study staff involved in the management of study patients, or needs to be known to 
treat an individual patient for an AE, the Sponsor must be notified promptly by the 
Investigator and if possible, before unblinding.
6.2.5
Methods for unblinding the study
The IWRS will be programmed with blind-breaking instructions. The blind may be broken 
if, in the opinion of the Investigator, it is in the patient’s best interest for the Investigator to 
know the study treatment assignment. The Sponsor must be notified before the blind is 
broken unless identification of the study treatment is required for a medical emergency in 
which the knowledge of the specific blinded study treatment will affect the immediate 
management of the patient’s condition (eg, antidote available). In this case, the Sponsor 
must be notified within 24 hours after breaking the blind. The date and reason that the 
blind was broken must be recorded in the source documentation and eCRF. Study 
unblinding should not occur until DBL and all decisions on the evaluability of the data 
from each individual patient have been made and documented.
If the blind is broken, a patient should continue to be followed up per the SoAs outlined in 
Table 3.
6.3
Treatment compliance
The administration of IP should be recorded in patient source documents.
Any change from the dosing schedule, dose delays/interruptions, and dose discontinuations 
should be recorded in patient source documents.
Treatment compliance will be ensured by reconciliation of site drug accountability logs.
The Investigational Product Storage Manager is responsible for managing the IP from 
receipt by the study site until the destruction or return of all unused IP. The Investigator(s) 
is responsible for ensuring that the patient has returned all unused IP.


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6.4
Concomitant therapy
6.4.1
Restrictions for patients during the first screening and surveillance 
periods
This section will no longer apply following CSP v2.0 implementation; patients who are
in first screening and surveillance will be discontinued from the study.
Patients who have signed ICF1 and have initiated the surveillance period are prohibited 
from taking any anti-cancer medication.
The Investigator must be informed as soon as possible about any anti-cancer therapy taken 
from the time of the first screening and during the surveillance period (see Table 9).
6.4.2
Restrictions for patients during the second screening and treatment
The Investigator must be informed as soon as possible about any medication taken from 
the time of the second screening through 90 days following the last dose of study treatment 
(either blinded study treatment or open-label durvalumab) or (if the patient will not receive 
open-label durvalumab) until patient discontinuation from study.
Any medication or vaccine, including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements, that the patient is receiving at the time of enrollment 
or receives during the study (including treatment with open-label durvalumab and 
associated 90-day follow-up period) must be recorded in patient source documents along 
with:
!
Reason for use
!
Dates of administration including start and end dates
!
Dosage information including dose and frequency
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 Table 9 and 
Table 10. Refer also to the Dosing Modification and Toxicity Management Guidelines (see 
Section 8.4.5).
Table 9
Prohibited concomitant medications
Medication/class of drug:
Usage:
Any investigational anticancer therapy other 
than those under investigation in this study
Should not be given concomitantly while the patient is 
on study treatment (second screening and 
randomization [initiated with the signing of ICF2a]) 
mAbs against CTLA-4, PD-1, or PD-L1 other 
than those under investigation in this study
Should not be given concomitantly while the patient is 
on study treatment


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Table 9
Prohibited concomitant medications
Medication/class of drug:
Usage:
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal 
therapy for cancer treatment other than those 
under investigation in this study
Should not be given concomitantly while the patient on 
study treatment (second screening and randomization; 
initiated with the signing of ICF2a). Concurrent use of 
hormones for non-cancer-related conditions [eg, 
insulin for diabetes and hormone replacement therapy] 
is acceptable at any time in the study. 
Live attenuated vaccines 
Should not be given through 30 days after the last dose 
of IP
Immunosuppressive medications including, but 
not limited to systemic corticosteroids at doses
exceeding 10 mg/day of prednisone or 
equivalent methotrexate, azathioprine, and 
tumor necrosis factor –alpha blockers
Should not be given concomitantly or used for 
premedication prior to the IO infusions. The following 
are allowed exceptions:
•
Use of immunosuppressive medications for the 
management of IP-related AEs
•
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 (eg, chronic obstructive 
pulmonary disease, radiation, nausea, etc).
Drugs with laxative properties and herbal or 
natural remedies for constipation
Should be used with caution through to 30 days after 
the last dose of IP 
Herbal and natural remedies which may have 
immune-modulating effects
Should not be given concomitantly unless agreed by 
the Sponsor
AE Adverse event; CTLA-4 cytotoxic T-lymphocyte-associated antigen-4; ICF Informed consent form; 
IO Immuno-oncologic therapy; IP Investigational Product; PD-1 Programmed cell death 1; 
PD-L1 Programmed cell death ligand 1.
Table 10
Supportive medications
Supportive medication/class of drug:
Usage:
Concomitant medications or treatments (eg, 
acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications 
identified as “prohibited,” as listed above 
To be administered as prescribed by the Investigator
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy 
to non-target lesions, etc])
Should be used, when necessary, for all patients
Inactivated viruses, such as those in the 
influenza vaccine
Permitted


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6.4.3
Other concomitant treatment
Medication other than that described above, which is considered necessary for the 
subject’s safety and wellbeing, may be given at the discretion of the Investigator and 
recorded in the patient source notes.
For the first screening, surveillance, and exploratory observation periods, any anti-cancer 
medication given must be recorded in the appropriate section of the eCRF prior to patient 
discontinuation from the study.
For the second screening, randomization and study treatment, and follow-up periods, any 
concomitant medications must be reported in the appropriate section of the eCRF or (if 
patient has started open-label durvalumab or has discontinued the study) in patient source 
notes.
In the event that an SAE occurs during either the first or second screening period, the 
concomitant medications given for that SAE must be reported in the appropriate section of 
the eCRF.
6.4.4
Durvalumab drug-drug interactions
There is no information to date on drug-drug interactions with durvalumab either pre-
clinically or in patients. As durvalumab is a mAb and therefore a protein, it will be 
degraded to small peptides and amino acids and will be eliminated by reticuloendothelial 
clearance. It is therefore not expected that durvalumab will induce or inhibit the major 
drug metabolizing cytochrome P450 pathways. As a result, there are no expected PK drug-
drug interactions. The mechanism of action of durvalumab involves binding to PD-L1, and 
therefore significant pharmacodynamic drug interactions with the commonly administered 
concomitant medications are not expected. Despite this, appropriate clinical monitoring in 
all of the planned clinical studies will be conducted to evaluate any potential drug-drug 
interactions.
6.5
Dose modification
This section is not applicable following implementation of CSP v2.0 at site. Refer to 
Dosing Modification and Toxicity Management guidelines (Section 8.4.5).
Dose delays are permitted for IO therapy (see Dosing Modification and Toxicity 
Management Guidelines) (See Section 8.4.5).
The patient should receive up to 26 cycles of durvalumab or placebo, even if a dose delay 
causes the treatment period to extend beyond 24 months.
However, dose reduction is not permitted.
6.6
Treatment after the primary DFS analysis
This section is not applicable following implementation of CSP v2.0 at site.


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After the primary DFS analysis, the study will be unblinded and AstraZeneca will continue 
to supply open-label drug to patients receiving durvalumab up to completion of a patient's 
24-month treatment period (26 cycles of treatment) or the time that they discontinue the 
treatment for whatever reason (including roll-over to another study) (see Section 6.1.3 and 
7.3).
Patients who are still receiving durvalumab at the time of primary DFS analysis should 
follow the scheduled visits as described in Table 2. Safety data, including safety labs, and 
OS should be reported and entered into the database until final DCO. Efficacy scans will 
be collected in accordance with local clinical practice.
Subsequent therapy and OS data will continue to be collected following the DBL for 
primary DFS analysis on all patients in follow-up and in observation until final DCO.
7
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL
7.1
Discontinuation of study treatment
Patients receiving durvalumab
An individual patient will not receive any further IP (durvalumab) 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 (eg, 
for safety and survival follow-up) unless they specifically withdraw their consent to 
all further participation in any study procedures and assessments (see Section 7.3).
!
An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates further 
dosing
!
Any AE that meets criteria for discontinuation as defined in the Dosing Modification 
and Toxicity Management Guidelines (see Section 8.4.5)
!
Pregnancy or intent to become pregnant
!
Non-compliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from treatment with IP (eg, refusal to adhere to 
scheduled visits)
!
Initiation of alternative anticancer therapy including another investigational agent
!
Documented recurrence of disease (Section 8.1.1 and Appendix G text is retained in 
this protocol version as guidance for Investigators) or Investigator determination that 
the patient is no longer benefiting from treatment with IP.
!
Completion of study treatment (see Section 10.3.1 for updated treatment duration 
details applicable following implementation of the amendment at site).
7.1.1
Procedures for discontinuation of study treatment
This section is not applicable following implementation of CSP v2.0 at site.


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Randomized patients only
This section is applicable only to randomized patients who have initiated treatment with IP 
(ie, it is not applicable to patients in the surveillance or observation periods of the study).
At any time, patients are free to discontinue treatment without prejudice to further 
treatment.
Discontinuation of study treatment, for any reason, does not impact the patient’s 
participation in the study. A patient who decides to discontinue IP will always be asked 
about the reason(s) for discontinuation and the presence of any AE, and the site should 
carefully review the follow-up checklist with the patient. The patient should continue 
attending subsequent study visits, and data collection should continue according to the 
study protocol. If the patient does not agree to continue in-person study visits, a modified 
follow-up must be arranged to ensure the collection of endpoints and safety information. 
This follow-up could be a telephone contact with the patient, a contact with a relative or 
treating physician, or information from medical records. The approach taken should be 
recorded in the medical records. A patient that agrees to modified follow-up is not 
considered to have withdrawn consent or to have withdrawn from the study.
Patients who are permanently discontinued from further receipt of IP, regardless of the 
reason, will be identified as having permanently discontinued treatment. Patients who are 
permanently discontinued will enter follow-up (see the SoAs Table 3).
Patients who prematurely permanently discontinue IP prior to completing 24 months 
(26 cycles) of treatment for reasons other than RECIST 1.1-defined disease recurrence 
should continue to have scans performed q12w ±1w (relative to the date of randomization) 
until completion of the study or until RECIST 1.1-defined disease recurrence plus an 
additional follow-up scan or death (whichever comes first) as defined in the SoAs 
(Table 3).
If a patient is discontinued for RECIST 1.1-defined disease recurrence, then the patient 
should have 1 additional follow-up scan performed between 4-8 weeks after the prior 
assessment of disease recurrence.
All patients will be followed for survival until the end of the study.
Patients who decline to return to the site for evaluations should be contacted by telephone 
as indicated in the SoAs as an alternative.
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IWRS.
7.2
Lost to follow-up
From CSP v2.0 implementation at site, please refer to Section 10 for lost to follow-up 
definitions for patients who receive open-label durvalumab.


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All enrolled patients
The procedures in this subsection apply to all patients who participate in either the 
surveillance and/or observation periods of this study or who are randomized to treatment 
with IP.
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (see Section 4.3), 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 the secondary endpoint of OS, the survival status of all patients in the 
FAS and the safety analysis set (SAS) should be re-checked; this includes those patients 
who withdrew consent or are classified as “lost to follow-up.” The survival status of all 
patients in the observation period should also be re-checked, including those who 
withdrew consent or are classified as “lost to follow-up”.
!
Potentially lost to follow-up – site personnel should check hospital records, the 
patients’ current physician, and a publicly available death registry (if available) to 
obtain a current survival status. (The applicable eCRF modules will be updated.)
!
In the event that the patient has actively withdrawn consent to the processing of their 
personal data, the survival status of the patient can be obtained by site personnel from 
publicly available death registries (if available) where it is possible to do so under 
applicable local laws to obtain a current survival status. (The applicable eCRF 
modules will be updated.)
The following actions must be taken if a patient fails to return to the clinic for a required 
study visit:
!
The site must attempt to contact the patient and reschedule the missed visit as soon as
possible and counsel the patient on the importance of maintaining the assigned visit
schedule.
!
Before a patient is deemed lost to follow-up, the Investigator or designee must make
every effort to regain contact with the patient or next of kin by, for example, repeat
telephone calls, certified letter to the patient’s last known mailing address, or local
equivalent methods. These contact attempts should be documented in the patient’s
medical record.
!
Efforts to reach the patient should continue until the end of the study. Should the 
patient be unreachable at the end of the study, the patient should be considered to be 
lost to follow-up.


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7.3
Withdrawal from the study
7.3.1
All patients
This section remains in effect following implementation of CSP v2.0 at site.
The procedures in this subsection apply to all patients who participate in either the 
surveillance and/or observation periods of this study or who are randomized to treatment 
with IP.
Patients are free to withdraw from the study at any time (IP and/or 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.
If a patient withdraws consent, the site should review the withdraw consent checklist and 
specifically ask the patient if they are also withdrawing consent to the use of any already 
collected/donated samples (see Section 8.7.3).
7.3.2
MRD- patients who are withdrawn from surveillance by the Sponsor
This section is no longer applicable following implementation of CSP v2.0 at site.
Based on internal Sponsor data, it is estimated that 
 of randomized patients will be 
PD-L1 TC≥1%. To ensure that the target of 
 PD-L1 TC≥1% patients are randomized in 
the study, enrollment of PD-L1 TC<1% patients into surveillance will end after 
PD-L1 TC<1% patients have been randomized to treatment. The remaining PD-
L1 TC<1% patients in surveillance will no longer be tested for MRD nor included in 
subsequent analyses of the study.
Similarly, enrollment into the study will end once 284 MRD+ patients are randomized to 
treatment. The remaining MRD- patients still in surveillance will no longer be tested for 
MRD nor included in subsequent analyses of the study.
In both cases, patients may choose to continue to have CT scans every 12 weeks as part of 
the study until 96 weeks have elapsed (relative to the start of their surveillance), until 
evidence of RECIST 1.1-defined disease recurrence, or until the end of the study 
(whichever occurs first), after which they will receive SoC per local clinical practice. No 
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data, including OS data, will be collected on these patients after they are withdrawn from 
surveillance.
8
STUDY ASSESSMENTS AND PROCEDURES
From CSP v2.0 implementation at site, please use Section 10 as a reference point for the 
study. This study has closed enrolment early and patients will either start open-label
durvalumab or be discontinued from the study.
Study assessments are clearly indicated in Section 10. Assessments and reporting of 
adverse events (Sections 8.3and 8.4) have been retained; these sections must be followed 
for AE assessments and reporting prior to patient starting open-label durvalumab 
treatment or discontinuing the study. Sections 8.6 and 8.7 have been retained as a 
reference for samples collected prior to CSP v2.0 implementation at site; please note that 
no additional samples will be collected from patients once they have discontinued the 
study or have started to receive open-label durvalumab. Sections 8.1, 8.2, and 8.5 below 
refer to the original study assessments and procedures; these sections are not applicable
following implementation of CSP v2.0 but are included below for reference and data 
completion.
Study procedures and their timing are summarized in the SoAs (Table 1, Table 2, Table 3,
and Table 4).
The Investigator will ensure that data are recorded on the eCRFs. The RAVE Web Based 
Data Capture system will be used for data collection and query handling.
The Investigator ensures the accuracy, completeness, legibility, and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement. The Investigator will sign the completed eCRFs. A copy of the completed 
eCRFs will be archived at the study site.
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue study 
treatment.
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the patient’s routine clinical management (eg, blood count 
and imaging assessments) and obtained before signing of ICF1 and/or ICF2a may be 


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utilized for screening or baseline purposes provided the procedures met the protocol-
specified criteria and were performed within the time frame defined in the SoAs.
8.1
Efficacy assessments
This study will evaluate the primary endpoint of DFS in the PD-L1 TC ≥1% analysis set, 
using Investigator assessments according to RECIST 1.1. See Section 8.1.1 for details on 
the assessment of DFS.
Secondary efficacy endpoints will include DFS in all patients (FAS), also using 
Investigator assessment according to RECIST 1.1; DFS in both the PD-L1 TC≥1% patients 
and the FAS using Blinded Independent Central Review (BICR) assessments according to 
RECIST 1.1; and PFS, 
, 
 
, and OS in both PD-L1 TC ≥1% analysis set and the FAS.
Radiological assessment of scans will be according to RECIST 1.1 guidelines 
(Appendix G).
A “baseline” scan of MRD+ patients must be performed within 28 days ± 7 days prior to
randomization (Table 2). Subsequent scans are to be performed every 8 weeks (q8w±1w) 
from week 8-48, and then every 12 weeks (q12w±1w) until RECIST 1.1-defined disease 
recurrence is recorded. If an unscheduled assessment is performed and the patient has not 
shown evidence of disease recurrence, every attempt should be made to resume subsequent 
assessments according to the original imaging visit schedule. For patients who discontinue 
treatment due to toxicity or other reasons in the absence of RECIST 1.1-defined 
radiological disease recurrence, disease assessments should continue according to the 
schedule of assessments.
!
Note: MRD- patients in surveillance will have CT scans q12w±1w for up to 96 weeks 
of surveillance, until they become MRD+ (and thus eligible for randomization), or 
until RECIST 1.1-defined disease recurrence is recorded.
!
Note: For MRD- patients who enter the observation arm, scans will be performed 
q12w±1w for 24 months (up to 8 additional visits) or until RECIST 1.1-defined 
disease recurrence is recorded.
8.1.1
Disease-free survival
Disease-free survival is the primary endpoint in this study and is defined as the time from 
the date of randomization until any one of the following events:
!
Disease recurrence
Local, regional or distant disease recurrence
Diagnosis of a second primary NSCLC
OR
!
Death from any cause
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As DFS is the primary endpoint in this study, it is vital that it be adequately and precisely 
documented.
The imaging modalities used for radiological assessments will be CT scans of the chest 
and abdomen (including liver and adrenal glands) with contrast. In the rare case where a 
patient is contrast intolerant, the preferred imaging would be CT chest without contrast and 
MRI abdomen with contrast; however, a non-contrast abdominal CT will also be accepted. 
The methods used at baseline (CT or MRI) must be used at each subsequent follow-up 
assessments.
The “baseline” scan of MRD+ patients must be performed within 28 days ± 7 days prior 
to randomization (Table 2). Subsequent assessments are to be performed every 8 weeks 
(q8w±1w) until Week 48, and then every 12 weeks (q12w±1w) until RECIST 1.1-defined 
disease recurrence is recorded. If a patient discontinues treatment prior to disease 
recurrence or receives other anti-cancer treatment, patient should continue to be imaged in 
accordance with this schedule until disease recurrence is noted. It is important to follow 
the assessment schedule as closely as possible. If scans are performed outside of the 
scheduled visit (± 7 days window interval; unscheduled assessment) and the patient has not 
recurred, every attempt should be made to perform the subsequent scans at their scheduled 
timepoints. Any other sites at which a new disease is suspected should also be 
appropriately imaged during the study.
8.1.1.1
Evidence of disease recurrence
Disease recurrence is defined as evidence of RECIST 1.1-defined disease recurrence on 
CT or MRI scan and/or pathological disease on biopsy by investigational site assessment
NOTES:
1
The finding of a new lesion should be unequivocal. If a new lesion is equivocal, for 
example because of its small size, continued therapy and follow-up evaluation will 
clarify if it represents truly new disease. If repeat scans (4-8 weeks later) definitively 
confirm there is a new lesion, then recurrence should be declared using the date of the 
initial scan where the equivocal new lesion was first identified.
2
For all patients, upon detection of definitive recurrent disease, an additional follow-up 
scan should be performed 4-8 weeks later. Additional scans to be completed per 
standard practice post progression.
3
Please refer to Appendix G for measurability and criteria for new lesions according to 
RECIST 1.1, and further guidance on defining disease recurrence.
4
Invasive biopsy is recommended for all cases of disease recurrence.
Recurrence will be categorized as local/regional, distant, or second primary NSCLC. 
When recurrence is first documented at any site, complete restaging is required to identify 
all sites of recurrence.


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Local or regional recurrence
Local or regional recurrence is defined as recurrence in the area of the tumor bed, hilum or 
mediastinal lymph nodes. Loco-regional recurrence of the disease should be 
cytologically/histologically confirmed.
Distant recurrence
Distant recurrence is defined as spread of disease beyond the area of the tumor bed, hilum 
or mediastinal lymph nodes and can describe extrathoracic disease, metastasis to the 
contralateral lung, pleural metastasis, pleural effusion, or pericardial effusion. Distant 
recurrence should be diagnosed by radiological examination and/or histopathological 
confirmation when the metastatic lesion is easily accessible for biopsy.
Second primary NSCLC
Second primary NSCLC is defined as diagnosis of a new primary invasive NSCLC and 
should be pathologically or molecularly defined. A new cancer other than NSCLC is 
defined as diagnosis of a new malignancy excluding second primary NSCLC or recurrent 
NSCLC and should be pathologically defined as well.
If the site staff is unsure whether a new lesion represents NSCLC recurrence, a second 
primary NSCLC, or a new malignancy, a tissue biopsy should be performed to characterize 
the nature of the new lesion. If a new lesion cannot be unequivocally confirmed as a 
second primary NSCLC or a new malignancy other than NSCLC by tissue analysis, the 
new lesion should be considered a NSCLC recurrence and documented as such.
The development of a new cancer other than NSCLC should be regarded as an SAE (see 
Section 8.3.10).
8.1.1.2
Dating of recurrence
Dating of recurrence should always be based on the first onset of a sign but never on the 
onset of a symptom. The date of first detection of a palpable lesion is acceptable only 
when the diagnosis of tumor involvement is subsequently established. The diagnosis of 
recurrent disease by radiographs or scans should be dated from the date of the first positive 
record, even if this is determined in retrospect, or tissue confirmation occurs subsequent to 
the initial appearance of a suspicious area/lesion on a scan.
If there is equivocal progression and the site staff is unsure whether to consider this a DFS 
event, the medical monitor/study physician should be contacted.
8.1.1.3
Post-recurrence
Following recurrence, patient management is at the discretion of the Investigator, and 
tumor assessments will be in accordance with local policy. First PFS 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 


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progression, or death. Date of PFS as indicated in the SoAs (Table 2 and Table 3) will be 
collected per local practice and entered into the database
8.1.2
Computed tomography and magnetic resonance imaging
Efficacy evaluation of DFS will be derived using Investigator assessments according to 
RECIST 1.1. The management of patients will be based solely upon the results of the 
RECIST 1.1 assessment conducted by the Investigator.
8.1.2.1
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 for BICR. Guidelines for image acquisition, de-identification, storage of 
digital copies at the investigative site (as source documents), and transfer to the imaging 
CRO will be provided in a separate document. A BICR of images will be performed at the 
discretion of AstraZeneca. Results of these independent reviews will not be communicated 
to Investigators, and results of Investigator RECIST 1.1 assessments will not be shared 
with the central reviewers. The management of patients will be based in part upon the 
results of the RECIST 1.1 assessment conducted by the Investigator. Further details of the 
BICR will be documented in the Independent Review Charter.
8.1.3
Survival assessments
Survival assessments must be made according to the SoAs in Table 3 after study treatment 
discontinuation and during the observation period according to the SoAs in Table 4. 
Survival information may be obtained via telephone contact with the patient or the 
patient’s family, or by contact with the patient’s current physician.
The details of first and subsequent therapies for cancer, after discontinuation of study 
treatment, will be collected.
In addition, patients on treatment or in survival follow-up will be contacted following the 
DCO for the primary analysis and all subsequent survival analyses to provide complete 
survival data. These contacts should generally occur within 7 days of the DCO.
8.1.4
Clinical outcome assessments
A Clinical Outcome Assessment (COA) is any assessment that may be influenced by 
human choices, judgment, or motivation and may support either direct or indirect evidence 
of treatment benefit. Patient-Reported Outcome (PRO) is one of the types of COAs. PRO, 
an umbrella term referring to all outcomes and symptoms, is directly reported by the 
patient. PRO has become a significant endpoint when evaluating effectiveness of 
treatments in clinical studies. The following PROs have been administered in this study: 
EORTC QLQ-C30; EORTC QLQ-LC13, 
, 
 
, 
, 
, and 
. Each is 
described below.
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8.1.4.1
EORTC QLQ-C30 and EORTC QLQ-LC13
The EORTC QLQ-C30 was developed by the EORTC Quality of Life Group in 1993. It 
consists of 30 items and measures symptoms, functioning, and global health status/quality 
of life (QoL) (Aaronson et al 1993) for all cancer types. Questions are grouped into 5 
multi-item functional scales (physical, role, emotional, cognitive, and social); 3 multi-item 
symptom scales (fatigue, pain, and nausea and vomiting); a 2-item global QoL scale; 5 
single items assessing additional symptoms commonly reported by cancer patients 
(dyspnea, loss of appetite, insomnia, constipation, and diarrhea), and 1 item on the 
financial impact of the disease. The EORTC QLQ-C30 is a valid and reliable PRO 
instrument in this patient population (see Appendix I).
The EORTC QLQ-LC13 is a well-validated complementary module measuring lung 
cancer associated symptoms (Bergman et al 1994). The QLQ-LC13 includes questions 
assessing cough, hemoptysis, dyspnea, site-specific pain, sore mouth, dysphagia, 
peripheral neuropathy, alopecia, and pain medication (see Appendix I).
8.1.4.2
The 
 will be used to explore the impact of treatment and disease state on health 
state utility.
The 
, developed by the 
, is a generic questionnaire that provides 
a simple descriptive profile of health and a single index value for health status for 
economic appraisal 
. The 
 questionnaire comprises  
questions that cover  dimensions of health
 
 
 
8.1.4.3
 
 
 
 
 
 
 
8.1.4.4
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CCI
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CCI
CCI
CCI
CCI
CCI
CCI
CCI
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8.1.4.5
Administration of patient-reported outcome questionnaires
The PRO instruments will be self-administered by the patients using a handheld electronic 
device. Patients will start to report PROs on Cycle 1 Day 1 before dosing (baseline 
assessments), to ensure that the device is correctly set up and working properly.
Thereafter, PRO assessments should be completed by the randomized patients at home 
according to the SoAs in Table 2 and Table 3. Multiple PRO assessments scheduled for the 
same time do not have to be completed on the same day, but should be completed within a 
window of ±3 days prior to treatment administration.
The instructions below should be followed when collecting PRO data via an electronic 
device:
!
The research nurse or appointed site staff must explain to patients the value and 
relevance of electronic patient-reported outcomes (ePRO) participation so they are 
motivated to comply with questionnaire completion. Inform the patient that these 
questions are being asked to find out, directly from them, how they feel
!
PRO questionnaires must be completed prior to treatment administration and before 
discussion of health status to avoid biasing the patient’s responses to the questions.
!
Each site must allocate the responsibility for the administration of the ePRO devices to 
a specific individual (eg, a research nurse or study coordinator) and, if possible, assign 
a backup person to cover if that individual is absent
!
The research nurse or appointed site staff should stress that the information is not 
routinely shared with study staff. Therefore, if patient has any medical problems, they 
should discuss them with the doctor or research nurse separately from the ePRO 
assessment.
!
The research nurse or appointed site staff must remind patients that there are no right 
or wrong answers and avoid introducing bias by not clarifying items. The patient 
should not receive help from relatives, friends, or clinic staff to answer the PRO 
questionnaires. The patients should be given sufficient time to complete the PRO 
questionnaires at their own speed.
!
The research nurse or appointed site staff must train the patient on how to use the 
ePRO device using the materials and training provided in the ePRO device.
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!
The research nurse or appointed site staff must provide guidance on whom to call if 
there are problems with the device if the patient is completing the ePRO at home.
!
All questionnaires must be completed using the ePRO device; paper questionnaires are 
not allowed in this study.
!
If the patient is unable to read the questionnaire (eg, is blind or illiterate), that patient 
should be exempted from completing PRO questionnaires but may still participate in 
the study. Patients exempted in this regard should be flagged appropriately by the site 
staff in the source documents and in the eCRF.
A key aspect of study success is to have high PRO compliance. To minimize missing data, 
compliance must be checked and discussed with the patient at each site visit, and the 
reason(s) why the patient could not complete assessments should be documented in source 
documents and in eCRF. 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.
8.2
Safety assessments
Planned timepoints for all safety assessments are provided in the SoAs (Table 2 and 
Table 3).
8.2.1
Clinical safety laboratory assessments
Blood and urine samples for determination of clinical chemistry, hematology, and 
urinalysis will be taken at the times indicated in the assessment schedules and as clinically 
indicated (see the SoAs [Table 2 and Table 3]).
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. 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 11 (clinical chemistry), 
Table 12 (hematology), and Table 13 (urinalysis).
Other safety tests to be performed at screening include assessment for hepatitis B surface 
antigen, hepatitis C antibodies, and HIV antibodies.
The following laboratory variables will be measured:


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Table 11
Clinical chemistry
Albumin
Lipaseb
Alkaline phosphatase
Magnesiumc
ALTa
Potassium
Amylaseb
Sodium
ASTa
Total bilirubina
Bicarbonatec
Total protein
Calcium 
TSHe
Chloridec
T3 freef (reflex)
Creatinined
T4 freef (reflex)
Gamma glutamyltransferasec
Urea or blood urea nitrogen, depending on local practice
Glucose
Lactate dehydrogenase
a
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed 
concurrently. If total bilirubin is ≥2 × upper limit of normal (and no evidence of Gilbert’s syndrome), 
then fractionate into direct and indirect bilirubin.
b
It is preferable that both amylase and lipase parameters are assessed. For sites where only 1 of these 
parameters is routinely measured, either lipase or amylase is acceptable.
c
Bicarbonate (where available), chloride, creatinine clearance, gamma glutamyltransferase, magnesium, 
testing are to be performed at baseline, on Day 1 (unless all screening laboratory clinical chemistry 
assessments are performed within 3 days prior to Day 1), and if clinically indicated.
d
Creatinine clearance will be calculated by data management using Cockcroft-Gault (using actual body 
weight).
e
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at 
Day 1.
f
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE 
related to the endocrine system.
AE Adverse Event; ALT Alanine aminotransferase; AST Aspartate aminotransferase; T3
Triiodothyronine; T4 Thyroxine; TSH Thyroid-stimulating hormone.
Table 12
Hematology
Absolute neutrophil counta
Absolute lymphocyte counta
Hemoglobin
Platelet count
Total white cell count
a
Can be recorded as absolute counts or as percentages. Absolute counts will be calculated by Data 
Management if entered as percentage. Total white cell count therefore has to be provided.
Note: For coagulation parameters, activated partial thromboplastin time (either as a ratio or as an absolute 
value, in seconds) and international normalized ratio are to be assessed at baseline on Day 1 (unless all 
screening laboratory hematology assessments are performed within 3 days prior to Day 1), and as clinically 
indicated.
Table 13
Urinalysis
Bilirubin
Ketones
Blood
pH
Color and appearance
Protein
Glucose
Specific gravity
Note: Urinalysis should be done at baseline (screening) and then as clinically indicated.


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Note: Microscopy is preferred to investigate white blood cells with the use of high-power field for red and 
white blood cells; dipstick can be used as well.
If a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, refer 
to Appendix E for further instructions on cases of increases in liver biochemistry and 
evaluation of Hy’s Law. These cases should be reported as SAEs if, after evaluation, they 
meet the criteria for a Hy’s law case or if any of the individual liver test parameters fulfill 
any of the SAE criteria.
All patients should have further chemistry profiles performed at 30 days (±3 days), 2 
months (±1 week), and 3 months (±1 week) after permanent discontinuation of IP 
(Table 3).
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF. Situations in which laboratory safety results should 
be reported as AEs are described in Section 8.3.7.
All patients with Grade 3 or 4 laboratory values at the time of completion or 
discontinuation from IP must have further tests performed until the laboratory values have 
returned to Grade 1 or 2, unless these values are not likely to improve because of the 
underlying disease.
8.2.2
Medical history
A complete medical history will be obtained at the second screening prior to 
randomization (Table 2) and on the day of or prior to entry into the observation period 
(Table 4); medical history information will be obtained only in in the event of a reported 
SAE during the first screening period or surveillance period (Table 1). A complete medical 
history may also be obtained from screen failed patients (see Section 5.5).
Findings from current medical history will be assigned a baseline grade according to NCI 
Common Terminology Criteria for Adverse Events (CTCAE) v5.0 guidelines, whenever 
applicable. As a result, increases in severity of pre-existing conditions during the study 
will be considered AEs, with resolution occurring when the grade returns to the baseline 
grade or below.
8.2.3
Physical examinations
No physical examination will be performed during the first screening (initiated by the 
signing of ICF1).
Physical examinations will be performed according to the assessment schedules (see the 
SoAs [Table 2 and Table 3]). 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 the second screening only. Targeted physical 
examinations are to be utilized by the Investigator on the basis of clinical observations and 


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symptomatology. Situations in which physical examination results should be reported as 
AEs are described in Section 8.3.7.
8.2.4
Vital signs
Vital signs (BP, pulse, temperature, and respiration rate) will be evaluated according to the 
SoAs (Table 2 and Table 3). Body weight is also recorded at each visit along with vital 
signs.
First infusion of durvalumab or placebo
On the first infusion day, patients 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.
BP and pulse will be collected from patients 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 [ie, the beginning of the infusion])
!
Approximately 30 minutes during the infusion (halfway through infusion)
!
At the end of the infusion (approximately 60 minutes ±5 minutes)
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. If 
there are no clinically significant concerns after the first cycle, reducing the observation 
period after durvalumab administration to 30 minutes is recommended, at the 
Investigator’s discretion.
Subsequent infusions of durvalumab or placebo
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.
Situations in which vital signs results should be reported as AEs are described in 
Section 8.3.7. For any AEs of infusion reactions, the vital signs values should be entered 
into the CRF.
8.2.5
Electrocardiograms
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout 
the study (see the SoAs). ECGs should be obtained after the patient has been in a supine 
position for 5 minutes and recorded while the patient remains in that position.


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In case of clinically significant ECG abnormalities, including a QT interval corrected for 
heart rate using Fridericia’s formula (QTcF) value >470 ms, 2 additional 12-lead ECGs 
should be obtained over a brief period (eg, 30 minutes) to confirm the finding.
Situations in which ECG results should be reported as AEs are described in Section 8.3.7.
8.2.6
Early patient review for safety
It is recommended that patients are contacted 2 weeks after receiving the first 3 cycles of 
durvalumab or placebo (Cycle 1 Day 14, Cycle 2 Day 14, and Cycle 3 Day 14) of IP(s) to 
ensure early identification and management of toxicities.
8.2.7
WHO/ECOG performance status
WHO/ECOG performance status will be assessed at the times specified in the assessment 
schedules (see the SoAs) based on the following:
0
Fully active; able to carry out all usual activities without restrictions
1
Restricted in strenuous activity, but ambulatory and able to carry out light work or 
work of a sedentary nature (eg, light housework or office work)
2
Ambulatory and capable of self-care, but unable to carry out any work activities; up 
and about more than 50% of waking hours.
3
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours
4
Completely disabled; unable to carry out any self-care and totally confined to bed or 
chair
5
Dead
Any significant change from baseline or screening must be reported as an AE.
8.2.8
Other safety assessments
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormality 
suggestive of pneumonitis/ILD is observed, toxicity management as described in detail in 
the Dosing Modification and Toxicity Management Guidelines (see Section 8.4.5) will be 
applied. The results of the full diagnostic workup (including high-resolution computed 
tomography [HRCT], blood and sputum culture, hematological parameters, etc) will be 
captured in the eCRF. It is strongly recommended to perform a full diagnostic workup, to 
exclude alternative causes such as lymphangitic carcinomatosis, infection, allergy, 
cardiogenic edema, or pulmonary hemorrhage. In the presence of confirmatory HRCT 
scans where other causes of respiratory symptoms have been excluded, a diagnosis of 
pneumonitis (ILD) should be considered and the Dosing Modification and Toxicity 
Management Guidelines should be followed.


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Pneumonitis (ILD) investigation
The following assessments, and additional assessments if required, will be performed to 
enhance the investigation and diagnosis of potential cases of pneumonitis. The results of 
the assessment will be collected.
!
Physical examination
Signs and symptoms (cough, shortness of breath, and pyrexia, etc) including 
auscultation for lung field will be assessed.
!
SpO2
Saturation of peripheral oxygen (SpO2)
!
Other items
When pneumonitis (ILD) is suspected during study treatment, the following markers 
should be measured where possible:
o
ILD Markers (KL-6, SP-D) and β-D-glucan
o
Tumor markers: Particular tumor markers which are related to disease 
progression
o
Additional Clinical chemistry: C-reactive protein, lactate dehydrogenase
8.3
Collection of adverse events
The Principal Investigator (PI) is responsible for ensuring that all staff involved in the 
study are familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative).
The Investigator and any designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. For information on how to 
follow up on AEs, see Section 8.3.3.
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.
8.3.2
Time period and frequency for collecting AE and SAE information
SAEs will be collected from the time of the patient signing ICF1 and for patients who 
participate in the surveillance and observation periods. Both AEs and SAEs will be 
collected from the time the patient signs ICF2a, which initiates the second screening, until 
the follow-up period is completed (90 days after the last dose of IP). If an event that starts 
post the defined safety follow-up period noted above is considered to be due to a late onset 


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toxicity to IP then it should be recorded in patient source notes as an AE or SAE as 
applicable and (in the case of an SAE) reported.
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix B. The Investigator will submit any updated SAE data to the 
Sponsor within 24 hours of it being available.
Investigators are not obligated to actively seek AEs or SAEs in former study subjects. 
However, if the Investigator learns of any SAE, including a death, at any time after a 
subject’s last visit and he/she considers the event to be reasonably related to the Study 
treatment or study participation, the Investigator may notify the Sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow-up of adverse events and serious adverse events
After the initial AE/SAE report, the Investigator is required to proactively follow each 
subject at subsequent visits/contacts. All events will be followed until resolution, 
stabilization, the event is otherwise explained, or the subject is lost to follow-up
Any AEs that are unresolved at the patient’s last AE assessment are followed up by the 
Investigator for as long as medically indicated (this may be beyond the 90 days after last 
dose of IP). AstraZeneca retains the right to request additional information for any subject 
with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
8.3.4
Adverse event data collection
The following variables will be collected for each AE:
!
AE (verbatim)
!
The date when the AE started and stopped
!
The maximum CTCAE grade reported
!
Changes in CTCAE grade (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
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for serious AE
!
Date Investigator became aware of serious AE
!
Seriousness criteria


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!
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)
!
Causality assessment to other medication, as explained in Section 8.3.5
!
Description of SAE
The grading scales found in the revised NCI CTCAE version 5.0 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 5.0 can 
be downloaded from the Cancer Therapy Evaluation Program website 
(http://ctep.cancer.gov).
8.3.5
Causality collection
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ 
or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event 
may have been caused by the IP?’
For SAEs, causal relationship will also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure, the 
causal relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B.
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you 
were last asked?’, or revealed by observation will be collected and recorded in the CRF. 
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.
8.3.7
Adverse events based on examinations and tests
The results from the Clinical Study Protocol-mandated laboratory tests and vital signs will 
be summarized in the clinical summary report (CSR). Deterioration as compared to 
baseline in protocol-mandated laboratory values and vital signs should therefore only be 
reported as AEs if they fulfill any of the SAE criteria or are the reason for discontinuation 
of treatment with the IP.


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If deterioration in a laboratory value/vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory 
result/vital sign will be considered as additional information. Wherever possible the 
reporting Investigator uses the clinical, rather than the laboratory term (eg, anemia versus 
low hemoglobin value). In the absence of clinical signs or symptoms, clinically relevant 
deteriorations in non-mandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which 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 unless 
unequivocally related to the disease under study, see Sections 8.3.9 and 8.3.10.
8.3.8
Hy’s law
Cases where a patient shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 
2xULN may need to be reported as SAEs. Please refer to Appendix E for further 
instruction on cases of increases in liver biochemistry and evaluation of Hy’s Law
8.3.9
Disease recurrence
Events, which are unequivocally due to RECIST 1.1-defined disease recurrence, should 
not be reported as an AE during the study.
8.3.10
New cancers
The development of a new cancer (new non-NSCLC malignancy) 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.
8.3.11
Deaths
All deaths that occur during the study treatment period, or within the protocol-defined 
follow-up period after the administration of the last dose of IP, must be reported as 
follows:
!
Death clearly resulting from disease progression should be reported to the Study 
Monitor/Physician at the next monitoring visit and should be documented in the eCRF 
in the Statement of Death page. It should not be reported as an SAE.
!
Where death is not due (or not clearly due) to progression of the disease under study, 
the AE causing the death must be reported to the Study Monitor/Physician as an SAE 
within 24 hours. It should also be documented in the Statement of Death page in the 
eCRF. The report should contain a comment regarding the co-involvement of PD, if 
appropriate, and should assign main and contributory causes of death.
!
Deaths with an unknown cause should always be reported as an SAE. It should also be 
documented in the Statement of Death page in the eCRF. A post mortem may be 
helpful in the assessment of the cause of death, and if performed, a copy of the post 


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mortem results should be forwarded to AstraZeneca Patient Safety or its representative 
within the usual timeframes.
Deaths occurring after the protocol-defined safety follow-up period after the 
administration of the last dose of IP should be documented in the Statement of Death page. 
If the death occurred as a result of an event that started post the defined safety follow-up 
period and the event is considered to be due to a late onset toxicity to IP, then it should 
also be reported as an SAE.
8.3.12
Adverse events of special interest
An adverse event of special interest (AESI) is one of scientific and medical interest 
specific to understanding of the IP 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 IP.
AESIs for durvalumab include but are not limited to events with a potential inflammatory 
or immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy 
and combination therapy. An imAE is defined as an AESI that is associated with drug 
exposure and is consistent with an immune-mediated mechanism of action and where there 
is no clear alternate etiology. Serologic, immunologic, and histologic (biopsy) data, as 
appropriate, should be used to support an imAE diagnosis. Appropriate efforts should be 
made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the 
imAE.
If the Investigator has any questions in regard to an event being an imAE, the Investigator 
should promptly contact the Study Physician.
AESIs/imAEs observed with anti-PD-L1 agents such as durvalumab include pneumonitis, 
hepatitis, diarrhea/colitis, and intestinal perforation, endocrinopathies (hypo- and hyper-
thyroidism), adrenal insufficiency, hypophysitis/hypopituitarism, and Type I diabetes 
mellitus, nephritis, rash/dermatitis, myocarditis, myositis/polymyositis, pancreatitis, and 
rare/less frequent imAEs including neuromuscular toxicities such as myasthenia gravis and 
Guillain-Barre syndrome.
Other inflammatory responses that are rare/less frequent with a potential immune-mediated 
etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and other events 
involving the eye, skin, hematological, rheumatological events, vasculitis, non-infectious 
meningitis and non-infectious encephalitis. It is possible that events with an inflammatory 
or immune-mediated mechanism could occur in nearly all organs.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology are also considered AESIs.


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Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the durvalumab IB. More specific guidelines for their evaluation and treatment 
are described in detail in the Dose Modification and Toxicity Management Guidelines (see 
also Section 8.4.5). These guidelines have been prepared by the Sponsor to assist the 
Investigator in the exercise of his/her clinical judgment in treating these types of toxicities. 
These guidelines apply to AEs considered causally related to the IP/study regimen by the 
reporting Investigator.
8.3.13
Safety data to be collected following the final DCO of the study
Note for CSP v2.0: Please refer to Section 10.3.2.
For patients continuing to receive durvalumab treatment after final DCO and database 
closure, it is recommended that the patients continue the scheduled site visits and 
Investigators monitor the patient’s safety laboratory results prior to and periodically during 
treatment with durvalumab in order to manage AEs in accordance with the durvalumab 
Dose Modification and Toxicity Management Guidelines (see Section 8.4.5). All data post 
the final DCO and database closure will be recorded in the patient notes but, with the 
exception of SAEs, will not otherwise be reported for the purposes of this study.
All SAEs that occur in patients still receiving durvalumab treatment (or within the 90 days 
following the last dose of durvalumab treatment) after the final DCO and database closure 
must be reported as detailed in Section 8.4.1.
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP, or to 
the study procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel 
inform the appropriate AstraZeneca representatives within one day ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
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 adverse events where important or relevant information is 
missing, active follow-up is undertaken immediately. Investigators or other site personnel 
inform AstraZeneca representatives of any follow-up information on a previously reported 
SAE within one calendar day ie, immediately but no later than 24 hours of when he or 
she becomes aware of it.


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Once the Investigators or other site personnel indicate an AE is serious in the Electronic 
Data Capture (EDC) system, an automated email alert is sent to the designated 
AstraZeneca representative.
If the EDC system is not available, then the Investigator or other study site staff reports a 
SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to 
proceed.
For further guidance on the definition of a SAE, see Appendix B.
8.4.1.1
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 (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the IB or and will notify the IRB/IEC, if appropriate according 
to local requirements.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except if 
the pregnancy is discovered before the study subject has received any IP.
If a patient become pregnant while in surveillance, the patient will be withdrawn from 
surveillance.
If a pregnancy is reported after the patient has received any IP, the Investigator should 
inform the Sponsor within 24 hours of learning of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.


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8.4.2.1
Maternal exposure
If a patient becomes pregnant while in surveillance, the patient will be withdrawn from 
surveillance. If a patient becomes pregnant after they are randomized in this study, IP 
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/birth defects and spontaneous miscarriages should be reported and handled 
as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and 
documented even if the patient was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day (ie, 
immediately but no later than 24 hours of when he or she becomes aware of it).
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 
or 5 calendar days for SAEs (see Section 8.4.1) and within 30 days for all other 
pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is 
used to report the outcome of the pregnancy.
8.4.2.2
Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study and 
for 90 days after the last dose of IP. Please follow the local prescribing information 
relating to contraception.
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, or congenital abnormality) occurring from the date of the first dose until 90 days 
after the last dose of IP should, if possible, be followed up and documented.
Where a report of pregnancy is received, prior to obtaining information about the 
pregnancy, the Investigator must obtain the consent of the patient’s partner. Therefore, the 
local study team should adopt the generic ICF template in line with local procedures and 
submit it to the relevant Ethics Committees/ IRBs prior to use.
Patients who are permanently discontinued from further receipt of IP, regardless of the 
reason, will be identified as having permanently discontinued treatment.


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8.4.3
Overdose
Use of durvalumab in doses in excess of that specified in the protocol is considered to be 
an overdose. There is currently no specific treatment in the event of overdose of 
durvalumab, and possible symptoms of overdose are not established.
!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.
!
An overdose without associated symptoms is only reported on the Overdose CRF 
module
If an overdose on an AstraZeneca IP occurs in the course of the study, then the Investigator 
or other site personnel informs the appropriate AstraZeneca representatives immediately, 
or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see 
Section 8.3.2. For other overdoses, reporting must occur within 30 days.
8.4.4
Medication error
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day ie, 
immediately but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow-up 
Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is 
an SAE associated with the medication error (see Section 8.3.2), and within 30 days for all 
other medication errors.
The definition of a Medication Error can be found in Appendix B.
8.4.5
Specific toxicity management and dose modification information –
Durvalumab
The following general guidance should be followed for management of toxicities.
!
Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity if required).
!
If the symptoms promptly resolve with supportive care, consideration should be given 
to continuing the same dose of the assigned IP along with appropriate continuing 
supportive care. If medically appropriate, dose modifications are permitted.
!
All dose modifications should be documented with clear reasoning and documentation 
of the approach taken.


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!
Patients should be thoroughly evaluated to rule out any alternative etiology (eg, 
disease progression, concomitant medications, or infections).
All toxicities will be graded according to NCI CTCAE, Version 5.0.
Comprehensive toxicity management guidelines (TMG) have been developed to assist 
Investigators with the recognition and management of toxicities associated with the use of 
the immune checkpoint inhibitor durvalumab (PD-L1 inhibitor). These guidelines are 
applicable when durvalumab is used alone or in combination (concurrently or sequentially) 
with other anticancer drugs (ie, antineoplastic chemotherapy, targeted agents), 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 dose modifications (including 
discontinuations) and treatment interventions. Investigators are advised, however, to use 
local practice guidelines and consult local references for the management of toxicities 
observed with the SoC chemotherapy regimen(s) administered. The most current version 
of the TMGs 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” is provided to the investigative site as an Annex document 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 imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an 
imAE diagnosis. In the absence of a clear alternative etiology, events should be considered 
potentially immune-related. In addition, there are certain circumstances in which 
durvalumab should be permanently discontinued (see Section 7.1 of this protocol and refer 
to the Dosing Modification and Toxicity Management Guidelines). 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 regimen by the reporting 
Investigator.
Dose reductions are not permitted. In case of doubt, the Investigator should consult with 
the Study Physician.
Dose Delays: Patients may delay dosing under certain circumstances.
!
Dosing may be delayed per the Dosing Modification and Toxicity Management 
Guidelines (see above), due to either an immune or a non-immune-related AE.


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!
If dosing must be delayed for reasons other than treatment-related toxicity, dosing will 
resume as soon as feasible.
!
Subsequent time between 2 consecutive doses cannot be less than 21 days, based on 
the half-life of durvalumab (see current IB for durvalumab).
If unsure of how to manage a patient, please contact the Study Physician at AstraZeneca to 
discuss individual cases.
8.5
Pharmacodynamics
Plasma ctDNA will be evaluated during and after study treatment as a pharmacodynamic 
parameter. See Section 8.7.2.1 for information on method related to on-study evaluation of 
plasma samples for ctDNA. No other pharmacodynamic parameters were evaluated in this 
study.
8.6
Genetics
8.6.1
Collection of mandatory genetic samples
The patient’s consent to participate in the genetic MRD testing components of the study is 
mandatory and will be obtained in ICF1. See Section 8.7.1.2 for details on sample 
collection, analyses performed, and data storage. This mandatory genetic testing is 
conducted for the detection of MRD and is distinct from the optional genetic research 
component of the study. As part of this mandatory genetic testing, germline DNA (exome 
only) is analyzed to enable the design of the personalized panel for MRD detection and 
subsequent testing for ctDNA.
See Section 8.7.1, Appendix E, and the Laboratory Manual for additional information on 
collection of mandatory genetic samples.
8.6.2
 
 
 
8.6.3
Storage and destruction of genetic samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality. Samples may be stored for a maximum of 
CCI
CCI
CCI
CCI


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15 years or as per local regulations from the date of the Last Patient’s Last Visit, after 
which they will be destroyed. DNA is a finite resource that may be used up during 
analyses. The results of any further analyses will be reported either in the CSR or as an 
addendum, or separately in a scientific report or publication.
No personal details identifying the individual will be available to AstraZeneca or 
designated organizations working with the DNA.
8.7
Biomarkers
By participating in this study, the patient consents to the mandatory collection and use of 
donated biological samples as described here. Samples will be obtained from all screened 
patients. Mandatory samples (described in Section 8.7.1) will be collected from all patients 
who participate in the first screening period (initiated by the signing of ICF1). Samples for 
exploratory endpoints (described in Section 8.7.2) will be collected according to the SoAs 
from patients who participate in the surveillance, second screening, treatment, and/or 
follow-up period(s) and patients in the observation arm.
All samples collected for biomarker analyses will be stored at the study site, a reference 
laboratory, or at AstraZeneca facilities and may be used for subsequent research relevant 
to evaluating biological and/or clinical response to immunotherapy as described in the 
exploratory analyses section.
The results may be pooled with biomarker data from other durvalumab studies to evaluate 
biological responses across indications.
Details for collection, volumes, storage, and shipment of biologic samples are presented in 
a separate Laboratory Manual.
8.7.1
Mandatory biomarkers
8.7.1.1
Assessment of EGFR/ALK mutation status
Results from local EGFR/ALK testing of either a pre-surgery biopsy or the resected tumor 
tissue performed as part of local clinical practice may be used for this study, provided 
testing was performed using a well-validated, local regulatory-approved kit.
If a patient’s EGFR/ALK status was previously determined for MERMAID-1 
(D910LC00001), testing does not need to be repeated, provided a well-validated, local 
regulatory-approved kit was used to test. Patients must sign ICF1 for MERMAID-2 
(D910MC00001) to allow the Sponsor retrospective access to these results (see Section 
5.4).
EGFR/ALK wild-type patients will be enrolled in the study. If local testing or the results of 
local testing are unavailable, EGFR/ALK will be tested by a central reference laboratory 
using resected tumor tissue.


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8.7.1.2
Minimal residual disease
Tumor samples and whole blood for whole exome sequencing and development of 
personalized assay
This study requires comparison of genetic data from a patient’s tumor and blood cells to 
identify tumor-specific mutations for MRD determination (see Section 8.6.1). Countries, 
centers, or patients that do not permit or consent to such analyses will not be able to 
participate in the study.
Detection of MRD in solid tumors requires a complex multi-step assay. Firstly, WES of 
the patient’s tumor is performed on the resected tumor tissue and controlled for germline
mutations by WES of the patient’s whole blood (as indicated in Table 1). A Sponsor-
approved personalized panel is then developed, comprised of the patient’s tumor variants 
expressed at high frequency (see Appendix E for more detail). This panel is then used to 
identify the presence of these variants on ctDNA extracted from the patient’s plasma and 
the patient is considered MRD+ if the panel detects patient-specific tumor variants. This 
personalized approach allows detection of the patient’s tumor variants in DNA at high 
sensitivity. Tumor and whole blood samples, as well as WES data, will be used for 
diagnostic development and exploratory research.
The buffy coat layers obtained from a separate baseline whole blood sample will be 
retained and may be analyzed for germline mutations for future diagnostic development.
If a patient’s MRD panel has already been created during screening for MERMAID-1 
(D910LC00001), that panel can be used for this study (see Section 5.4).
Details on tumor and whole blood sample collection, processing, storage, and shipment are 
provided in the Laboratory Manual.
Plasma samples for determination of MRD status based on ctDNA
Once plasma has been drawn, cell-free DNA is extracted and a polymerase chain reaction 
is performed using primers from the patient-specific panel designed based on the WES 
data (the generation of which is described above). The resulting amplicons are then 
sequenced and analyzed by the proprietary Analysis MRD bioinformatics pipeline at the 
designated organization, which reports on the presence or absence of ctDNA and detection 
of MRD.
A plasma sample will be collected 8 weeks ± 1 week after the completion of adjuvant 
therapy (which can include PORT) or 12 weeks ± 1 week after surgery (for patients who 
do not undergo further curative therapy), as indicated in the SoAs (Table 1). Collection of 
this plasma sample marks the start of surveillance.
Note: The Sponsor will obtain the pre-surgery plasma samples (if collected) from patients 
who were screen fails during the first screening period for MERMAID-1 (D910LC00001) 
before enrolling in MERMAID-2 (D910MC00001) (see Section 5.4).


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In addition, surveillance, on- and post-treatment, and observation plasma samples will be 
collected longitudinally for retrospective exploratory evaluations of ctDNA and to support 
exploratory endpoints (see Section 8.7.2.1). Plasma samples, including derived DNA, will 
be used for diagnostic development and exploratory research. No treatment decisions will 
be made based on the results from these samples.
All samples submitted for ctDNA analysis will be coded to prevent patient identification. 
Sequencing data and variant calls from ctDNA analysis will be stored in a secure system at 
designated organizations and/or at AstraZeneca to analyze the sample.
Details on plasma collection, processing, storage, and shipment are provided in the 
Laboratory Manual.
8.7.1.3
Tissue samples for PD-L1 TC expression assessment and biomarker 
research
PD-L1 TC expression will be evaluated prospectively on resected tumor tissue collected 
during surgical resection in all screened patients. Data will be compared between arms to 
determine if baseline PD-L1 status is prognostic and/or predictive of outcomes associated 
with durvalumab versus placebo. Baseline tumor requirements are described in Section 
5.1.
MANDATORY: Provision of tumor tissue from the primary resection, formalin-fixed and 
embedded in paraffin, for the purpose of PD-L1 TC expression analysis (and for enabling 
exploratory analyses as described in Section 8.7.2.2).
Details for collection, volumes, storage, and shipment of biologic samples are presented in 
a separate Laboratory Manual.
PD-L1 TC analysis will be performed by at a central reference laboratory testing service 
using the Ventana SP263 PD-L1 IHC assay.
If a patient’s PD-L1 status has already been determined during screening for MERMAID-1 
(D910LC00001), those results can be used for this study provided the Ventana SP263 
PD-L1 IHC assay was used (see Section 5.4).
A brief description of exploratory tumor markers to be explored is provided in 
Section 8.7.2.2.
8.7.2
Exploratory biomarkers
Additional exploratory analyses may be undertaken on participant’s samples to identify 
other biomarkers of sensitivity and resistance to study interventions and our understanding 
of cancer.
WES data generated during the development of the personalized panel (described above in 
Section 8.7.1.2) may also be used for exploratory purposes to better understand NSCLC 
and/or to identify biomarkers (eg, tissue TMB) which may correlate with patient outcomes.


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Blood and tumor samples for exploratory biomarker analyses will be obtained according to 
the schedules presented in the SoAs (Table 1, Table 2, Table 3, and Table 4). Details for 
collection, volumes, storage, and shipment of biologic samples are presented in a separate 
Laboratory Manual.
Measurements for randomized patients at baseline, on treatment, and/or at RECIST 1.1-
defined disease recurrence will be correlated with outcomes. Note that samples will be 
obtained from patients randomized to each treatment group. Comparisons may be made 
between baseline measures to determine if biomarkers (or combination of markers) are 
prognostic or predictive of outcomes associated with durvalumab versus placebo, 
subgrouped by histology.
Additional sample collections and analyses may be completed at select study sites by site-
specific amendment. All samples collected for such exploratory analyses will be stored at 
site, a reference laboratory, or at AstraZeneca’s facilities and may be used for subsequent 
research relevant to evaluating response to immunotherapy.
The exploratory biomarker plan is described by sample type below.
8.7.2.1
Plasma and serum
Plasma samples will be collected throughout the course of the study to assess the 
relationship between treatment effect on ctDNA clearance and DFS endpoint.
Plasma analyses may also include evaluating baseline mutations to treatment, changes in 
ctDNA levels on treatment, TMB, and correlations with clinical outcome. Overall 
mutational burden or somatic mutations/genomic alterations, RNA, and/or protein markers 
in plasma may be assessed using state-of-the-art methodologies.
Serum samples will be collected for analysis of circulating soluble prognostic and 
pharmacodynamic biomarkers, including, but not limited to, proinflammatory, regulatory, 
and chemotactic cytokines and chemokines.
8.7.2.2
Tumor markers
Tissue obtained as part of screening procedures and for establishing PD-L1 TC expression 
status may be analyzed for additional markers. TMB may also be assessed in tumor tissue. 
Based on availability of tissue, a panel of immune-relevant markers expressed on tumor-
infiltrating lymphocytes or on tumor cells may be assessed.
Attributes of tumor microenvironment that could be assessed using various methods, 
which may include, but are not limited to, high content imaging, multiplex 
RNA/DNA/protein analysis with spatial resolution such as Mass Spec, in situ
hybridization, or other technologies will be correlated with response and clinical outcome.
Exploratory analysis of RNA (mRNA/miRNA/lncRNA), DNA, or protein using 
state-of-the-art technologies including, but not limited to, RNAseq, WES, and QRT-PCR 
may be conducted to study association with response and clinical outcome.


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OPTIONAL: Provision of tumor tissue upon recurrence, formalin-fixed and embedded in 
paraffin is strongly encouraged. The Investigator must consult with the Study Physician if 
such sampling is not feasible. In addition, if the patient refuses to provide this sample, the 
reason for this refusal must be captured. After evaluation per local clinical practice (if 
applicable), any remaining sample(s) of the recurrent tumor should be submitted for 
exploratory analyses of biomarker changes compared to baseline (ie, resected tumor tissue 
from surgery).
8.7.2.3
Management of biomarker data
The biomarker data will have unknown clinical significance. AstraZeneca will not provide 
biomarker research results other than MRD measurements necessary for eligibility to 
patients, their family members, any insurance company, an employer, clinical study 
Investigator, general physician, or any other third party, unless required to do so by law. 
The patient’s samples will not be used for any purpose other than those described in the 
study protocol.
Individual patients will not be identified in any report or publication resulting from this 
work. The data and results of this research may be reviewed with collaborators and 
published, but neither the patient’s name nor any other personal identifiers will appear in 
any publication or report.
8.7.2.4
Optional Genomic Initiative samples
Details on the optional genetic research study can be found in Section 8.6.2.
8.7.3
Storage, re-use, and destruction of biomarker samples
Samples will be stored for a maximum of 15 years from the end of study, after which they 
will be destroyed. Summaries and analyses for exploratory biomarkers will be documented 
in a separate analysis plan and will be reported outside the CSR in a separate report. The 
results of this biomarker research may be pooled with biomarker data from other studies 
involving durvalumab to generate hypotheses to be tested in future research.
8.7.4
Labeling and shipment of biological samples
The PI will ensure that samples are labeled and shipped in accordance with the Laboratory 
Manual and the Biological Substance, Category B, Regulations (materials containing or 
suspected to contain infectious substances that do not meet Category A criteria); see 
Appendix C “IATA 6.2 Guidance Document”.
Any samples identified as Infectious Category A materials will not be shipped, and no 
further samples will be taken from the involved patients unless agreed upon with 
AstraZeneca and appropriate labeling, shipment, and containment provisions are approved.
8.7.5
Chain of custody of biological samples
A full chain of custody will be maintained for all samples throughout their life cycle.


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The PI at each center will keep full traceability of collected biological samples from the 
patients while in storage at the center until shipment or disposal (where appropriate) and 
will keep documentation of shipments.
The sample receiver will keep full traceability of the samples while in storage and during 
use until used or disposed of or until further shipment and will keep documentation of 
receipt upon arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of 
external laboratory providers.
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks and 
will be registered with the AstraZeneca Biobank Team during the entire life cycle.
8.7.6
Withdrawal of informed consent for donated biological samples
If a patient withdraws consent to the use of donated biological samples, the samples will 
be disposed of or destroyed and the action documented. If samples have already been 
analyzed, AstraZeneca is not obliged to destroy the results of this research.
The PI will:
!
Ensure that AstraZeneca is immediately notified of the patients’ withdrawal of 
informed consent to the use of donated samples
!
Ensure that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of or destroyed and the action documented
!
Ensure that the organization(s) 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 signed document is returned to the study site
!
Ensure that the patient and AstraZeneca are informed about the sample disposal
9
STATISTICAL CONSIDERATIONS
Note for CSP v2.0: All analyses of the objectives and endpoints will be descriptive only 
and considered exploratory. Interim analysis will not be performed. Medical resource 
use analysis will not be performed. Please see Section 10.4 for additional information.
The primary aim of the study is to compare the efficacy and safety of durvalumab to 
placebo in terms of DFS (using Investigator assessments according to RECIST 1.1) in 
randomized patients who are PD-L1 TC≥1% with an initial diagnosis of stage II-III 
NSCLC who have undergone curative intent therapy.
!
All personnel involved with the analysis of the study will remain blinded until 
database lock and Clinical Study Protocol deviations identified.
!
Analyses will be performed by AstraZeneca or its representatives.


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!
A statistical analysis plan (SAP) will be written to provide further details and will be 
finalized in advance of DBL.
9.1
Statistical hypotheses
The formal statistical analysis will be performed to test the main hypotheses:
!
H0: No difference between durvalumab and placebo
!
H1: Difference between durvalumab and placebo
The primary objective of this study is to compare the efficacy of durvalumab to placebo in 
terms of DFS in randomized patients who are PD-L1 TC≥1% following curative intent 
therapy. A secondary objective is to compare the efficacy of durvalumab to placebo in 
terms of DFS in the FAS. The details on the multiple testing procedure for controlling the 
type I error rate can be found in Section 9.5.7.
9.2
Sample size determination
Approximately 284 patients with stage II-III NSCLC who are MRD+ will be randomized 
1:1 to durvalumab or placebo. Of the patients randomized into the study, at least 170 
patients are required to be PD-L1 TC≥1% at study entry. The primary analysis is planned 
to be performed in the PD-L1 TC≥1% analysis set. An analysis on the FAS (all MRD+ 
stage II-III NSCLC patients randomized) will be performed as a secondary objective of the 
study. Randomization will be stratified by PD-L1 status (TC<1% vs TC≥1%), time from 
the start of surveillance to the emergence of MRD (≤6 months vs >6 months), and prior 
neoadjuvant immunotherapy (Yes vs No). In this study, the start of surveillance is defined 
as the day the plasma sample used to determine a patient’s MRD status post-curative intent 
therapy is collected.
The study is sized for the primary endpoint of DFS in the PD-L1 TC≥1% analysis set and 
for the secondary endpoint of DFS in the FAS.
The analysis of the primary endpoint (DFS) will occur when approximately 118 DFS 
events have occurred (69% maturity) in the PD-L1 TC≥1% analysis set. If the true DFS 
HR is 0.55 in the PD-L1 TC≥1% analysis set, the study will provide at least 90% power to 
demonstrate a statistically significant difference for DFS with overall 2-sided significance 
level of 5%; this translates to 3.2-month benefit in median DFS over 4 months on placebo, 
or 8.4% difference in 2-year DFS rate over 1.5% on placebo, if DFS is exponentially 
distributed. The smallest treatment difference that would be statistically significant is an 
HR of 0.7.
The study is also sized to provide at least 90% power for the DFS endpoint in the FAS. 
The analysis will be performed at the same time as the primary analysis, when it is 
expected that approximately 197 DFS events have occurred (69% maturity) in the FAS. If 
the true DFS HR is 0.63 in this population, this will provide at least 90% power to 
demonstrate a statistically significant difference for DFS, assuming overall 5% 2-sided 


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significance level; this translates to a 2.3-month benefit in median DFS over 4 months on 
placebo, or 5.6% difference in 2-year DFS rate over 1.5% on placebo, if DFS is 
exponentially distributed. The smallest treatment difference that would be statistically 
significant is an HR of 0.76.
It is estimated that analysis of DFS will occur approximately 
 after the first 
patient has been randomized assuming a 
 recruitment period and allowing for 
patients to have a minimum follow-up of 
OS will also be analyzed in the PD-L1 TC≥1% analysis set and in the FAS analyzed at the 
time of the DFS analysis. In the PD-L1 TC≥1% analysis set if the true HR is 0.79 then it is 
anticipated that approximately 59 events (35% maturity) will have occurred. This 
translates to a 4.3 month benefit in median OS over 16 months on placebo. In the FAS, if 
the true HR is 0.89, then it is anticipated that approximately 102 events (36% maturity) 
will have occurred. This translates to a 2 month benefit in median OS over 16 months on 
placebo. OS will be analyzed similarly to DFS.
A further analysis of OS will be performed at approximately 127 events (75% maturity) in 
the PD-L1 TC≥1% analysis set. At this time there is also expected to be approximately 218 
events (77% maturity) in the FAS. It is anticipated this analysis will occur approximately 
60 months after first patient is randomized. If events are accruing slower than expected, 
then the DCO may occur 60 months after the first patient is randomized, regardless of 
number of events accrued.
9.3
Populations for analyses
Definitions of the analysis sets for each outcome variable are provided in Table 14.
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Table 14
Summary of outcome variables and analysis populations
Outcome
Population
Efficacy data
DFS
PD-L1 TC≥1% analysis set
Full analysis set
PFS, 
, 
PD-L1 TC≥1% analysis set
Full analysis set
OS
PD-L1 TC≥1% analysis set
Full analysis set
PROs
PD-L1 TC≥1% analysis set
Full analysis set
Demography
PD-L1 TC≥1% analysis set
Full analysis set
Safety data
Exposure
Safety Analysis Set
AEs
Safety Analysis Set
Laboratory measurements
Safety Analysis Set
Vital signs
Safety Analysis Set
AEs Adverse events; DFS Disease-free progression; OS Overall survival; PD-L1 Programmed death 
ligand 1; PD-L1 TC Tumor-specific PD-L1 expression; PFS Progression-free survival; PROs Patient-
reported outcomes; TC Tumor cells; 
; 
 
.
9.3.1
Full analysis set
The FAS will include all randomized patients. The FAS will be used for all efficacy 
analyses including PROs. Treatment groups will be compared on the basis of randomized 
study treatment, regardless of the treatment actually received. Patients who were 
randomized but did not subsequently go on to receive study treatment are included in the 
analysis in the treatment group to which they were randomized.
9.3.2
PD-L1 TC≥1% analysis set
The PD-L1 TC≥1% analysis set will include the subset of patients in the FAS whose 
PD-L1 status is PD-L1 TC≥1% as defined by the Ventana SP263 PD-L1 IHC assay (ie, 
1% PD-L1–membrane expression in tumoral tissue) at randomization. The PD-L1 TC≥1% 
analysis set will be the primary analysis set for all efficacy and PRO analyses.
9.3.3
Safety analysis set
The SAS will consist of all randomized patients who received any amount of study 
treatment. Safety data will not be formally analyzed but summarized using the SAS, 
according to the treatment received. If a patient receives any amount of durvalumab, they 
will be summarized in the durvalumab treatment group. If a patient only receives placebo, 
they will be summarized in the placebo treatment group.
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9.4
Outcome measures for analyses
9.4.1
Calculation or derivation of efficacy variables
9.4.1.1
RECIST 1.1-based endpoints
The analysis of the primary endpoint, DFS, will be based on the Investigator assessments 
using RECIST 1.1.
Investigator RECIST 1.1-based assessments
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations. This is also regardless of whether a patient discontinues study treatment or 
receives another anticancer therapy.
Please refer to Appendix G for further details.
Blinded Independent Central Review
A secondary analysis of the DFS endpoint will be performed based on data assessed by a 
BICR for all patients.
All images will be collected centrally. The imaging scans will be reviewed by 2 
independent radiologists using RECIST 1.1 and will be adjudicated, if required. For each 
patient, the BICR will define the overall visit response data and the relevant scan dates for 
each timepoint (ie, for visits where recurrence is/is not identified).
Further details of the BICR will be documented in the Imaging Charter.
9.4.1.2
Primary endpoint: disease-free survival
DFS is defined as the time from the date of randomization until the date of disease 
recurrence (local, regional, or distant disease recurrence or second primary NSCLC) using 
Investigator assessments according to RECIST 1.1, or date of death due to any cause, 
whichever occurs first.
Patients who are disease-free, ie, have not experienced disease recurrence, and alive at the 
time of analysis will be censored at the latest date of assessment from their last evaluable 
RECIST 1.1 assessment. However, if the patient experiences disease recurrence or dies 
after 2 or more missed visits, the patient will be censored at the latest evaluable RECIST 
1.1 assessment prior to the 2 missed visits. If the patient has no evaluable assessments or 
does not have baseline data, they will be censored at Day 1 unless they die within 2 visits 
of baseline, then they will be treated as an event with the date of death as the event date. 
The primary endpoint analysis of DFS will be based on Investigator RECIST 1.1 
assessments.
The DFS time will always be based on scan/assessment dates and not visit dates.


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DFS rate at 6 and 12 months is defined as the proportion of patients alive and disease-free 
at 6 and 12 months respectively, estimated from Kaplan-Meier plots of the primary 
endpoint of DFS.
9.4.1.3
Secondary efficacy 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 (if agreed to by the patient and in compliance with local data privacy 
laws/practices) will be made following the date of DCO for the analysis (these contacts 
should generally occur within 7 days of the DCO). If patients are confirmed to be alive or 
if the death date is after the DCO date, these patients will be censored at the date of DCO. 
Death dates may be found by checking publicly available death registries.
9.4.1.4
Secondary efficacy endpoint: progression-free survival
PFS is defined as the time from the date of randomization to the date of post-recurrence 
disease progression (using local standard practice) or death. Patients alive, and for whom a 
disease progression has not been observed, should be censored at the last time known to be 
alive and without a disease progression; ie, censored at the last progression assessment 
date if the patient has not had a progression or died or at the last disease recurrence 
assessment date if the patient has not had a disease recurrence or died.
9.4.1.5
Secondary efficacy endpoint: 
 
 
. Any patient not known to have had a subsequent 
therapy/procedure or not known to have died at the time of the analysis will be censored at 
the last known time to have not received subsequent therapy; ie, the last follow-up visit 
where this was confirmed.
9.4.1.6
Secondary efficacy endpoint: 
 
 
 Any patient not known to have died at the time of the analysis 
and not known to have had a second subsequent therapy/procedure will be censored at the 
last known time to have not received second subsequent therapy, ie, the last follow-up visit 
where this was confirmed.
9.4.2
Calculation or derivation of safety variables
9.4.2.1
Adverse events
Safety and tolerability will be assessed in terms of AEs (including SAEs), deaths, 
laboratory data, vital signs, ECGs, and exposure. These will be collected for all patients. 
Data from all cycles of treatment will be combined in the presentation of safety data. “On 
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treatment” will be defined as assessments between date of start dose and 90 days following 
discontinuation of IP (ie, the last dose of durvalumab/placebo). For AEs, on treatment (or 
treatment-emergent AEs) will be defined as any AEs that started after dosing or prior to 
dosing and which worsens following exposure to the treatment. 
The SAS will be used for reporting of safety data.
Adverse events observed up until 90 days following discontinuation of the last dose of 
durvalumab/placebo or until the initiation of the first subsequent therapy following 
discontinuation of treatment (whichever occurs first) will be used for the reporting of the 
AE summary tables. This will more accurately depict AEs attributable to study treatment 
only as a number of AEs up to 90 days following discontinuation of durvalumab/placebo 
are likely to be attributable to subsequent therapy. However, to assess the longer-term 
toxicity profile, AE summaries will also be produced containing AEs observed up until 90 
days following discontinuation of durvalumab/placebo (ie, without taking subsequent 
therapy into account). Any events in this period that occur after a patient has received 
further therapy for cancer (following discontinuation of study treatment) will be flagged in 
the data listings.
A separate data listing of AEs occurring more than 90 days after discontinuation of IP will 
be produced. These events will not be included in AE summaries.
9.4.2.2
Safety assessments
For the change from baseline summaries for vital signs, laboratory data, ECGs (to be 
administered at baseline and as clinically indicated), and physical examinations, the 
baseline value will be the latest result obtained prior to the start of study treatment.
QTcF will be derived during creation of the reporting database using the reported ECG 
values (RR and QT) using the following formula:
QTcF = QT/RR^ (1/3) where RR is in seconds
Corrected calcium product will be derived during creation of the reporting database using 
the following formula:
Corrected calcium (mmol/L) = Total calcium (mmol/L) + ([40 – albumin (G/L)] × 0.02)
The denominator used in laboratory summaries will only include evaluable patients, ie, 
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.


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The denominator in vital signs data should include only those patients with recorded data.
9.4.3
Calculation or derivation of patient-reported outcome variables
Symptoms and overall QoL will be assessed using the EORTC QLQ-C30 and QLQ-LC13 
module (secondary endpoints). Questionnaires will be scored according to published 
scoring guidelines or the developer’s guidelines, if published guidelines are not available.
All PRO analyses will be conducted on both the PD-L1 TC≥1% analysis set and the FAS.
9.4.3.1
EORTC QLQ-C30 and EORTC QLQ-LC13
The EORTC QLQ-C30 consists of 30 questions that can be combined to produce 5 
functional scales (physical, role, cognitive, emotional, and social) and 3 symptom scales 
(fatigue, pain, and nausea and vomiting), 5 individual items (dyspnea, insomnia, appetite 
loss, constipation, and diarrhea), and a global measure of health status. The EORTC 
QLQ-LC13 is a lung cancer specific module from the EORTC for lung cancer comprising 
13 items/questions (cough, hemoptysis, dyspnea, site-specific pain, sore mouth, dysphagia, 
peripheral neuropathy, alopecia, and pain medication). With the exception of a multi-item 
scale for dyspnea, all are single items. The dyspnea scale will only be used if all 3 items 
have been scored; otherwise, the items are treated as single-item measures.
An outcome variable consisting of a score from 0 to 100 will be derived for each of the 
symptom scales/symptom items, the functional scales, and the global health status/QoL 
scale according to the EORTC QLQ-C30 Scoring Manual (Fayers et al 2001) and EORTC 
QLQ-LC13 instructions.
Higher scores on the global health status/QoL and functioning scales indicate better health 
status/function, but higher scores on symptom scales/items represent greater symptom 
severity.
Changes in score compared with baseline will be evaluated. For each subscale, if <50% of 
the subscale items are missing, then the subscale score will be divided by the number of 
non-missing items and multiplied by the total number of items on the subscales (Fayers et 
al 2001). If at least 50% of the items are missing, then that subscale will be treated as 
missing. Missing single items are treated as missing. The reason for any missing 
questionnaire will be identified and recorded. If there is evidence that the missing data are 
systematic, missing values will be handled to ensure that any possible bias is minimized.
Definition of clinically meaningful changes
Changes in score compared with baseline will be evaluated. A minimum clinically relevant 
change is defined as a change in the score from baseline of ≥10 for scales/items from the 
QLQ-C30 and the QLQ-LC13 (Osoba et al 1998). For example, a clinically relevant 
deterioration or worsening in chest pain (as assessed by QLQ-LC13) is defined as an 
increase in the score from baseline (defined as Day 1, pre-dose) of ≥10. A clinically 
relevant improvement in fatigue (as assessed by QLQ-C30) is defined as a decrease in the 


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score from baseline of ≥10. At each post-baseline assessment, change in 
symptoms/functioning from baseline will be categorized as improved, stable, or worsening 
as shown in Table 15.
Table 15
Visit responses for symptoms and health-related quality of life
Score
Change from baseline
Visit response
QLQ-C30/QLQ-LC13 symptom 
scales/items
≥+10
≤-10
Otherwise
Worsened
Improved
Stable
QLQ-C30 functional scales and 
global health status/QoL
≥+10
≤-10
Otherwise
Improved
Worsened
Stable
QLQ-C30 30-Item core quality-of-life questionnaire; QLQ-LC13 13-Item lung cancer quality-of-life 
questionnaire; QoL Quality of life.
Time to deterioration in symptom and functional scales/items and global health 
status/QoL, based on the clinically meaningful cut-offs, will be evaluated.
See SAP for further details.
9.4.3.2
Calculation or derivation of 
 data will be presented using summaries and descriptive statistics. 
Additionally, 
 data may be further explored. Further details will 
be provided in the SAP.
9.4.3.3
 data will be presented using summaries and descriptive statistics. 
Additionally, data may be further explored. Further details will be provided in the SAP.
9.4.3.4
Calculation or derivation of health economic variables
 index
The 
 index comprises
 
(See Section 8.1.4.2). For each 
dimension, respondents will select which statement best describes their health on that day 
from a possible 5 options of increasing levels of severity (no problems, slight problems, 
moderate problems, severe problems, and extreme problems). A unique 
 health 
state is referred to by a 5-digit code allowing for a total of 3125 health states. For example, 
state 11111 indicates no problems on any of the 
. These data will be 
converted into a weighted health state index by applying scores from 
 value sets 
elicited from general population samples (the base case will be the United Kingdom 
valuation set, with other country value sets applied in scenario analyses). Where value sets 
are not available, the 
 to 
 crosswalk will be applied 
 
. In addition to the descriptive system, respondents also 
assess their health on the day of assessment on a VAS, ranging from 0 (worst imaginable 
health) to 100 (best imaginable health). This score is reported separately.
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Health care resource use (HOSPAD)
The Health Resource Use Module will be assessed in terms of symptoms for admission 
and type of admission (planned/unplanned hospitalization, outpatient visits, or emergency 
department visits).
To investigate the impact of treatment and disease on health care resource use, the 
following variables will be captured:
Planned and unplanned hospital attendances beyond study protocol-mandated visits 
(including physician visits, emergency room visits, day cases, and admissions)
!
Primary sign or symptom the patient presents with
!
Length of hospital stay
!
Length of any time spent in an ICU
Where admitted overnight, the length of hospital stay will be calculated as the difference 
between the date of hospital discharge (or death date) and the start date of hospitalization 
or start of IP if the start of IP is after the start date of hospitalization (length of hospital 
stay=end date of hospitalization – start date of hospitalization + 1). Patients with missing 
discharge dates will be calculated as the difference between the last day with available data 
and the start date of hospitalization. The length of ICU stay will be calculated using the 
same method.
9.4.4
Calculation or derivation of pharmacokinetic variables
9.4.4.1
Pharmacokinetic analysis
Not applicable for this study.
9.4.4.2
Immunogenicity analysis
Not applicable for this study.
9.4.5
Calculation or derivation of biomarker variables
Biomarker status, as defined in the exploratory objectives, will be assessed for evaluable 
patients in each cohort according to pre-specified criteria that will be detailed in the SAP.
9.4.6
Calculation or derivation of pharmacogenetic variables
In the case of optional genetic data, only the date that the patient gave consent to 
participation in the optional genetic research and the date the blood sample was taken from 
the patient will be recorded in the eCRF and database. The optional genetic data generated 
from the study will be stored in the AstraZeneca Laboratory Information Management 
System (LIMS) database or other appropriate system. This database is a secure database, 
which is separate from the database used for the main study. Some or all of the dataset 
from the mandatory main study may be duplicated within the AstraZeneca LIMS 
database for exploratory genetic analysis. Data will be reported outside the CSR (please 
see Appendix C).


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9.5
Statistical analyses
The patient populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data will be described in the SAP. This section is a 
summary of the planned statistical analyses of the primary and secondary endpoints. Any 
deviations from this plan will be reported in the CSR.
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment group. Continuous variables will be summarized by the number of observations, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized by frequency counts and percentages for each category. Unless otherwise 
stated, percentages will be calculated out of the population total for the corresponding 
treatment arm.
For efficacy variables and analyses performed on the FAS, baseline is defined as the last 
visit prior to randomization, for all other reporting, baseline will be the last assessment of 
the variable under consideration prior to the intake of the first dose of IP.
All data collected will be listed. Efficacy and PRO data will be summarized and analyzed 
based on the PD-L1 TC≥1% analysis set and FAS. Safety data will be summarized on the 
SAS.
Results of all statistical analysis will be presented using a 95% CI and 2 sided p-value, 
unless otherwise stated.
9.5.1
Efficacy analyses
The primary aim of the study is to assess the efficacy of durvalumab versus placebo in 
terms of DFS, using Investigator assessments according to RECIST 1.1, in the PD-L1 
TC≥1% analysis set. DFS, using Investigator assessments according to RECIST 1.1, in the 
FAS is a secondary endpoint.
Table 16 details which endpoints are to be subjected to formal statistical analyses, together 
with pre-planned sensitivity analyses, making it clear which analysis is regarded as 
primary for that endpoint. Note, all endpoints compare durvalumab versus placebo in the 
PD-L1 TC≥1% analysis set and all randomized patients (FAS) unless otherwise indicated. 
Results of all statistical analysis will be presented using a 95% CI and 2-sided p-value, 
unless otherwise stated.


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Table 16
Pre-planned statistical and sensitivity analyses to be conducted
Endpoints analyzed
Notes
DFS
Primary analysis using stratified log-rank test using Investigator 
assessments according to RECIST 1.1 for PD-L1 TC≥1% analysis set.
Secondary analysis using stratified log-rank test using Investigator 
assessments according to RECIST 1.1 for FAS
Secondary analysis using stratified log-rank test using BICR assessments 
(RECIST 1.1) for PD-L1 TC≥1% analysis set
Secondary analysis using stratified log-rank test using BICR assessments 
(RECIST 1.1) for FAS
Estimate of DFS rates at 6 and 12 months based on the Kaplan-Meier curve
OS
Stratified log-rank test
PFS, 
, 
Stratified log-rank test
Change from baseline (EORTC 
QLQ-C30 and QLQ-LC13)
Summary statistics, change from baseline including mixed model repeated 
measures (MMRM)
Time to deterioration (EORTC 
QLQ-C30 and QLQ-LC13)
Stratified log-rank test
For the PD-L1 TC≥1% analysis set 2 stratification factors will be included in the model; time from start of 
surveillance to emergence of MRD (≤6 months vs >6 months) and prior neoadjuvant immunotherapy (Yes vs 
No). For the FAS 3 stratification factors will be included in the model; PD-L1 status (TC<1% vs TC≥1%), 
time from start of surveillance to emergence of MRD (≤6 months vs >6 months) and prior neoadjuvant 
immunotherapy (Yes vs No).
BICR Blinded independent central review; DFS Disease-free survival; EORTC European Organisation for 
Research and Treatment of Cancer ; FAS Full analysis set; OS Overall survival; PD-L1 Programmed cell 
death ligand-1; PFS Progression-free survival; QLQ-C30 30-item Core Quality of Life Questionnaire; 
QLQ-LC13 13-item Lung Cancer Quality of Life Questionnaire; RECIST Response Evaluation Criteria in 
Solid Tumors; TC Tumor cells; 
; 
 
.
Analyses of data from the observation cohort will be described in the SAP.
9.5.1.1
Primary endpoint: disease-free survival
DFS (using Investigator assessments according to RECIST 1.1) will be analyzed using the 
log-rank test stratified by time from start of surveillance to emergence of MRD (≤6 months 
vs >6 months), and prior neoadjuvant immunotherapy (Yes vs No) on the PD-L1 TC≥1% 
analysis set.
The treatment effect will be estimated in terms of the HR and its associated 95% CI from a 
Cox proportional hazards model (Cox 1972) stratified by time from start of surveillance to 
emergence of MRD (≤6 months vs >6 months), and prior neoadjuvant immunotherapy 
(Yes vs No) on the PD-L1 TC≥1% analysis set.
The stratification factor covariates in the statistical modeling will be based on the values 
entered into IWRS at randomization, even if it is subsequently discovered that these values 
were incorrect. For the purpose of statistical analysis of the primary and relevant 
secondary endpoints, a plan for reducing the number of strata cells will be included in the 
SAP in case there are insufficient events in one level of any strata.
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Kaplan-Meier plots of DFS will be presented by treatment group. Summaries of the 
number and percentage of patients experiencing a DFS event will be provided along with 
median DFS with 95% CI for each treatment estimated based on the Kaplan-Meier curves.
The DFS rates at month 6 (DFS-6) and month 12 (DFS-12) will be estimated based on the 
Kaplan-Meier curves along with their 95% CIs and presented by treatment arms.
Subgroup analyses will be conducted comparing DFS between durvalumab versus placebo 
in the following subgroups of the PD-L1 TC≥1% analysis set and FAS (but not limited to):
!
PD-L1 status (TC <1% versus ≥1%)
!
PD-L1 status (TC <25% and ≥25%)
!
TMB (high, low)
!
Histology (squamous versus non-squamous)
!
Sex (male versus female)
!
Age (<65 versus ≥65 years of age)
!
Smoking status (smoker versus non-smoker [never smoked])
!
Race (Asian versus non-Asian)
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 subgroup and sensitivity analyses will be made 
since all these analyses will be considered supportive of the analysis of DFS.
Cox proportional hazards modeling will be employed to assess the effect of covariates on 
the HR estimate. A model will be constructed, containing treatment and the stratification 
factors, to ensure that any output from the Cox modeling is likely to be consistent with the 
results of the stratified log-rank test. Interactions between treatment and stratification 
factors will also be tested to rule out any qualitative interaction using the approach of Gail 
and Simon 1985 (Gail and Simon 1985).
Additionally, for each subgroup, the HR (durvalumab plus SoC chemotherapy: placebo 
plus SoC chemotherapy) and 95% CI will be calculated from a Cox proportional hazards 
model with treatment as the only covariate. These will be presented on a forest plot 
including the HR and 95% CI.
If there are too few events available for a meaningful analysis of a particular subgroup (it 
is not considered appropriate to present analyses where there are less than 20 events in a 
subgroup), the relationship between that subgroup and DFS will not be formally analyzed. 
In this case, only descriptive summaries will be provided.




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In addition, physical and role functioning and overall global health status/QoL domains of 
the EORTC-CT30 are furthermore pre-specified endpoints of interest.
Summaries of original and change from baseline values of each symptom scale/item, the 
global HRQoL score, and each functional domain will be reported by assessment timepoint 
for each treatment group. Graphical presentations may also be produced as appropriate. 
Summaries of the number and percentage of patients in each response category at each 
assessment timepoint for each ordinal item (in terms of the proportion of patients in the 
categories of improved, stable, and worsened as defined in Table 15) will also be produced 
for each treatment group.
A Mixed-effect Model with Repeated Measures will be utilized to model the change from 
baseline in EORTC QLQ-C30 and QLQ-LC13 symptoms (primary PRO measures only), 
EORTC QLQ-C30 global health status/QoL, and each functional domain over time.
Time to deterioration will be analyzed for each of the symptom scales/items, function 
scales, and global health status/QoL using a stratified log-rank test as described for the 
primary analysis of DFS. The HR and 95% CI for each scale/item will be presented 
graphically on a forest plot.
For each of the symptom scales/items, functional scales, and global health status/QoL, 
time to deterioration will be presented using a Kaplan-Meier plot. Summaries of the 
number and percentage of patients experiencing a clinically relevant deterioration as well 
as who are censored will also be provided along with the medians for each treatment 
group.
Additional analyses and data visualizations may be considered. Further details will be 
provided in the SAP.
 data will be presented using summaries and descriptive statistics. 
Further details will be provided in the SAP.
 data will be presented using summaries and descriptive statistics. 
Further details will be provided in the SAP.
Health state utility
Descriptive statistics will be calculated for each scheduled visit/timepoint in the study, for 
each study group, and as a total. These will report the number of patients, the number of 
 questionnaires completed at each visit, and the number and proportion of patients 
responding to each dimension of the 
 Additionally, summary statistics (eg, n, 
mean, median, standard deviation, minimum, and maximum) will be reported for the 
 index score and the EQ-VAS score, and the change from baseline for the 
 
index score and the EQ-VAS score.
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Graphical plots of the mean 
 index score and EQ-VAS score, including change 
from baseline, and associated 95% CI by scheduled visits/timepoints in the study may be 
produced. To support submissions to payers, additional analyses may be undertaken, and 
these will be outlined in a separate Payer Analysis Plan.
Medical resource use
The potential impact the disease and treatment has on health care resource use will be 
analyzed for the purposes of submissions to payers. Descriptive statistics (as appropriate, 
including means, median, ranges or frequencies, and percentages) will be provided for 
each arm on the different types of hospital admissions, the length of stay of people 
admitted to the hospital for at least 1 overnight stay, and the length of stay of people 
admitted to intensive care/high dependency units, as well as the primary sign or symptom 
the patient presents with. To support submissions to payers, additional analyses may be 
undertaken, and these will be outlined in a separate Payer Analysis Plan.
An exploratory health economic analysis of hospital episodes including type of contact 
(hospitalization, outpatient, or day case), reason, length of stay by ward type (including 
ICU), procedures, and tests may be undertaken to examine the impact of disease and 
treatment on resource use to primarily support the economic evaluation of durvalumab in 
comparison to SoC, and will be outlined in the payer analysis plan. This would include 
providing descriptive statistics as appropriate, including means, median, and ranges.
9.5.2
Safety analyses
All safety and tolerability data will be presented by treatment arm using the SAS.
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. The number of patients 
experiencing each AE will be summarized by treatment arm and CTCAE grade. 
Additionally, data presentations of the rate of AEs per person-years at risk may be 
produced.
Other safety data will be assessed in terms of physical examination, clinical chemistry, 
hematology, vital signs, and ECGs (conducted at baseline and as clinically indicated). 
Exposure to durvalumab and placebo will be summarized. Time on study and durvalumab, 
including any dose delays, will also be summarized. At the end of the study, appropriate 
summaries of all safety data will be produced, as defined in the SAP.
9.5.3
Pharmacokinetic data
Not applicable for this study.
9.5.4
Immunogenicity data
Not applicable for this study.
CCI


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9.5.5
Pharmacokinetic/pharmacodynamic relationships
Not applicable for this study.
9.5.6
Biomarker data
The relationship of PD-L1 TC expression and, if applicable, of exploratory biomarkers to 
clinical outcomes (including but not restricted to) of DFS and OS will be presented.
PD-L1 TC expression determined by IHC will be reported in the CSR. Summaries and 
analyses for exploratory biomarkers will be documented in a separate analysis plan and 
will be reported outside the CSR in a separate report.
9.5.7
Methods for multiplicity control
In order to provide strong control of the type I error rate, α=5% (2-sided), a multiple 
testing procedure with gatekeeping strategy will be used across the primary endpoint of 
DFS in the PD-L1 TC≥1% analysis set and the secondary endpoint of DFS in the FAS. 
The first two layers of the MTP are shown in Figure 4. If DFS is significant in the FAS the 
alpha may be recycled to other secondary endpoints. Full details of the MTP, including 
testing of any additional secondary endpoints, will be specified in the SAP prior to DBL.
The overall 5% type I error rate will be allocated to the DFS analysis on the PD-L1 
TC≥1% analysis set. If that analysis is statistically significant, 5% alpha (2-sided) will be 
allocated to the DFS analysis in the FAS.
Figure 4
Multiple testing procedure for controlling the type 1 error rate
α=5%
DFS Disease-free survival; FAS Full analysis set; PD-L1 TC≥1% Expression of PD-L1 on tumor membrane, 
at any intensity, in ≥1% of tumor cells.
9.6
Interim analyses
An interim analysis of OS will be performed at the time of the DFS analysis. At this time 
it is expected that approximately 59 events (35% maturity) will have occurred in the 
PD-L1 TC≥1% analysis set and approximately 102 events (36% maturity) will have 
occurred in the FAS.
A further analysis of OS will be performed at approximately 127 events (75% maturity) in 
the PD-L1 TC≥1% analysis set. At this time there is also expected to be approximately 


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218 events (77% maturity) in the FAS. It is anticipated this analysis will occur 
approximately 60 months after first patient is randomized. If events are accruing slower 
than expected then the DCO may occur 60 months after the first patient is randomized, 
regardless of number of events accrued. An alpha spending function will be used to control 
the overall type I error for the interim and the final analysis of OS at the 5% level. Details 
of the OS testing plan will be provided in the SAP.
9.6.1
Data monitoring committee (DMC)
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 meet approximately 12 months after the 
first subject has been dosed with IP or after approximately 50 patients have received at 
least 1 dose of IP (whichever occurs first) to assess the safety and tolerability of 
durvalumab. The IDMC will review unblinded safety data and make recommendations to 
continue, amend, or stop the study based on safety findings. The frequency of subsequent 
reviews will be determined by the IDMC but will be no more frequent than every 
6 months. The IDMC safety reviews will be conducted in an unblinded manner.
Full details of the IDMC procedures and processes can be found in the IDMC Charter.


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10
RATIONALE FOR AND PROCEDURES FOLLOWING CSP 
V2.0 IMPLEMENTATION
At the time of CSP v2.0 implementation at site, Section 10 (this section) should be 
fully utilized as the reference point for the study. Original protocol language is 
maintained in version 2.0 of the CSP where relevant in order to ensure that the
history of the study is accessible to study site staff for reference. Please see 
Sections 1-9 for notes regarding their applicability and updated text following 
implementation of CSP v2.0 at site.
10.1
Overall rationale
Two Phase III clinical studies have reported positive results for PD-(L)1 inhibitors (used as 
monotherapy) in the adjuvant setting. IMpower010 is a Phase III trial which randomized 
1280 patients with completely resected Stage IB (≥4cm) to Stage IIIA NSCLC 
(UICC/AJCC version 7) after cisplatin-based chemotherapy to atezolizumab, given every 
3 weeks for up to 16 cycles, or to best supportive care (Felip et al 2021). The primary 
endpoints tested hierarchically were DFS in: (i) the PD-L1 ≥1%, Stage II-IIIA population; 
(ii) the all-randomized Stage II-IIIA population; and (iii) the intent-to-treat population. At 
interim analysis the first and second of these were found to be statistically significant with 
HRs of 0.66 (95% CI 0.50, 0.88) and 0.79 (95% CI 0.64, 0.96), respectively. These data 
led, in October 2021, to FDA approval of atezolizumab for adjuvant treatment following 
resection and platinum-based chemotherapy for adult patients with Stage II-IIIA NSCLC 
whose tumors have PD-L1 expression ≥1% (using a Ventana SP263 PD-L1 IHC assay). 
PEARLS/KEYNOTE-091 is a Phase III study which randomized 1177 patients with 
completely resected Stage IB (≥4cm) to Stage IIIA NSCLC (UICC/AJCC version 7) 
± adjuvant chemotherapy to pembrolizumab or placebo (given every 3 weeks for up to 
18 cycles) (Paz-Ares et al 2022). The dual primary endpoints were DFS in the overall 
population and DFS in the PD-L1≥50% stage IB-IIIA population. At a second interim 
analysis, the HR for the first of these endpoints was statistically significant (0.76; 95% CI
0.63, 0.91). 
One Phase III clinical study has reported positive results for nivolumab (anti-PD-1 
immunotherapy) in the neoadjuvant setting. In the Checkmate816 study, 358 patients with 
Stage IB (≥4cm) to Stage IIIA NSCLC (UICC/AJCC version 7) were randomized to 
neoadjuvant platinum-based chemotherapy with or without open label nivolumab (given 
every 3 weeks for up to 3 cycles) (Forde et al 2022). The co-primary endpoints were 
pathological complete response rate and event-free survival (EFS). The trial was positive 
for both primary endpoints. The hazard ratio for EFS was 0.63 (97.38% CIs 0.43-0.91) at 
interim analysis. This regimen was approved by the FDA in March 2022, for the treatment 
of patients with resectable (tumors ≥4cm or node-positive) NSCLC in the neoadjuvant 
setting, in combination with platinum-doublet chemotherapy.
Considering the approval of neoadjuvant and adjuvant immunotherapy options for patients 
with resectable Stage II-III NSCLC, AstraZeneca has decided to close enrollment early to 


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MERMAID-2 (D910MC00001). A total of 416 patients have signed informed consent for 
the study. This section describes the procedures required for all patients enrolled in the 
study and ensures that eligible patients have access to open-label durvalumab where 
appropriate (see Section 10.2 for details). At the time of implementation of CSP v2.0 at 
site, durvalumab will be supplied to sites for patients eligible to start open-label treatment. 
Study assessments will cease (except for serious adverse event identification and reporting 
and pregnancy reporting) and patients will continue with standard of care safety and 
efficacy assessments (based on local clinical practice).
10.2
Next steps for patients
At the time of CSP v2.0 implementation at site, given the current disposition of patients 
within the study, it is expected that the majority of patients will be discontinued from the 
study.
The following subsections describe the procedures to be followed for patients at various 
stages of the study following implementation of this amendment at site as summarized in 
Figure 5.


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Figure 5
Patients with opportunity to receive open-label durvalumab following CSP v2.0 implementation at site
a Any eligible patient has signed ICF2a and who is either in second screening or currently receiving study treatment (either durvalumab or placebo) at the time CSP v2.0 is 
implemented at site will have the opportunity to receive open-label durvalumab. If patients do not choose to receive open-label durvalumab, or where Investigators deem 
this to be inappropriate, patients will discontinue the study after all required data have been entered in the study database.
b Patients who choose to receive open-label durvalumab, and where Investigators deem this to be appropriate, must sign a new informed consent (ICF3).
c See Section 10.3.1 for details regarding treatment with open-label durvalumab. In general, patients who choose to receive open-label durvalumab may do so until 
treatment completion or discontinuation criteria are met (whichever occurs first). The Investigator should refer to the discontinuation criteria summarized in Section 7.1
for further guidance on treatment discontinuation.
Note: Prospective MRD testing will stop at time of CSP v2.0 implementation at site. All patients in first screening, surveillance, or study-specific follow-up at the time of 
CSP v2.0 implementation at site will discontinue the study as specified in Section 10.2.1.3. Site staff must enter all required data in the study database prior to discontinuing a 
patient from the study.
ICF Informed consent form; MRD Minimal residual disease; NSCLC Non-small cell lung cancer; q4w Every 4 weeks; R Randomization.


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10.2.1
Patients in first screening, surveillance, or follow-up
10.2.1.1
Patients in first screening or surveillance
At the time of CSP v2.0 implementation at site, patients in first screening or surveillance will 
be discontinued from the study.
Table 17 outlines the minimum data requirements that must be entered in the study database 
for all patients who are not randomized. Only the indicated data are required to be entered 
prior to discontinuation of any patient who is not randomized from the study.
Table 17
Required data entry for patients in first screening or surveillance 
All enrolled (but not randomized) patients
Additional data required for patients with MRD resulta
!
Demographics (age, sex, ethnicity, race, 
region)b
!
Smoking history and pack-years
!
Stage (post-surgery)
!
Local EGFR/ALK statusc
!
Date of surgeryc
!
Date(s) of sample collectionc
!
Reason(s) for screen failure (if applicable)
!
Reason(s) for discontinuation
!
Patient status at completion or 
discontinuation of study
!
Any SAE related to study procedures
!
Prior therapy for NSCLC under study (if applicable)
!
Pre-surgical details (including imagingc)
!
Histology, pre- and post-surgery
!
Specific surgical details:
o Extent of resection
o Pleural invasion status
o Nodal disease/confirmation of node-negative 
disease
o Extracapsular disease
o Mediastinal lymph node examination/dissection
o Confirmation of complete resection
o Extended pulmonary resection performed
!
Post-surgical scan datac
a
Includes patients in surveillance and/or who received an MRD status under MERMAID-1 (D910LC00001) 
prior to transferring to MERMAID-2 (D910MC00001).
b
Where allowed by local laws and regulations.
c
Where available.
ALK Anaplastic lymphoma kinase; EGFR Epidermal growth factor receptor; MRD Minimal residual disease; 
NSCLC Non-small cell lung cancer; SAE Serious adverse event.
10.2.1.2
Randomized patients in study-specific follow-up
At the time of CSP implementation at site, randomized patients in study-specific follow-up 
(randomized patients who are not actively receiving study treatment) will be discontinued 
from the study. Investigators and all randomized patients at that site will be unblinded to study 
treatment allocation.
All data must be entered into the study database prior to discontinuation of each patient.
10.2.1.3
Discontinuation of patients from the study
A visit for patients who will be discontinued from study must occur within 31 days of 
CSP v2.0 implementation at site. The purpose of this visit is to collect safety data, to ensure 


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all patients are fully informed of the changes to the study and the implications of these 
changes, and to ensure that indicated data are collected and entered accurately into the study 
database. This visit may be performed on site or via telemedicine. The nature of the visit, and 
what has been discussed, must be recorded in the source documents. At a minimum, the 
following assessments will be performed: assessments of AEs/SAEs and changes in 
concomitant medications.
Any safety events identified after the patient has been discontinued from the study 
should be managed per local standard of care. No study assessments (e.g., blood samples
or imaging) will be performed for after patient discontinuation from study.
10.2.2
Patients in second screening or randomized and receiving study 
treatment
At the time of CSP v2.0 implementation at site, Investigators and all randomized patients at 
that site will be unblinded to study treatment allocation. Patients in second screening (signed 
ICF2a but not yet randomized) who are deemed eligible and all patients currently receiving 
study treatment (regardless of treatment arm allocation) will have the option to receive 
open-label durvalumab (see Section 10.3.1).
For patients in second screening or currently receiving study treatment, there must be a visit 
within 31 days of CSP v2.0 implementation at site to discuss the option to start or continue 
open-label durvalumab. This visit can be performed on site or via telemedicine; the discussion 
between the patient and Investigator and its outcome must be recorded in the source 
documents. If this visit does not occur within 31 days of CSP v2.0 implementation at site, the 
patient will be considered lost to follow-up.
!
For patients who do not choose to receive open-label treatment, or where Investigators 
deem this to be inappropriate, there must be a visit within 31 days of CSP v2.0
implementation at site to ensure all applicable data are collected and entered accurately 
into the study database. This visit may be performed on site or via telemedicine (and can 
coincide with the discussion indicated above) and must be recorded in the source 
documents. Once this final visit has been completed, the patient will then be discontinued 
from the study (see Section 10.2.1.3).
!
For patients who choose to receive open-label durvalumab (and where Investigators deem 
this to be appropriate) they must sign the new ICF (ICF3) within 31 days of CSP v2.0
implementation at site, and prior to receipt of open-label durvalumab.


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10.3
End of study/study closure
10.3.1
Treatment with open-label durvalumab
Eligible patients who sign the new ICF (ICF3) may receive open-label durvalumab. This will 
be for a maximum of 13 cycles (including any durvalumab already received in a blinded 
manner). There will only be the following exceptions:
!
Patients who have already received ≥13 cycles of durvalumab within the MERMAID-2 
study prior to CSP v2.0 implementation at site, at the discretion of the Investigator and 
patient, may continue to receive treatment with open-label durvalumab but must not 
exceed 26 cycles of durvalumab in total. In such a scenario, treatment will end following 
the patient’s 26th cycle of durvalumab.
!
In exceptional circumstances, patients who have received <13 cycles of durvalumab at 
the time of CSP v2.0 implementation at site may receive up to a maximum of 26 cycles. 
This must be agreed with the global study medical team prior to obtaining patient consent 
and take into account prevailing clinical evidence for treatment duration.
Patients should be treated according to the investigational site’s standard of care procedures 
and the medical judgment of the Investigator. The nature and content of each discussion with 
each patient regarding the treatment plan must be recorded in the source documentation.
The Investigator should refer to the discontinuation criteria (summarized in Section 7.1) for 
guidance on treatment discontinuation.
10.3.2
Safety data to be collected
Any AEs and SAEs will be collected for a minimum of 90 days after the last dose of study 
treatment, but only SAEs will be reported. In addition, it is recommended that Investigators 
monitor the patient’s safety laboratory results periodically for at least 90 days after the last 
dose of study treatment in order to manage AEs consistent with the durvalumab Dose 
Modification and Toxicity Management Guidelines (see Section 8.4.5).
10.3.3
End of study definition
The end of the study is defined as when the last patient has received their last dose of 
durvalumab. Following implementation of CSP v2.0, the DCO will occur after the last patient 
has either discontinued the study or has signed consent (ICF3) to receive open-label 
durvalumab, whichever occurs later.
10.4
Statistical considerations
Under CSP v2.0, as a result of the decision by AstraZeneca to close enrollment to the study 
and end study assessments early, all analyses of the objectives and endpoints listed in 
Section 3 will be descriptive only and considered exploratory.
Further details will be included in the SAP.




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of monoclonal antibodies in adult clinical trials. J Clin Pharmacol 2009;49:1012–24.
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for patients with non-small cell lung cancer: the surgical setting of the Big Lung Trial. Eur J 
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Mar;42(3):426-32.


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12
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS


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


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A 3
Informed consent process
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study.
Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center.
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study.
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative.
If a patient declines to participate in any voluntary exploratory genetic research component of 
the study, there will be no penalty or loss of benefit to the patient and he/she will not be 
excluded from other aspects of the study. This does not apply to the mandatory genetic testing 
required to generate the personalized panel required for MRD assay.
If a patient’s partner becomes pregnant during within 90 days after the last dose of 
durvalumab, the partner is asked to sign the "Adult Study Informed Consent Form for 
Pregnant Partners of Study Patients" and provide information about the pregnancy 
accordingly.
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The Investigator or authorized designee will 
explain to each patient the objectives of the exploratory research. Patients will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. The patient will give a separate agreement to allow any 
remaining specimens to be used for exploratory research. Patients who decline to participate 
in this optional research will indicate this in the ICF. If a patient withdraws consent to the use 
of donated biological samples, the samples will be disposed of/destroyed, and the action 
documented. If samples already have been analyzed at the time of the request, AstraZeneca 
will not be obliged to destroy the results of this research.


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A 4
Data protection
The ICF will incorporate wording that complies with relevant data protection and privacy 
legislation. In some cases, such wording will be in a separate accompanying document. 
AstraZeneca will not provide individual genotype results to patients, their family members, 
their general physician, any insurance company, any employer, or any other third party, unless 
required to do so by law.
Precautions are taken to preserve confidentiality and prevent genetic data from being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and might also have access to his or her genetic data. Also, regulatory authorities may 
require access to the relevant files. Even so, the patient’s medical information and the genetic 
files would remain physically separate.
Each patient will be assigned a unique identifier by the Sponsor. Any patient records or data 
sets transferred to the Sponsor will contain only the identifier; patient names or any 
information which would make the patient identifiable will not be transferred.
The patient must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient.
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees structure
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance this could involve amendments to the Clinical Study Protocol and 
letters to Investigators.
A 6
Dissemination of clinical study data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the main study results when they are available. The clinical study and/or 
summary of main study results may also be available on other websites according to the 
regulations of the countries in which the main study is conducted.


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A 7
Data quality assurance
All patient data relating to the study will be recorded on electronic CRF (eCRF) unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by electronically signing the 
eCRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor.
A 8
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.
All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the reconstruction and 
evaluation of the study are defined as source documents. Source data are contained in source 
documents (original records or certified copies).


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A 9
Publication policy
The results of this study may be published or presented at scientific meetings once the primary 
analysis is completed and the study is unblinded. No other publications prior to that timepoint 
is allowed.
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Subsequent to the primary publication, if an investigator plans to publish any subset of data, or 
case report, the investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments.


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Appendix B
Adverse event definitions and additional safety information
B 1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence (other than 
progression of the malignancy under evaluation) in a patient or clinical study patient 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, an 
abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no Study treatment has been administered.
B 2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-subject hospitalisation or prolongation of existing hospitalisation
!
Results in persistent or significant disability or incapacity.
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardise the subject or may require medical 
treatment to prevent one of the outcomes listed above.
!
Adverse Events (AEs) for malignant tumors reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical 
Event’ criterion should be used. In certain situations, however, medical judgment on an 
individual event basis should be applied to clarify that the malignant tumor event should 
be assessed and reported as a Non-Serious AE. For example, if the tumour is included as 
medical history and progression occurs during the study, but the progression does not 
change treatment and/or prognosis of the malignant tumor, the AE may not fulfill the 
attributes for being assessed as serious, although reporting of the progression of the 
malignant tumor as an AE is valid and should occur. Also, some types of malignant 
tumours, which do not spread remotely after a routine treatment that does not require 
hospitalization, may be assessed as Non-Serious; examples include Stage 1 basal cell 
carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.
!
Malignant tumors that – as part of normal, if rare, progression – undergo transformation 
(eg, Richter's transformation of B cell chronic lymphocytic leukemia into diffuse large B 
cell lymphoma) should not be considered a new malignant tumor


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B 3
Life threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (e.g., hepatitis that resolved without hepatic failure).
B 4
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
B 5
Important medical event or medical treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the patient or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse
B 6
CTCAE grade
The grading scales found in the revised National Cancer Institute CTCAE latest version will 
be utilized for all events with an assigned CTCAE grading. For those events without assigned 
CTCAE grades, the criteria recommended in the CTCAE manual that converts severity levels 
into CTCAE grades should be used. A copy of the CTCAE can be downloaded from the 
Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable version 
of CTCAE should be described clearly.


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It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
B 7
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.
!
Time Course. Exposure to suspect drug. Has the patient actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?
!
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
!
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?
!
No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.
!
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.


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Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca IP that either causes harm to the participant or has 
the potential to cause harm to the participant.
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error.
!
occurred
!
was identified and intercepted before the participant 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 eg, medication prepared incorrectly, even if it was not actually given to 
the participant
!
Drug not administered as indicated, for example, wrong route or wrong site of 
administration
!
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet
!
Drug not stored as instructed eg, kept in the fridge when it should be at room temperature
!
Wrong participant received the medication (excluding IVRS/IWRS errors)
!
Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IVRS/IWRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error
!
Participant accidentally missed drug dose(s) eg, forgot to take medication
!
Accidental overdose (will be captured as an overdose)
!
Participant failed to return unused medication or empty packaging
!
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product


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Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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


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


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


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Appendix D
Genetics (for Optional Genetic Research Study)
This appendix relates to the optional genetic research study only. This is separate from the 
mandatory genetic components of this study. Details pertaining to the mandatory genetic 
samples and analyses that are required in this study are addressed in the Laboratory Manual.
D 1
Use/analysis of DNA
Genetic variation may impact a patient’s response to therapy, susceptibility to, and severity 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis from consenting patients.
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications. Genetic research may lead to better understanding of diseases, better diagnosis of 
diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications.
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical studies 
and, possibly, to genetically guided treatment strategies.
Genetic research may consist of the analysis of the structure of the patient´s DNA (ie, the 
entire genome).
The results of genetic analyses may be reported in the clinical study report (CSR) or in a 
separate study summary.
The Sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be retained while research on durvalumab continues but no longer than 15 
years or other period as per local requirements.


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D 2
Genetic research plan and procedures
Selection of genetic research population
Study selection record
All patients will be asked to participate in this genetic research. Participation is voluntary and 
if a patient declines to participate there will be no penalty or loss of benefit. The patient will 
not be excluded from any aspect of the main study.
Inclusion criteria
!
For inclusion in this genetic research, patients must fulfill all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and: Provide informed consent 
for the genetic sampling and analyses.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:
!
Previous allogeneic bone marrow transplant
!
Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection
Withdrawal of consent for genetic research:
Subjects may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study. Voluntary withdrawal will not 
prejudice further treatment. Procedures for withdrawal are outlined in Appendix C 2.
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the patients pre-dose at the first 
dosing visit. Although DNA is stable, early sample collection is preferred to avoid introducing 
bias through excluding patients who may withdraw due to an adverse event (AE), such 
patients would be important to include in any genetic analysis. If for any reason the sample is 
not drawn at the first dosing visit, it may be taken at any visit until the last study visit. Only 
one sample should be collected per patient for genetics during the study. Samples will be 
collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality. Samples will be stored for a maximum of 
15 years, from the date of last patient last visit, after which they will be destroyed. DNA is a 
finite resource that is used up during analyses. Samples will be stored and used until no further 
analyses are possible or the maximum storage time has been reached.


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An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube. Thereafter, the sample will be 
identifiable only by the second, unique number. This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organization. No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organizations working with the DNA).
The link between the patient enrolment/randomization code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organizations. The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit, 
and permit tracing of samples for destruction in the case of withdrawal of consent.
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix B.
Informed consent
The genetic component of this study is optional and the patient may participate in other 
components of the main study without participating in the genetic component. To participate 
in the genetic component of the study the patient must sign and date both the consent form for 
the main study and the genetic component of the study. Copies of both signed and dated 
consent forms must be given to the patient and the original filed at the study center. The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 
patient understands that they may freely withdrawal from the genetic aspect of the study at 
any time.
Patient data protection
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data 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 also have access to his or her genetic data. In addition, Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate.


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Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyze the samples.
AstraZeneca and its designated organizations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as hospitals, academic organizations or health insurance companies. This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease. The researchers can 
only use this information for health-related research purposes. Researchers may see summary 
results but they will not be able to see individual patient data or any personal identifiers.
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Statistical methods and determination of sample size
The number of patients that will agree to participate in the genetic research is unknown. It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A Statistical 
Analysis Plan may be prepared where appropriate.


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Appendix E
Mandatory Genetic analysis for Minimal Residual Disease
This appendix relates to the mandatory genetic component of this study.
Use/analysis of DNA in mandatory genetic study
Minimal residual disease (MRD) will be detected using a Sponsor-approved, complex 
personalized multi-step assay. Firstly, whole exome sequencing (WES) of the patient’s tumor 
is performed on primary resection sample and controlled for by germline mutations by WES 
of whole blood (as indicated in the Schedule of Activities Table 1), using 
 
 Germline exome sequencing will be performed at a depth of >25x, whereas tumor 
exome sequencing will have a mean sample coverage of 
 
 
 
 
 
 This personalized approach 
allows detection of the patient’s tumor variants in circulating tumor DNA (ctDNA) at high 
sensitivity. Tumor and whole blood samples, including DNA derived from those samples, as 
well as WES data, will be used for diagnostic development and exploratory research.
Sample coding and storage
All samples submitted for MRD will be coded to prevent patient identification. Sequencing 
data and variant calls from MRD analysis will be stored in a secure system at designated 
organizations to analyze the sample and/or at AstraZeneca. Germline data analysis will be 
conducted for the purpose of identifying tumor-specific variants not present in the patient’s 
non-cancerous cells.
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this mandatory 
genetic research component, are outlined in Appendix B.
Informed consent
Patients must sign Informed Consent Form 1 (ICF1) of the overall study to participate in this 
mandatory genetic component of the study.
Patient data protection
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
CCI
CCI


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Extra precautions are taken to preserve confidentiality and prevent genetic data 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 also have access to his or her genetic data. In addition, Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyze the samples.


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Appendix F
Actions required in cases of increases in liver biochemistry
and evaluation of Hy’s Law
F 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a subject meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory.
The Investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
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 Serious Adverse Events (SAEs) and Adverse Events (AEs) according to the 
outcome of the review and assessment in line with standard safety reporting processes.
F 2
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).


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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.
F 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination:
!
ALT ≥ 3xULN
!
AST ≥ 3xULN
!
TBL ≥ 2xULN
Central laboratories being used:
When a subject meets any of the PHL 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 PHL 
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 without delay
!
Complete the appropriate unscheduled laboratory CRF module(s) with the original local 
laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:
!
Determine whether the subject meets PHL criteria (see Section F 2 within this Appendix 
for definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results)


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Local laboratories being used:
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 subject meets PHL criteria (see Section F 2 Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits
!
Promptly enter the laboratory data into the laboratory CRF
F 4
Follow-up
F 4.1
Potential Hy’s Law Criteria not met
If the subject does not meet PHL criteria the Investigator will:
!
Inform the AstraZeneca representative that the subject has not met PHL criteria.
!
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol.
F 4.2
Potential Hy’s Law Criteria met
If the subject does meet PHL criteria the Investigator will:
!
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment
!
Notify the AstraZeneca representative who will then inform the central Study Team
!
Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting.
!
For subjects that met PHL criteria prior to starting IMP, the investigator is not required to 
submit a PHL SAE unless there is a significant change# in the subject’s condition
!
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up (including any further laboratory testing) and 
the continuous review of data
!
Subsequent to this contact the Investigator will:
Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.
Investigate the aetiology of the event and perform diagnostic investigations as discussed 
with the Study Physician. This includes deciding which the tests available in the Hy’s 
law lab kit should be used


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Complete the three Liver CRF Modules as information becomes available
# A ‘significant’ change in the subject’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.
F 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
As soon as possible 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, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from date PHL criteria was met. The AstraZeneca Global Clinical Lead or equivalent and 
Global Safety Physician will also be involved in this review together with other subject matter 
experts as appropriate.
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
Where 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: update the previously submitted Potential 
Hy’s Law SAE and AE CRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following 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:
!
Send updated 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


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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 15 calendar days 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:
!
Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE reporting.
!
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 still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
F 6
Laboratory tests
Hy’s Law lab kit for central laboratories
Additional standard chemistry and 
coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA
IgG anti-HCV
HCV RNA* 
IgM anti-HEV
HEV RNA


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Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-
transferrin)**
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
* HCV RNA is only tested when IgG anti-HCV is positive or inconclusive
** Carbohydrate deficient transferrin (CD-transferrin) is not available in China. Study teams should amend this 
list accordingly
REFERENCES
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf


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Appendix G
Guidelines for evaluation of objective tumor response using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid 
Tumors)
Introduction
This appendix details the implementation of Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST 1.1) guidelines (Eisenhauer et al 2009). Investigator assessments will 
use the RECIST 1.1 guidelines described in this Appendix. Additional special guidance is 
provided for evaluation of scans collected after a RECIST 1.1-defined radiological 
progression.
Imaging modalities and acquisition specifications for RECIST 1.1
A summary of the imaging modalities that can be used for tumor assessment of Target Lesions 
(TLs), Non-Target Lesions (NTLs), and New Lesions (NLs) is provided in Table 18.
Table 18
Summary of imaging modalities for tumor assessment
Target Lesions 
Non-Target Lesions
New Lesions
CT
MRI
CT
MRI
Plain X-ray
Chest X-ray
CT
MRI
Plain X-ray
Chest X-ray
Bone scan (Scintigraphy)
FDG-PET/CT
CT Computed tomography; FDG-PET/CT 18F-Fluoro-deoxyglucose positron emission tomography/CT; 
MRI Magnetic resonance imaging.
CT and MRI
Computed tomography (CT) with intravenous (IV) contrast is the preferred imaging modality 
(although magnetic resonance imaging [MRI] with IV contrast is acceptable if CT is 
contraindicated) to generate reproducible anatomical images for tumor assessments (ie, for 
measurement of TLs, assessment of NTLs, and identification of NLs). It is essential that the 
same correct imaging modality, image acquisition parameters (eg, anatomic coverage, 
imaging sequences, etc), imaging facility, tumor assessor (eg, radiologist), and method of 
tumor assessment (eg, RECIST 1.1) are used consistently for each patient throughout the 
study. The use of the same scanner for serial scans is recommended, if possible. It is important 
to follow the image collection/tumor assessment schedule as closely as possible (refer to the 
NOTE: for evaluation of disease recurrence, please refer to the RECIST 1.1 
definition of new lesions.  


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Schedule of Activities [SoA; Table 2]), and this on-study imaging schedule MUST be 
followed regardless of any delays in dosing or missed imaging visits. If an unscheduled 
assessment is performed (eg, to investigate clinical signs/symptoms of progression) and the 
patient has not progressed, every attempt should be made to perform the subsequent scan 
acquisitions at the next scheduled imaging visit.
Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice. Body 
scans should be performed with breath-hold scanning techniques, if possible. Therefore, CT of 
the chest is recommended over MRI due to significant motion artifacts (eg, heart, major blood 
vessels, breathing) associated with MRI. MRI has excellent contrast and spatial and temporal 
resolutions; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. The modality used at follow-up should be the same as 
was used at baseline, and the lesions should be measured/assessed on the same pulse 
sequence. In general, local oncology diagnostic imaging parameters are applied for scan 
acquisition. It is beyond the scope of this appendix to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.
The most critical CT and MRI image acquisition parameters for optimal tumor evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumors is the 
chest-abdomen. Coverage should encompass all areas of known predilection for metastases in 
the disease under evaluation and should additionally investigate areas that may be involved 
based on signs and symptoms of individual patients. Because a lesion later identified in a body 
part not scanned at baseline would be considered as a new lesion representing disease 
progression, careful consideration should be given to the extent of imaging coverage at 
baseline and at subsequent follow-up timepoints. This will enable better consistency not only 
of tumor measurements but also identification of new disease.
Required anatomical regions to be imaged for assessment of tumor burden (TLs and/or NTLs) 
at baseline and follow-up visits vary according to the study, and these timepoints are specified 
in the SoA (Table 2). Examples include the following:
!
IV contrast-enhanced CT of chest-abdomen (including liver and adrenal glands)
!
Non-contrast CT of chest and IV contrast-enhanced abdomen (including liver and adrenal 
glands)
!
IV contrast-enhanced CT or MRI of the head and neck
!
IV contrast-enhanced MRI (preferred) or CT of the brain


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For chest-abdomen imaging, the following are scanning options in decreasing order of 
preference, with additional options (2 to 4) for consideration when patients have sensitivity to 
IV contrast or have compromised renal function:
1
Chest-abdomen CT with IV CT contrast (most preferred)
2
Chest CT without IV contrast + abdomen MRI with IV MRI contrast, if CT IV contrast 
(iodine based) is medically contraindicated at any time during the study
3
Chest-abdomen CT without IV contrast, if both IV CT and MRI contrast are medically 
contraindicated or the patient has compromised renal function
4
Chest-abdomen MRI with IV MRI contrast, if CT cannot be performed at any time during 
the study
b. IV contrast administration: Optimal visualization and measurement of metastases in solid 
tumors require consistent administration (dose and rate) of IV contrast as well as timing of 
scanning. An adequate volume of a suitable contrast agent should be given so that the tumor 
lesions are demonstrated to best effect and a consistent method is used on subsequent 
examinations for any given patient. Oral contrast is recommended to help visualize and 
differentiate structures in the abdomen.
c. Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) slices with ≤5-mm thickness throughout the 
entire anatomic region of interest for optimal lesion measurements. Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses >5 mm. If this occurs, 
the minimum size of measurable lesions at baseline should be twice the slice thickness of the 
baseline scans.
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered. When measuring lesions, the 
TL should be measured on the same window setting for repeated examinations throughout the 
study.
Chest X-ray
Chest X-ray assessment will not be used for the assessment of TLs. Chest X-ray can, however, 
be used to assess NTLs and to identify the presence of NLs. However, there is preference that 
a higher resolution modality, such as CT, be used to confirm the presence of NLs.
Plain X-ray
Plain X-ray may be used as a method of assessment for bone NTLs and to identify the 
presence of new bone lesions.


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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 NTLs and followed by the same method per baseline 
assessment (CT, MRI, or X-ray).
Isotopic bone scans may be used as a method of assessment to identify the presence of new
bone lesions at follow-up visits. NLs may be recorded in case positive hot-spots appear on a 
bone scan that were not present on a previous bone scan; however, a newly observed 
equivocal hot-spot on a bone scan that cannot be verified with correlative imaging (CT, MRI, 
or X-ray) of the same anatomical region shall not be the only trigger for a progressive disease 
(PD) assessment at that timepoint.
FDG-PET/CT
18F-Fluoro-deoxyglucose positron emission tomography/computed tomography/CT 
(FDG-PET/CT) scans may be used as a method for identifying new extrahepatic lesions (but 
not intrahepatic lesions) for RECIST 1.1 assessments according to the following algorithm: 
NLs will be recorded where there is positive 18F-Fluoro-deoxyglucose uptake1 not present on 
baseline or prior FDG-PET scan or in a location corresponding to a NL on a companion 
CT/MRI collected close in time to the FDG-PET scan. The PET portion of the PET/CT 
introduces additional data that may bias an Investigator if it is not routinely or serially 
performed. Therefore, if there is no baseline or prior FDG-PET scan available for comparison, 
and no evidence of NLs on companion CT/MRI scans, then follow-up CT/MRI assessments 
should continue as per the regular imaging schedule to verify the unequivocal presence of 
NLs.
At present, low dose or attenuation correction CT portions of a combined FDG-PET/CT scan 
are of limited use in anatomically based efficacy assessments, and it is therefore suggested 
that they should not substitute for dedicated diagnostic contrast-enhanced CT scans for tumor 
measurements by RECIST 1.1. In exceptional situations, if a site can document that the CT 
performed, as part of a PET/CT examination, is of identical diagnostic quality (with IV 
contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT can be used 
for RECIST 1.1 tumor assessments. Caution that this is not recommended because the PET 
portion of the CT introduces additional (PET) data that may bias an Investigator if it is not 
routinely or serially performed.
Ultrasound
Ultrasound examination will not be used for RECIST 1.1 assessment of tumors as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation, and may 
                                               
1
A positive FDG-PET scan lesion should be reported only when an uptake (eg, SUV) greater than twice that of the surrounding tissue or liver is observed.


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not provide an accurate assessment of the true tumor size. Tumors identified by ultrasound 
will need to be assessed by correlative CT or MRI anatomical scan.
Other tumor assessments
Clinical examination
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for RECIST 1.1 assessments. Tumors identified by clinical examination will need 
to be assessed by correlative CT or MRI anatomical scans.
Endoscopy and laparoscopy
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated 
in the context of tumor assessment.
Histology and cytology
Histology or tumor markers on tumor biopsy samples will not be used as part of the tumor 
response assessment as per RECIST 1.1.
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, and pleural effusion) that appears or worsens during the study will not be 
used as part of the tumor response assessment as per RECIST 1.1.
Furthermore, an overall assessment of complete response (all other disease disappears/reverts 
to normal) would be changed to partial response if an effusion remains present radiologically.
Measurability of tumor lesions at baseline
RECIST 1.1 measurable lesions at baseline:
A tumor lesion that can be accurately measured at baseline as ≥10 mm in the longest diameter 
for non-nodal lesions or ≥15 mm in short axis2 diameter for lymph node lesions with IV 
contrast-enhanced CT or MRI and that is suitable for accurate repeated measurements. Please 
see additional RECIST 1.1 guidance below on measurability of intrahepatic hepatocellular 
carcinoma lesions and porta hepatis lymph nodes.
Non-measurable lesions at baseline:
!
Truly non-measurable lesions include the following:
Bone lesions (see exception below for soft tissue component)
Leptomeningeal disease
Ascites, pleural effusion, or pericardial effusion
                                               
2
The short axis is defined as the longest in-plane axis perpendicular to the long axis.


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Inflammatory breast disease
Lymphangitic involvement of skin or lung
!
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10-mm to <15-mm short axis diameter at baseline3)
!
Previously irradiated lesions4 <<Study Specific: Previously irradiated lesions are 
typically allowed only as (non-measurable) Non-Target Lesions; however, some studies 
may allow a previously irradiated measurable lesion as a Target Lesion if this is the only 
lesion available.>>
!
Brain metastasis
Special considerations regarding lesion measurability at baseline:
!
Bone lesions
Bone scan, PET scan, or plain X-ray are not considered adequate imaging techniques to 
measure bone lesions; however, these techniques can be used to confirm the presence 
or disappearance of bone lesions.
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 lesions thought to represent 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 over cystic 
lesions as TLs.
RECIST 1.1 TL selection at baseline:
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 TLs at baseline. TLs should be selected on the basis of their size 
(longest diameter for non-nodal lesions or short axis diameter 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 
                                               
3
Lymph nodes with <10-mm short axis diameter are considered non-pathological and should not be recorded 
or followed as NTLs.
4
Localized post-radiation changes that affect lesion size may occur. Therefore, lesions that have been 
previously irradiated are typically considered non-measurable and as NTL at baseline and followed up as 
part of the NTL assessment.


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measurement, in which circumstance the next largest lesion that can be measured reproducibly 
should be selected.
Lymph nodes, in any location (local/regional and distant), are collectively considered as a 
single organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, adrenal 
glands), a segmented organ (eg, liver), or a multilobed organ (eg, lung) is each considered as a 
single organ.
The site and location of each TL should be documented, as well as the longest axis diameter 
for non-nodal lesions (or short axis diameter for lymph nodes). All measurements should be 
recorded in whole (integer) millimeters and calculated values should be rounded to whole 
numbers. At baseline, the sum of the diameters for all TLs will be calculated and reported as 
the baseline sum of diameters. At follow-up visits, the sum of diameters for all TLs will be 
calculated and reported as the follow-up sum of diameters.
Special cases for TL assessment at baseline:
!
For TLs 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 
diameter.
!
When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
vector of the longest diameter should be used to determine the perpendicular vector for 
the maximal short axis diameter of the coalesced mass. Non-nodal lesions that coalesce 
should similarly be assessed by the longest axis diameter.
!
Tumor lesions selected for fresh screening biopsy should not be selected as TLs, unless 
imaging occurred at least approximately 2 weeks after biopsy, allowing time for healing.
!
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 diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as a New 
Lesion.
RECIST 1.1 NTL selection at baseline:
All other lesions, including non-measurable lesions and surplus measurable lesions, not 
recorded as TLs should be identified as NTLs at baseline. Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout follow-up.
Evaluation of tumor response and progression
RECIST 1.1 TL assessment at follow-up
This section defines the criteria used to determine objective tumor visit response for 
RECIST 1.1-defined TLs. The imaging modality, location, and scan date of each TL identified 
previously at baseline should be documented at follow-up visits with the long axis diameter 


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for non-nodal lesions or short axis diameter for lymph node lesions. All measurements should 
be recorded in millimeters. The sum of the diameters for all TLs at each follow-up visit will 
be compared to the baseline sum of diameters (for response or stable disease) or to the 
smallest prior (nadir) sum of diameters (for progression).
Special cases for TL assessment at follow-up:
!
If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL.
!
If a TL splits into 2 or more parts, the sum of the diameters of those parts should be 
recorded.
!
If 2 or more TLs merge, then the sum of the diameters of the combined lesion should be 
recorded for 1 of the lesions and 0 mm recorded for the other lesion(s). If the merged TLs 
are non-nodal lesions, record the long axis diameter of the merged lesion. If pathologic 
lymph nodes coalesce and are no longer individually separable within a conglomerate 
mass, the vector of the longest diameter of the coalesced mass should be used to 
determine the perpendicular vector for the maximal short axis diameter.
!
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. The choice of “Too large to measure” in the case report form will 
trigger an overall visit response of PD.
!
When a TL has had an intervention, the following apply:
Target Lesion Intervention may include radiotherapy, embolization, excisional biopsy, 
surgery, etc. that is not a part of study treatment and might adversely affect the size of 
that Target lesion
If an Intervention on a Target Lesion is ticked in the case report form, the diameter of the 
lesion is still recorded (0 mm if no longer present) and is included in the sum of 
diameters.
If a Target Lesion Intervention is ticked, the Intervention must be reported for all 
subsequent assessments of that Target lesion.
If a Target Lesion has an Intervention, the only Overall Visit Responses allowed to be 
recorded by the Investigator are NE or PD, with PD if the sum of diameters exceeds a 
20% increase and at least a 5 mm absolute increase in the visit sum of diameters 
compared to the previous minimum (nadir) sum of diameters.
No visit with a recorded Target Lesion Intervention can be used as the minimum (nadir) 
sum of diameters.


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Table 19
RECIST 1.1 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 diameter 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 decrease in the sum of diameters 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 previous sum of diameters (nadir)—This includes 
the baseline sum if that is the smallest on study. In addition to the 
relative increase of 20%, the sum must demonstrate an absolute increase 
of at least 5 mm from nadir.
Not evaluable (NE)
Only relevant if any of the TLs at follow-up were not assessed or not 
evaluable (eg, missing anatomy) or had a lesion intervention at this 
visit. Note: If the sum of diameters meets the progressive disease 
criteria, progressive disease overrides not evaluable as a TL response.
Not applicable (NA)
Only relevant if no TLs present at baseline.
CR Complete response; NE Not evaluable; PD Progression of disease; PR Partial response; SD Stable disease; 
TL Target lesion.
RECIST 1.1 NTL assessment at follow-up
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs 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.
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 
unequivocal progression by NTLs. A modest ‘increase’ in the size of 1 or more NTLs is 
usually not sufficient to qualify for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of stable disease 
(SD) or progressive disease (PR) of target disease will therefore be extremely rare.
Table 20
RECIST 1.1 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 1 or more NTLs.
Progression (PD)
Unequivocal progression of existing NTLs. Unequivocal progression 
may be due to an important progression in 1 lesion only or in several 
lesions. In all cases, the progression MUST be clinically significant 
for the physician to consider changing (or stopping) therapy.


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Not evaluable (NE)
Only relevant when 1 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.
Not applicable (NA)
Only relevant if no NTLs present at baseline
CR Complete response; NE Not evaluable; NTL Non-target lesion; PD Progression of disease; TL Target 
lesion.
RECIST 1.1 NL identification at follow-up
Details, including the imaging modality, the date of scan, and the location of any NLs will 
also be recorded in the case report form. The presence of 1 or more NLs is assessed as 
progression. The finding of a NL should be unequivocal, ie, not attributable to differences in 
scanning technique, change in imaging modality, or findings thought to represent something 
other than tumor. If a NL is equivocal, for example because of its small size, the treatment and 
tumor assessments should be continued until the previously (pre-existing) new lesion has been 
assessed as unequivocal at a follow-up visit, and then the progression date should be declared 
using the date of the initial scan when the NL first appeared.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate disease progression.
RECIST 1.1 evaluation of overall visit response at follow-up
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs uses the algorithm shown in Table 21.
Table 21
RECIST 1.1 overall visit response
Target Lesions
Non-Target Lesions
New Lesions
Overall visit response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non CR/Non PD 
No
PR
CR
NE
No 
PR
PR
Non PD or NE or NA
No
PR
SD 
Non PD or NE or NA
No
SD
NA
Non-CR/Non-PD
No
SD (non-CR/non-PD)
NE
Non PD or NE
No
NE
NA
NE
No
NE


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Target Lesions
Non-Target Lesions
New Lesions
Overall visit response
NA
NA
No
NED
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Non-CR/Non-PD for Overall Response if only non-target lesions (no TLs) are present at baseline.
Note: An overall assessment of Complete Response (all other disease disappears/reverts to normal) would be 
changed to Partial Response if ascites remains present radiologically.
CR Complete response; NA Not applicable (only relevant if there were no target lesions at baseline or 
non-target lesions at baseline), NE Not evaluable; NED No Evidence of Diseases (only relevant if there were 
neither target lesions nor non-target lesions at baseline); PD Progressive disease; PR Partial response; 
SD Stable disease; TL Target Lesion.
The following overall visit responses are possible depending on the extent of tumor disease at 
baseline:
!
For patients with TLs (at baseline): complete response (CR), partial response (PR), stable 
disease (SD), progression of disease (PD), or not evaluable (NE)
!
For patients with NTLs only (at baseline): CR, Non-CR/Non-PD, PD, or NE
!
For patients with no disease at baseline: NED (no evidence of disease; available as an 
option in the electronic case report form), PD, or NE
Evaluation of scans subsequent to RECIST 1.1-defined progression
A follow-up scan is requested at least 4 weeks after a RECIST 1.1-defined radiological 
progression and no longer than the next regularly scheduled imaging visit. The follow-up 
scans provide additional information to the Investigator for patient management and further 
treatment decisions, and since the published RECIST 1.1 criteria (Eisenhauer 2009) do not 
provide guidance on how to assess scans acquired after RECIST 1.1-defined PD, 
supplemental instructions for Investigators on how to evaluate these follow-up scans are 
provided below. An immediate prior RECIST 1.1-defined radiologic PD would be considered 
confirmed if any of the following criteria are met in the subsequent follow-up scan:
!
≥20% increase and at least a 5-mm increase in the sum of diameters of TLs compared 
with the nadir sum of diameters at 2 consecutive visits, and a further increase of ≥5 mm in 
the sum of diameters at the follow-up scan timepoint compared with the immediate prior 
timepoint
!
significant progression (worsening) of NTLs at the follow-up scan timepoint compared 
with the immediate prior timepoint
!
significant progression (worsening) of previously new lesions (pre-existing new lesions) 
at the follow-up scan timepoint compared with the immediate prior timepoint
!
additional brand-new unequivocal lesions at the follow-up scan timepoint


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Central imaging
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed imaging Contract Research Organization (iCRO) for QC, storage, and 
for Blinded Independent Central Review (BICR). Guidelines for image acquisition, de-
identification, storage of digital copies at the investigative site (as source documents), and 
transfer to the iCRO will be provided in a separate document. Electronic image transfer from 
the sites to the iCRO is strongly encouraged. A BICR of images will be performed at the 
discretion of AstraZeneca. Results of these independent reviews will not be communicated to 
Investigators, and results of Investigator RECIST 1.1 assessments will not be shared with the 
central reviewers. The management of patients will be based in part upon the results of the 
RECIST 1.1 assessment conducted by the Investigator. Further details of the BICR will be 
documented in the Independent Review Charter.
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 H
Contraception Requirements
The following contraception requirements should be verified/adjusted for each study and 
should be further adjusted to take into account Clinical Trial Facilitation Group guidelines for 
embryotoxicity if observed with the study intervention.
Contraception requirements for this study are as follows.
H 1
Female Participants
Women not of childbearing potential are defined as those who are surgically sterile (ie, 
bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or who are 
post-menopausal.
Women will be considered post-menopausal if they have been amenorrhoeic 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 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy 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 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy, or had radiation-induced menopause with last menses >1 year ago, or had 
chemotherapy-induced menopause with last menses >1 year ago.
Women of childbearing potential who are not totally sexually abstinent (ie, refraining from 
heterosexual intercourse during the entire period of risk associated with study interventions) 
and intend to be sexually active with a non-sterilized male partner must use at least 1 highly 
effective method of contraception (Table 22). They should have been stable on their chosen 
method of birth control for a minimum of 3 months before entering the study and continue to 
use it throughout the total duration of the drug treatment and the drug washout period (90 days 
after the last dose of study intervention).
Non-sterilized male partners of a woman of childbearing potential must use a male condom 
plus spermicide (condom alone 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 contraception. Total sexual abstinence is an acceptable method 
provided it is the usual lifestyle of the participant. Female participants should refrain from 
breastfeeding throughout this period.


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H 2
Male Participants with a Female Partner of Childbearing 
Potential
Non-sterilized male participants (including males sterilized by a method other than bilateral 
orchidectomy, eg, vasectomy) who intend to be sexually active with a female partner of 
childbearing potential must be using an acceptable method of contraception such as male 
condom plus spermicide (condom alone in countries where spermicides are not approved) 
from the time of screening throughout the total duration of the study and the drug washout 
period (90 days after the last dose of study intervention) to prevent pregnancy in a partner.
If more than 1 treatment group is included in the study, add additional time periods as 
necessary here (eg, <<XX>> days after the last dose of <<study intervention 1>> or <<XX>> 
days after the last dose of <<study intervention 2>>). 
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception. Male participants should refrain from sperm donation or banking 
throughout this period.
Vasectomised (ie, sterile) males are considered fertile and should still use a male condom plus 
spermicide as indicated above during the clinical study.
Even if the female partner is pregnant, male participants should still use a condom plus 
spermicide (where approved), as indicated above during the clinical study, if there is a 
concern about damaging the developing fetus from drug in ejaculate.
Female partners (of childbearing potential) of male participants must also use a highly 
effective method of contraception throughout this period (Table 22).
H 3
Highly Effective Methods of Contraception
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly, are described in Table 22. 
Note that some contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills).


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Table 22
Highly Effective Methods of Contraception (<1% Failure Rate)
Non-Hormonal Methods
Hormonal Methods
•
Total sexual abstinence (evaluate in relation to 
the duration of the clinical study and the 
preferred and usual lifestyle choice of the 
participant)
•
Vasectomised sexual partner (with participant 
assurance that partner received post-vasectomy 
confirmation of azoospermia)
•
Tubal occlusion
•
Intrauterine device (provided coils are 
copper-banded)
•
Injection: Medroxyprogesterone injection 
(eg, Depo-Provera®)a
•
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®)a
•
Implants: Etonogestrel-releasing implants 
(eg, Implanon® or Norplant®)
•
Intravaginal devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®) 
•
Combined pill: Normal and low dose combined 
oral contraceptive pill
•
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Ortho Evra®)
•
Mini pill: Progesterone-based oral contraceptive 
pill using desogestrel: Cerazette® is currently the 
only highly effective progesterone-based pill
d
Hormonal methods not prone to drug-drug interactions.


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Appendix I
This appendix includes example copies of the following 
 
questionnaires:
!
European Organisation for Research and Treatment of Cancer (EORTC) 30-item Core 
Quality of Life Questionnaire
!
EORTC 13-item Lung Cancer Quality of Life Questionnaire
!
!
 
!
!
CCI
CCI
CCI
CCI
CCI
CCI


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Appendix J
Abbreviations
Abbreviation or 
special term
Explanation
AE
adverse event
AESI
adverse event of special interest
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BICR
Blinded Independent Central Review
BP
blood pressure
CD
cluster of differentiation
CI
confidence interval
CL
clearance
CRO
Contract Research Organization
CSP
clinical study protocol
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
circulating tumor DNA
CTLA-4
cytotoxic T-lymphocyte-associated antigen 4
DBL
database lock
DCO
data cut-off
DFS
disease-free survival
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EGFR
epidermal growth factor receptor
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire – Core 30 items
EORTC QLQ-LC13
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire – Lung Cancer 13 items
ePRO
electronic Patient-reported Outcomes
FAS
full analysis set
FDA
United States Food and Drug Administration
FDG-PET
18F-Fluoro-deoxyglucose positron emission tomography
GCP
Good Clinical Practice
HBsAg
hepatitis B virus surface antigen
HBV
hepatitis B virus
CCI
CCI


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Abbreviation or 
special term
Explanation
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
HRCT
high-resolution computed tomography
HRQoL
health-related quality of life
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
iCRO
imaging Contract Research Organization
ICU
intensive care unit
IDMC
independent data monitoring committee
IEC
independent ethics committee, synonymous to ethics committee (EC) and IRB
IHC
immunohistochemistry
ILD
interstitial lung disease
imAE
immune-mediated adverse event
IO
immune-oncologic
IP
investigational product
IRB
institutional review board
International Coordinating 
Investigator
If a study is conducted in several countries the International Coordinating 
Investigator is the Investigator coordinating the Investigators and/or activities 
internationally. 
IV
intravenous
IWRS
interactive web response system
LIMS
Laboratory Information Management System
mAb
monoclonal antibody
mRNA
messenger ribonucleic acid
MRD
minimal residual disease
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
NTL
non-target lesion
OS
overall survival
PD
progression of disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography
PFS
progression-free survival


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Abbreviation or 
special term
Explanation
PI
Principal Investigator 
PK
pharmacokinetic(s)
PORT
post-operative radiotherapy
PR
partial response
PS
performance status
q3w
every 3 weeks
q4w
every 4 weeks
 
QoL
quality of life
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
SAE
serious adverse event 
SAP
statistical analysis plan
SAS
safety analysis set
SD
stable disease
SoA
Schedule of Activities
SoC
standard of care
sPD-L1
soluble programmed cell death ligand 1
SpO2
saturation of peripheral oxygen
TL
target lesion
TMB
tumor mutational burden
UICC/AJCC
Union for International Cancer Control–American Joint Committee on Cancer
ULN
upper limit of normal
US
United States
VAS
visual analog scale
VATS
video-assisted thoracoscopic surgery
WES
whole exome sequencing
w/v
weight per volume
WHO
World Health Organization
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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: d910mc00001-csp-v2
Document Title:
D910MC00001 Clinical Study Protocol version 2
Document ID:
Doc ID-004122807
Version Label:
3.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
10-Aug-2022 18:19 UTC
Content Approval
10-Aug-2022 16:55 UTC
Qualified Person Approval
11-Aug-2022 09:17 UTC
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan 
Study Code
D910MC00001
Version Number 
2.0
Date
14 March 2023
A Phase III, Randomized, Multicenter, Double-blind, Placebo-controlled 
Study of Durvalumab for the Treatment of Stage II-III NSCLC Patients 
with Minimal Residual Disease Following Surgery and Curative Intent 
Therapy (MERMAID-2)
ed 
III, Random
III, Random
rvalum
rvalu
Redacted
ed for 
ab for
ab fo
esidual Dise
sidual D
Therap
Ther
or Public Disclosure


Statistical Analysis Plan, v2.0
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Study Code D910MC00001
Date 14 March 2023
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A Phase III, Randomized, Multicenter, Double blind, Placebo controlled 
Study of Durvalumab for the Treatment of Stage II III NSCLC Patients 
with Minimal Residual Disease Following Surgery and Curative Intent 
Therapy (MERMAID 2)
 
 
 
Study Statistician
Date
PPD


Statistical Analysis Plan, v2.0
AstraZeneca 
Study Code D910MC00001
Date 14 March 2023
CONFIDENTIAL AND PROPRIETARY
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A Phase III, Randomized, Multicenter, Double blind, Placebo controlled 
Study of Durvalumab for the Treatment of Stage II III NSCLC Patients 
with Minimal Residual Disease Following Surgery and Curative Intent 
Therapy (MERMAID 2)
 
 
 
Global Product Statistician
Date
PPD






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Table 3
Definition of Two Missed Visits ...........................................................26
LIST OF FIGURES
Figure 1 
Original Study Design...........................................................................19


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LIST OF ABBREVIATIONS 
Abbreviation or 
special term
Explanation
AE
Adverse event  
AEPI
Adverse event of possible interest
AESI
Adverse event of special interest
ALK
Anaplastic lymphoma kinase
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AZ SOL
AstraZeneca standard output library
BMI
Body mass index
CL
Clearance
COVID-19
Coronavirus Disease 2019
CrCl
Creatinine clearance
CRF
Case report form
CSP
Clinical study protocol 
CSR
Clinical study report 
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
Circulating tumor DNA
DBL
Database lock
DBP
Diastolic blood pressure
DCO
Data cut-off
DFS
Disease-free survival
ECG
Electrocardiogram
ECOG
Easter Cooperative Oncology Group
eCRF
Electronic case report form
EGFR
Epidermal growth factor receptor


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Abbreviation or 
special term
Explanation
 
 
FAS
Full analysis set
GGT
Gamma-glutamyl transferase
HLT
Higher-level term
HRQoL
Health related quality of life
ICF1
Informed consent form 1
ICF2
Informed consent form 2
ICU
Intensive care unit
IDMC
Independent data monitoring committee 
IHC
Immunohistochemistry
imAE
Immume-mediated adverse events
IP
Investigational product
IPD
Important protocol deviation
IV
Intravenous
IWRS
Interactive Web Response System
LLN
Lower limit of normal
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MRD
Minimal residual disease
MRD+
MRD-positive
MRD-
MRD-negative
MTP
Multiple testing procedure
NA
Not applicable
NCI
National Cancer Institute
NE
Not evaluable
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Abbreviation or 
special term
Explanation
NED
No evidence of diseases
NL
New lesion
NSCLC
Non-small cell lung cancer
OS
Overall survival
PD
Progression of disease
PD-L1
Programmed cell death ligand 1
PFS
Progression free survival
PORT
Post-operative radiotherapy
 
PT
Preferred term
q4w
Every 4 weeks
q6w
Every 6 weeks
q12w
Every 12 weeks
QoL
Quality of Life
RDI
Relative dose intensity
RECIST
Response Evaluation Criteria in Solid Tumours
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SAS!
A commercially available integrated system of software products, 
commonly used for reporting and analysis of Clinical Studies
SBP
Systolic blood pressure
SI
International System of Units
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Abbreviation or 
special term
Explanation
SoC
Standard of Care
SOC
System organ class
TC
Tumour cell
TEAE
Treatment-emergent adverse event
TMB
Tumour mutational burden
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
VAF
Variant allele frequencies
VAS
Visual analogue scale
WHODD
World Health Organization drug dictionary
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AMENDMENT HISTORY
Date
Brief description of change
V1.0 (25Feb2021)
V2.0 (14Mar2023)
NA – first version
Updated to reflect CSP V2.0, including changes to primary, secondary and 
exploratory objectives.
Updated the planned analyses throughout the document (All analyses of the 
objectives and endpoints are now descriptive only and considered 
exploratory.)
Removed any references to blinded independent central review endpoints 
and analyses throughout the document.
Throughout the document, when both PD-L1 TC≥1% analysis set and FAS 
are mentioned, the order has been changed such that the FAS is mentioned 
first and thereafter the PD-L1 TC≥1% analysis set, to align with the revised 
primary endpoint as per CSP V2.0.
Section 2.1 – Table 1 updated as per CSP V2.0.
Section 2.2 – removed ‘deviation bias’ sensitivity analysis.
Section 4 – in alignment with CSP V2.0, clarified that no formal statistical 
analyses will be performed. 
Section 4.1 – revised decimal places for continuous data as per AZSOL 
general principles. 
Section 4.2 – general wording and Table 5 revised in line with changes to 
objectives.
Section 4.2.1 – removed methods for multiplicity.
Section 4.2.2 – removed some supportive summaries/graphs, sensitivity and 
secondary analyses of Disease-free survival.
Section 4.2.2.1 
∀
removed summary of treatment status of patients at disease 
recurrence.
∀
removed summary of patients prematurely censored.
∀
removed summary of number of weeks between the time of disease 
recurrence and the last RECIST assessment.
∀
removed summary of patients who miss two or more consecutive 
RECIST assessments.
Section 4.2.2.2 – removed subgroup analyses.
Section 4.2.3 – revised Overall survival description to be listed only.
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Date
Brief description of change
Section 4.2.4 – revised Progression-free survival description to be listed 
only.
Section 4.2.5 – revised time to first and second subsequent therapy or death  
description to be listed only.
Section 4.2.6 – Data Cut-Offs revised as per CSP V2.0.
∀
∀
 
Section 4.2.9  
∀
removed section on summary of long term tolerability.
∀
revised wording for AE with outcome of death, as per AZSOL.
Section 4.2.9.1
∀
removed summaries for time to onset and duration of the first AE, 
event rate, and longer-term toxicity profile.
∀
replaced summary table on “most common AEs with CTCAE grade 
3 or 4” with summary table on “most common AEs with maximum 
CTCAE grade 3 or 4”.
∀
summary for death limited to all deaths on the FAS.
Section 4.2.9.2 – removed AESI/AEPI summaries leading to steroid use, 
discontinuation of study treatment and dose delay of study treatment.
Section 4.2.9.3
∀
removed all graphical presentations of laboratory data, as well as 
summaries of absolute value and change from baseline in 
hematology and chemistry, and urinalysis shift table.
∀
Thyroid function tests: removed summaries on elevated on-treatment 
TSH. Added shift tables to maximum and minimum on-treatment.
∀
Renal function tests: removed summaries of CrCl reversibility.
Section 4.2.9.4 – revised electrocardiograms description to be listed only.
Section 4.2.9.5 – revised vital signs description to be listed only.
Section 4.2.11 – added a summary of subsequent anti-cancer therapy.
Section 4.2.13 – removed sensitivity analyses.
Section 4.4 – Observation period removed as per CSP V2.0.
Section 5.1 – aligned with CSP V2.0, no interim analyses are planned.
Section 5.2 – added provision of a final safety report post-DBL.
Section 6 – updated to include reference to the CSP amendment.
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Date
Brief description of change
Section 7 – removed references no longer used in this document due to 
updates as listed above.
Appendix B – revised imputation for completely missing 
medication/therapy end dates, partial death dates.
Minor formatting changes throughout.
AZ Global Product Statistician signatory updated.


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1. STUDY DETAILS
This statistical analysis plan (SAP) contains a more detailed description of the analyses in the 
clinical study protocol (CSP) version 2.0, dated 02 August 2022, and on version 2.0 of the 
Protocol Deviations Plan, dated 12 May 2021. Any changes to any specifications in the CSP 
will be described in Section 6 of this document.
Prior to CSP V2.0, the primary objective of this study was to compare the efficacy of 
durvalumab to placebo in terms of DFS in the PD-L1 TC≥1% analysis set. A secondary 
objective was to compare the efficacy of durvalumab to placebo in terms of DFS in the FAS. 
The study was sized for the primary endpoint of DFS in the PD-L1 TC≥1% analysis set and 
for the secondary endpoint of DFS in the FAS. 
Following changes in the treatment landscape and the approvals of neoadjuvant and adjuvant 
immunotherapy options for patients with resectable NSCLC, AstraZeneca decided to close 
recruitment to MERMAID-2 on May 25, 2022. These approvals were based on the two Phase 
III clinical studies (IMpower010 and PEARLS/KEYNOTE-091) that reported positive results 
for PD-(L)1 inhibitors (used as monotherapy) in the adjuvant setting. In addition, one Phase 
III clinical study (Checkmate816) has reported positive results for nivolumab (anti-PD-1 
immunotherapy) in the neoadjuvant setting.
Under CSP V2.0 as a result of the decision to close study enrollment, the intended patient 
numbers will not be reached. The primary objective of this study is now to assess DFS in both 
treatment arms in the FAS rather than in the PD-L1 TC≥1% analysis set. The secondary 
objective is now to report the safety in both treatment arms. All analyses of the objectives and 
endpoints are descriptive only and considered exploratory, therefore there will be no 
requirement to include a multiple testing procedure to control the type I error rate.
1.1
Study Objectives
1.1.1
Primary Objective
Primary objective:
Endpoint/variables:
To assess the efficacy of durvalumab compared 
to placebo as measured by DFS in all 
randomized patients
DFS in FAS (using Investigator assessments 
according to RECIST 1.1)
DFS Disease-free survival; FAS Full analysis set; RECIST Response Evaluation Criteria in Solid Tumours.


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1.1.2
Secondary Objectives
Secondary/Safety objective:
Endpoint/variables:
To assess the safety and tolerability profile of 
durvalumab monotherapy compared to placebo
AEs, physical examinations, vital signs, and 
laboratory findings
AE Adverse event.
1.1.3
 
 
 
 
 
 
 
 
 
 
 
 
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∀
 
∀
∀
∀
∀
∀
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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∀
 
∀
∀
∀
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1.2
Study Design
This is a Phase III, randomized, multicenter, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of durvalumab adjuvant therapy compared to placebo in 
patients with stage II-III non-small cell lung cancer (NSCLC) who have undergone curative 
intent therapy (complete resection ± neoadjuvant and/or adjuvant therapy), who have no 
evidence of RECIST 1.1- defined disease recurrence, and who become minimal residual 
disease-positive (MRD+) during a 96-week surveillance period.
Prior to CSP V2.0, the study was designed to screen approximately 
 patients and 
randomize approximately 
 MRD+ patients with stage II-III NSCLC whose tumors are 
epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild type, 
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and who have completed curative intent therapy. Randomized patients were to include 
approximately 
PD-L1 TC≥1% and 
 PD-L1 TC<1% patients.
Following the decision to close recruitment early, a total of 416 patients have signed informed 
consent for the study and approximately 30 are expected to be randomized within the study.
Eligible patients will be enrolled in a 96-week surveillance period during which they will be 
monitored for the emergence of MRD. During surveillance, the patient will be evaluated for 
MRD by plasma sampling every 6 weeks (q6w±3d) and will receive computed tomography 
(CT) scans every 12 weeks (q12w±1w) for up to 96 weeks.
Patients who become MRD+ during surveillance (including cases where analysis of the first 
plasma sample collected [marking the start of surveillance] returns an MRD+ status) will 
undergo a second screening period. Note: Patients who received prior neoadjuvant 
immunotherapy must be MRD- based on analysis of the first plasma sample collected (which 
marks the start of surveillance). 
MRD+ patients will be randomized 1:1 to treatment with durvalumab monotherapy 1500 mg 
or placebo every 4 weeks (q4w) intravenously (IV). Randomization will be stratified by PD-
L1 status (TC<1% vs TC≥1%), time from start of surveillance to emergence of MRD (≤6 
months vs >6 months), and prior neoadjuvant immunotherapy (Yes vs No). 
Patients will be treated for up to a total of 24 months (26 cycles), until disease recurrence, or 
until other specific treatment discontinuation criteria are met (whichever comes first). 
Up to 142 of the patients who complete their 96-week surveillance period, remain MRD-, and 
have no evidence of RECIST 1.1-defined disease recurrence may be eligible for entry into an 
observation period. These patients will be followed for serious adverse events (SAEs), 
disease-free survival (DFS), overall survival (OS), subsequent anti-cancer therapy, and MRD 
assessments for 24 months or until primary DFS analysis (whichever occurs first) after which 
patients will be followed for OS until the end of the study. For an overview of the original 
study design described above, see Figure 1, in the CSP. [Note: following implementation of 
CSP V2.0 no patients will enter the observation period.]
On 25 May 2022, AstraZeneca closed study recruitment. This was based on changes in the 
treatment landscape as outlined in Section 10.1 of the CSP. At the time of CSP V2.0 
implementation at site, patients in first screening for surveillance and randomized patients in 
study specific follow-up (i.e. who are not actively receiving study treatment) will be 
discontinued from the study.  Patients in second screening (signed ICF2a but not yet 
randomized) and patients currently receiving study treatment will have the option to receive 
open-label durvalumab.  Given the current disposition of patients within the study, it is 
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expected that the majority of patients will be discontinued from the study.  For an overview of 
the original study design, see Figure 1.
Figure 1
Original Study Design 
a
Results from local EGFR/ALK testing of either a pre-surgery biopsy or the resected tumor tissue performed 
as part of standard care may be used for this study, provided testing was performed using a well-validated, 
local regulatory-approved kit. EGFR/ALK status can also be assessed by the central laboratory using either a 
pre-surgical biopsy or on resected tumor tissue from surgery if local testing is not available. Patients whose 
tumors are positive for EGFR mutations and/or ALK translocations will be excluded from the study. Only 
patients with wild-type status should provide a plasma sample for MRD assessment at the start of 
surveillance (see footnote f). 
b
Patients will receive curative intent therapy (complete resection ± neoadjuvant and/or adjuvant therapy) as 
SoC within the clinics. Details of surgery and prior therapy will be captured in the appropriate section of the 
eCRF and will be included as a subgroup analysis. Please note that PORT can be included as part of 
adjuvant therapy and must be completed before starting surveillance. See CSP Figure 2 for potential 
scenarios for permissible curative therapy in this study.
c
ICF1 can be signed during or immediately following the completion of curative intent therapy and should be 
signed as soon as possible to allow the Sponsor access to the biosamples required for creation of the 
personalized panel for MRD detection (see footnote d) and for central testing of EGFR/ALK and/or PD-L1 
(if required, see footnotes a and e).
d
The whole blood and resected tumor tissue samples must be sent as soon as possible after ICF1 is signed but 
no later than 1-2 weeks after completion of adjuvant therapy or 3-5 weeks after surgery (if no adjuvant 
therapy is given) to enable creation of the personalized panel for MRD detection.
e
PD-L1 status must be known prior to and is required for randomization. 
f
Surveillance is initiated once the first plasma sample used to determine MRD status is collected
(approximately 8±1 weeks after completion of adjuvant therapy or up to 12±1 weeks post-surgery [if no 
adjuvant therapy is given; See CSP Figure 2).
g
If scans conducted during the first screening or during surveillance demonstrates evidence of RECIST 1.1-
defined disease recurrence and/or metastatic disease, the patient is considered a screen failure and is no 
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h
Before an MRD+ patient can be randomized, a CT scan of the chest and abdomen (including liver and 
adrenal glands) and a brain MRI (preferred) or brain CT with IV contrast must be performed to confirm no 
evidence of disease recurrence and/or metastatic disease. 
i
During surveillance, patient visits will occur q6w±3d for plasma collection and q12w±1w for CT scans.
ALK Anaplastic lymphoma kinase; DFS Disease-free survival; EGFR Epidermal growth factor receptor; ICF 
Informed consent form; MRD Minimal residual disease; N number; NSCLC Non-small cell lung cancer; OS 
Overall survival; PD-L1 Programmed cell death ligand-1; q4w Every 4 weeks; R Randomization; WES Whole 
exome sequencing.
1.3
Number of Patients
The study was originally sized for the primary endpoint of DFS in the PD-L1 TC≥1% analysis 
set and for the secondary endpoint of DFS in the FAS.
Prior to CSP V2.0, approximately 284 patients with stage II-III NSCLC who are MRD+ were 
planned be randomized 1:1 to durvalumab or placebo. Of the patients randomized into the 
study, at least 170 patients were required to be PD-L1 TC≥1% at study entry. The primary 
analysis was planned to be performed in the PD-L1 TC≥1% analysis set. An analysis on the 
full analysis set (FAS) (all MRD+ stage II-III NSCLC patients randomized) was planned to be 
performed as a secondary objective of the study. 
Under CSP V2.0, the originally planned number of randomized patients will not be met.  
There will be one single analysis (i.e., primary DFS analysis) which will occur at end of study, 
i.e. after the last patient has either discontinued the study or has signed consent (ICF3) to 
receive open-label durvalumab, whichever occurs later. The study concludes the collection of 
data thereafter and clinical database will be locked approximately 4 weeks after the last 
patient last visit.  
2.
ANALYSIS SETS
2.1
Definition of Analysis Sets
The populations for analyses are summarized in Table 1 per outcome variable. 
Table 1
Summary of Outcome Variables and Analysis Populations
Outcome variable
Population
Primary efficacy data
  DFS (using Investigator assessments)
FAS
Secondary/ Safety data
  Exposure
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Outcome variable
Population
  AEs
Safety
  Laboratory measurements
Safety
  Vital signs
Safety
  ECGs
Safety
  
  
  
  
  
  
  
  
Study population/Demography data
  Demography
FAS, PD-L1 TC≥1%
  Baseline and disease characteristics
FAS, PD-L1 TC≥1%
  Important deviations
FAS
  Medical/surgical history
FAS
  Previous anti-cancer therapy
FAS
  Concomitant medications/procedures
FAS
  Subsequent anti-cancer therapy (including radiotherapy)
FAS
AE Adverse event; DFS Disease-free survival; ECG Electrocardiogram; 
 
; 
, 5 Level health state utility index; FAS 
Full analysis set; OS Overall survival; PD-L1 Programmed cell death ligand 1; PD-L1 TC≥1% Expression of 
PD-L1 on tumour cell membrane, at any intensity, in ≥1% of tumour cells; PFS Progression-free survival; 
 
; 
; 
; 
 
; 
; 
; TC Tumor cell; 
; 
 
.
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2.1.1
Full Analysis Set
The FAS will include all randomized patients. The FAS will be used for all efficacy analyses 
including patient-reported outcomes (PROs). Treatment groups will be compared on the basis 
of randomized study treatment, regardless of the treatment actually received. Patients who 
were randomized but did not subsequently receive study treatment are included in the analysis 
in the treatment group to which they were randomized. 
2.1.2
PD-L1 TC≥1% Analysis Set
The PD-L1 TC≥1% analysis set will include the subset of patients in the FAS whose PD-L1 
status is PD-L1 TC≥1% as defined by the Ventana SP263 PD-L1 immunohistochemistry 
(IHC) assay (i.e. 1% PD-L1– membrane expression in tumoral tissue) at randomization. 
Treatment groups will be presented based on the basis of the randomized study treatment.
2.1.3
Safety Analysis Set
The safety analysis set will consist of all randomized patients who received any amount of 
study treatment. Safety data will not be formally analyzed but summarized using the safety 
analysis set, according to the treatment received. If a patient receives any amount of 
durvalumab, they will be summarized in the durvalumab treatment group. If a patient only 
receives placebo, they will be summarized in the placebo treatment group.
2.2
Protocol Deviations
The following general categories will be considered important protocol deviations (IPDs) and 
will be listed and discussed in the CSR as appropriate:
∀
Inclusion criteria deviations: Patients who deviate from inclusion criteria 2, 6, 11 and/or 
13 per Section 5.1 of the CSP. 
∀
Exclusion criteria deviations: Patients who deviate from exclusion criteria 4 and/or 13 per 
Section 5.2 of the CSP.
∀
Discontinuation criteria for study product met but patient not withdrawn from study 
treatment.
∀
Investigational product (IP) deviation:
(a) Patient received incorrect IP to that to which they were randomized.
(b) Patients who were randomized but did not receive IP.
∀
Excluded medications taken: Received prohibited concomitant systemic anti-cancer 
therapy.
∀
Deviations related to study procedure: Baseline RECIST scan > 49 days before 
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Patients who receive the wrong treatment at any time will be included in the safety analysis 
set as described in Section 2.1. During the study, decisions on how to handle errors in 
treatment dispensing (with regard to continuation/discontinuation of study treatment or, if 
applicable, analytically) will be made on an individual basis with written instruction from the 
study team leader and/or statistician.
The IPDs will be listed and summarized by randomized treatment group. IP deviation of 
patients who were randomized but did not receive IP will lead to exclusion from the safety 
analysis set. None of the other deviations will lead to patients being excluded from the 
analysis sets described in Section 2.1. A per-protocol analysis excluding patients with specific 
IPDs is not planned.
The programmatic determination of the IPDs above will be a separate process outlined in the 
study Protocol Deviations Plan, which will also include full details regarding IPDs as well as 
the activities and responsibilities related to the IPD process.
In addition, other study deviations captured from the eCRF module for inclusion/exclusion 
criteria will be tabulated and listed. Any other deviations from monitoring notes or reports 
may be reported in an appendix to the CSR.
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Derivation of RECIST Visit Responses
For this adjuvant study, where patients with no evidence of disease at baseline (as assessed by 
CT/magnetic resonance imaging [MRI]) will be entered in the study, the definition of new 
lesions (NLs) in RECIST 1.1 is used for the assessment of disease recurrence.
For all patients, the RECIST tumour response data will be used to determine each patient’s 
visit response according to RECIST version 1.1. It will also be used to determine if and when 
a patient has progressed in accordance with RECIST.
Baseline radiological tumour assessments are to be performed no more than 28 days + 7 days 
prior to randomization and ideally as close as possible to the date of randomization. Tumour 
assessments are then performed every 8 weeks ± 1 week following randomization until week 
48, and then every 12 weeks ± 1 week until unequivocal disease recurrence or primary DFS 
analysis. Upon detection of disease recurrence, an additional follow-up scan should be 
performed 4 to 8 weeks later and evaluated using post-progression radiological criteria. 
If an unscheduled assessment is performed, and the patient has not had disease recurrence, 
every attempt should be made to perform the subsequent assessments according to the original 


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imaging visit schedule (relative to the date of randomization). If a dose delay of study 
treatment (i.e. durvalumab/placebo) occurs, RECIST scans should continue according to the 
original imaging visit schedule. 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.
3.1.1
New Lesions – Site Investigator Data
At each post-baseline visit, the Investigator should record an overall assessment based on the 
presence or absence of unequivocal NLs. This section provides the definitions of the criteria 
used to determine and record overall response at the investigational site at each visit.
Details of any NLs will be recorded with the date of assessment. The presence of one or more 
unequivocal NLs is assessed as progression and will indicate disease recurrence.
A lesion identified at a follow up assessment as local/regional, distant, or second primary 
NSCLC is considered a NL and will indicate disease recurrence. The development of a new 
cancer other than NSCLC should be regarded as an SAE.
The finding of a NL 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 NL is equivocal, for example, because of its small size, the treatment and tumor 
assessments should be continued until the previously (pre-existing) NL has been assessed as 
unequivocal at a follow-up visit. If repeat scans (4 to 8 weeks later) definitively confirm there 
is a NL, then recurrence should be declared using the date of the initial post-baseline scan 
where the equivocal NL was first identified, without an intervening period of lesion absence.
Both equivocal and unequivocal NLs will be recorded in the eCRF. Unequivocal NLs will be 
identified via a Yes/No tick box on the new unequivocal lesions (post-randomization) eCRF 
form. If the question ‘Any unequivocal new lesions since baseline’ has not been answered 
with Yes or No and the NL details are blank this is not evidence that no unequivocal NLs are 
present, but should not overtly affect the derivation. This scenario (i.e. whereby NL response 
is NE) should only occur in exceptional cases, as missing data for the NL field should always 
be queried.
3.1.2
Overall Visit Response – Site Investigator Data
Table 2 defines how NL information will be used to determine an overall visit response.


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Table 2
Overall Visit Responses
Target lesions
Non-target lesions
New lesions
Overall visit response
NA
NA
NE
NE
NA
NA
No
NED
NA
NA
Equivocal
NED*
NA
NA
Yes
PD
* Disease recurrence (i.e. PD) may be backdated to a timepoint where an equivocal NL was identified, under 
specific conditions outlined in section 3.1 and 3.2.1.
NA Not applicable; NE Not evaluable; NED No Evidence of Diseases (only relevant if there were
neither target lesions nor non-target lesions at baseline); PD Progressive disease.
3.2
Efficacy Variables
3.2.1
Disease-Free Survival (DFS)
Disease-free survival as assessed by the Investigator is the primary endpoint in this study and 
is defined as the time from the date of randomization until any one of the following events 
below, whichever occurs first, regardless of whether the patient withdraws from randomized 
therapy or receives another anti-cancer therapy prior to disease recurrence (i.e., date of DFS 
event or censoring – date of randomization + 1 day):
∀
Date of disease recurrence using Investigator assessments according to RECIST 1.1
-
Local, regional, or distant disease recurrence
-
Diagnosis of a second primary NSCLC
∀
Date of death from any cause
Disease recurrence should be based on the finding of an unequivocal NL. However, if a NL is 
initially equivocal (i.e. where an equivocal lesion converts to unequivocal), then the 
progression date should be backdated to the post-baseline follow-up scan when the NL first 
appeared without an intervening period of lesion absence. If equivocal lesions are present at 
baseline, they will not be documented on the baseline eCRF.
Patients who have not experienced disease recurrence and are alive at the time of DCO will be 
censored at the latest date of assessment from their last evaluable RECIST 1.1 assessment.
However, if the patient experiences disease recurrence or dies after 2 or more missed visits, 
the patient will be censored at the latest evaluable RECIST 1.1 assessment prior to the 
2 missed visits (note: an NE visit is not considered a missed visit). Given the scheduled visit 
assessment scheme (i.e. every 8 weeks ± 1 week after randomization for the first 48 weeks, 
then every 12 weeks ± 1 week thereafter until appearance of disease recurrence or until 


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primary DFS analysis) the definition of 2 missed visits will change. The definitions are shown 
in Table 3.
Table 3
Definition of Two Missed Visits
Previous RECIST 
assessment
Two missed 
visits 
(duration)
Explanation
Study day < 274 
(week 39)
18 weeks
2 × 8 weeks + 1 week for an early assessment + 
1 week for a late assessment = 18 weeks.
Study day 274 to < 344
(>week 39 to < week 49)
22 weeks
Over this period, the scheduled frequency of 
RECIST assessments changes from q8w to 
q12w. Take the average of 8 and 12 weeks 
which gives 10 weeks. 
2 × 10 weeks + 1 week for an early assessment 
+ 1 week for a late assessment = 22 weeks. 
Study day 344 onwards 
(week 49)
26 weeks
2 × 12 weeks + 1 week for an early assessment 
+ 1 week for a late assessment = 26 weeks.
RECIST Response Evaluation Criteria in Solid Tumours; q8w Every 8 weeks; q12w Every 12 weeks.
If the patient has no evaluable assessments or does not have baseline data, they will be 
censored at day 1 unless they die within 2 visits of baseline (i.e. 17 weeks [2 × 8 weeks + 
1 week for a late assessment]), then they will be treated as an event with the date of death as 
the event date. Additionally, patients with unequivocal evidence of disease at baseline (as 
assessed by the Investigator) will be censored at randomization (day 1).
The primary endpoint analysis of DFS on the FAS analysis set will be based on Investigator 
assessments according to RECIST 1.1. The DFS time will always be derived based on 
scan/assessment dates and not visit dates.
RECIST 1.1 assessments/scans contributing toward a particular visit may be performed on 
different dates. The following rules will be applied:
∀
For Investigator assessments, the date of disease recurrence will be determined based on 
the earliest of the RECIST assessment/scan dates of the component that indicates disease 
recurrence.
∀
When censoring a patient for DFS, the patient will be censored at the latest of the scan 
dates contributing to a particular overall visit assessment.


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3.3
Safety Variables
Safety and tolerability will be assessed in terms of AEs (including SAEs), deaths, laboratory 
data, vital signs, ECGs, and exposure. These will be collected for all patients. For physical 
examination, only information on whether the assessment was performed or not is recorded, 
and any abnormal findings are reported as either medical history or AEs.
Safety data will be summarized from the ‘On-treatment’ period, unless otherwise specified.
‘On-treatment’ is defined as assessments between the date/time of start of study treatment (i.e. 
durvalumab/placebo) and 90 days following discontinuation of study treatment (i.e. the last 
dose of durvalumab/placebo), or up to and including the date of initiation of the first 
subsequent anti-cancer therapy (including radiotherapy, except for palliative radiotherapy), 
whichever occurs first.
3.3.1
Study Treatments
Study treatment in this study refers to durvalumab or placebo. Study treatments are described 
in Table 4. Exposure will be defined for durvalumab and placebo regimens.
Table 4
Study Treatments
Study treatment name
Route of 
administration
Dosing instructions
Durvalumab
IV
1500 mg infusion over 60 min q4w.
Placebo
IV
Infusion over 60 min q4w.
IV Intravenous; min Minutes; q4w Every 4 weeks.
3.3.2
Exposure and Dose Interruptions
Exposure (i.e. duration of treatment) will be defined as follows:
∀
Total (or intended) exposure of study treatment
-
Total (or intended) exposure = min (last dose date where dose > 0mg + 27 days, date 
of death, date of DCO) – first dose date +1 day
∀
Actual exposure of study treatment
-
Actual exposure = intended exposure – total duration of dose interruptions and cycle 
delays
∀
Calculation of duration of dose delays/interruptions (for actual exposure)


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-
Duration of dose delays/interruptions = sum of positive values of [date of the dose –
date of previous dose – (28 + 3) days], where records corresponding to either a dose 
interruption or a dose delay are identified based on eCRF item “Action taken, study 
drug”=”Dose interruption” as collected in the Exposure eCRF form. 
Dose reductions of durvalumab/placebo are not permitted, and the actual exposure calculation 
makes no adjustment for any dose reductions that may have occurred.
Number of treatment cycles received
Exposure will also be measured by the number of cycles received. A cycle corresponds to a 
period of one dose of treatment (28 days). If a cycle is prolonged due to toxicity, this should 
still be counted as one cycle. A cycle will be counted if treatment is started even if the full 
dose is not delivered.
Patients who permanently discontinue during a dose delay
If a decision is made to permanently discontinue study treatment (i.e. durvalumab/placebo) 
in-between cycles or during a dose delay then the date of last administration of study 
medication recorded will be used in the calculation of exposure. 
3.3.3
Dose Intensity 
Relative dose intensity (RDI) is the percentage of the actual dose delivered relative to the 
intended dose through to treatment discontinuation. RDI will be defined as follows:
∀
RDI = 100% × d/D, where d is the actual cumulative dose delivered up to the actual 
last day of dosing and D is the intended cumulative dose up to the actual last day of 
dosing. D is the total dose that would be delivered, if there were no modification to 
dose or schedule. When accounting for the calculation of intended cumulative dose 
3 days should be added to the date of last dose to reflect the protocol allowed 
window for dosing.
When deriving actual dose administered the volume before and after infusion will also be 
considered.
3.3.4
Adverse Events
Adverse events and SAEs will be collected throughout the study. SAEs will be collected 
following signature of the first informed consent [ICF1] and following signature of the second 
informed consent for the observation period [ICF2b], and all SAEs and AEs will be collected 
following signature of the second informed consent for the treatment period [ICF2a]) until 90 
days after the last dose of study treatment (durvalumab/placebo). A treatment-emergent 


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adverse event (TEAE) is defined as an AE with an onset date, or a pre-existing AE worsening 
(by Investigator report of a change in intensity), during the ‘on-treatment’ period as defined in 
Section 3.3. The Medical Dictionary for Regulatory Activities (using the latest or current 
MedDRA version) will be used to code the AEs. Adverse events will be graded according to 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event 
(CTCAE) version 5.0.
Adverse Events of Special Interest and Adverse Events of Possible Interest
Some clinical concepts (including some selected individual preferred terms [PTs] and higher-
level terms [HLTs]) have been considered ‘AEs of special interest’ (AESI) and ‘AEs of 
possible interest’ (AEPI) to the durvalumab program.
The AESIs reported in the AstraZeneca-sponsored durvalumab studies are defined as AEs 
with a likely inflammatory or immune-mediated pathophysiological basis resulting from the 
mechanism of action of durvalumab and requiring more frequent monitoring and/or 
interventions such as corticosteroids, immunosuppressants, and/or endocrine therapy. 
Endocrine therapies include standard endocrine supplementation, as well as treatment of 
symptoms resulting from endocrine disorders (eg, therapies for hyperthyroidism include beta 
blockers [eg, propranolol], calcium channel blockers [eg, verapamil, diltiazem], methimazole, 
propylthiouracil, and sodium perchlorate).
The AEPIs reported in the AstraZeneca-sponsored durvalumab studies are defined as AEs that 
could have a potential inflammatory or immune-mediated pathophysiological basis resulting 
from the mechanism of action of durvalumab but are more likely to have occurred due to other 
pathophysiological mechanisms, thus, the likelihood of the event being inflammatory or 
immune-mediated in nature is not high and/or is most often or usually explained by the other 
causes.
These AESIs and AEPIs are identified as a list of categories provided by the clinical team. 
Other categories may be added as necessary or existing terms may be merged. An 
AstraZeneca medically qualified expert, after consultation with the Global Patient Safety 
Physician, has reviewed the AEs of interest and identified which PTs contribute to each 
AESI/AEPI. A further review will take place prior to DBL to ensure any further terms not 
already included are captured within the categories.
Immune-mediated Adverse Events (imAE)
Durvalumab belongs to a class of drugs called immune checkpoint inhibitors. Because the 
mechanism of action of this class of drugs is to block the inhibitory signals that prevent T-cell 
activation, this drug may potentially cause imAEs.


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Immune-mediated adverse drug reactions will be identified from both AESIs and AEPIs based 
on programmatic rules that consider interventions involving systemic steroid therapy, 
immunosuppressant use, and/or endocrine therapy (which, in the case of AEPIs, occurs after 
first considering an Investigator’s causality assessment and/or an Investigator’s designation of 
an event as immune-mediated). Infusion-related reactions and hypersensitivity/anaphylactic 
reactions are not considered imAE because they are common to monoclonal antibody drugs in 
general and occur due to a mechanism of action different than that for imAEs as defined in the 
imAE charter. Further details are provided in the imAE charter. 
In addition, medical review of those AESI/AEPI may be performed to classify them as imAEs 
or not imAEs via an independent manual adjudication process. 
3.3.5
Laboratory Data
Laboratory data will be collected throughout the study, from second screening to the second 
follow-up visit (12 weeks ± 1 week after completion or discontinuation of study treatment i.e. 
durvalumab/placebo). Blood and urine samples for determination of hematology, clinical 
chemistry, and urinalysis will be collected as described in Section 8.2.1 of the CSP. For the
definition of baseline and the derivation of post-baseline visit values considering visit window 
and how to handle multiple records, derivation rules as described in Section 4.1.2 will be used.
Change from baseline in hematology and clinical chemistry variables will be calculated for 
each postdose visit on-treatment. Common Terminology Criteria for Adverse Event (CTCAE) 
grades will be defined at each visit according to the CTCAE grade criteria using local or 
project ranges as required, after conversion of lab result to corresponding standard 
international (SI) units. The following parameters have CTCAE grades defined for both high 
and low values: Potassium, Sodium, Magnesium, and Corrected calcium.
Corrected calcium will be derived during creation of the reporting database using the 
following formula:
Corrected calcium (mmol/L) = Total Calcium (mmol/L) + ([40 – Albumin (g/L)] × 0.02)
Creatinine clearance (CL) will be derived according to the Cockcroft-Gault formula 
(Cockcroft and Gault 1976).
Males:
Creatinine CL (mL/min) = 
Weight (kg) × (140-Age at randomization)
72 × serum creatinine (mg/dL)


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Females:
Creatinine CL (mL/min) = 
Weight (kg) × (140-Age at randomization)
72 × serum creatinine (mg/dL)
× 0.85
Absolute values will be compared to the project reference range and classified as low (below 
range), normal (within range or on limits of range) and high (above range).
The maximum or minimum on-treatment value (depending on the direction of an adverse 
effect) will be defined for each laboratory parameter as the maximum (or minimum) 
post-baseline value at any time.
Local reference ranges will be used for the primary interpretation of laboratory data at the 
local laboratory. Project reference ranges will be used throughout for reporting purposes. The 
denominator used in laboratory summaries of CTCAE grades 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 baseline and at least 1 post-baseline (scheduled or unscheduled) value recorded.
∀
If a CTCAE criterion does not consider changes from baseline, to be evaluable the patient 
need only have at least 1 post-baseline (scheduled or unscheduled) value recorded.
3.3.6
Electrocardiograms
Resting 12-lead ECGs will be recorded at second screening and as clinically indicated 
throughout the study. Overall evaluation of ECG is collected in terms of normal or abnormal, 
and the relevance of the abnormality is termed as ‘clinically significant’ or ‘not clinically 
significant’. Triplicate ECGs will be obtained in case of clinically significant ECG 
abnormalities. 
At each time point the Investigator’s assessment of the ECG will be collected locally. Heart 
rate, duration of QRS complex, RR, PR and QT intervals will be collected. 
3.3.7
Vital Signs
Vital signs data will be collected throughout the study, from second screening to the first 
follow-up visit (4 weeks ± 3 days after completion or discontinuation of study treatment, i.e. 
durvalumab/placebo). 


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3.4
3.4.1
 
 
 
 
 
 
 
 
 
 
 
 
 
3.4.2
 
 
 
 
 
 
 
 
 
3.4.3
 
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3.4.4
3.4.4.1
 
 
 
 
 
 
 
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3.4.4.2
 
 
 
 
 
 
 
 
3.4.4.3
 
 
 
 
 
 
 
 
 
 
 
4.
ANALYSIS METHODS
Prior to CSP V2.0, a formal statistical analysis was to be performed to test the main 
hypotheses: 
∀
H0: No difference between durvalumab and placebo 
∀
H1: Difference between durvalumab and placebo
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Under CSP V2.0 no formal statistical analyses will be performed, and all analyses will be 
exploratory. All data will either be summarized or listed only.
4.1
General Principles
The below mentioned general principles will be followed throughout the study:
∀
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment group. Continuous variables will be summarized by the number of observations, 
mean, standard deviation, median, upper and lower quartiles, minimum, and maximum. 
For log-transformed data it is more appropriate to present geometric mean, coefficient of 
variation (CV), median, minimum and maximum. Categorical variables will be 
summarized by frequency counts and percentages for each category.
∀
Unless otherwise stated, percentages will be calculated out of the population total for the 
corresponding treatment group. Overall totals will be calculated for baseline summaries 
only.
∀
For continuous data, the mean, standard deviation, median and quartiles will be rounded to 
1 additional decimal place compared to the original data. Minimum and maximum will be 
displayed with the same accuracy as the original data.
∀
For categorical data, percentages will be rounded to 1 decimal place, with the exception of 
100% which will be presented as a whole number.
∀
SAS® version 9.4 or later will be used for all analyses.
4.1.1
Baseline
In general, for efficacy and PRO endpoints the last observed measurement prior to 
randomization will be considered the baseline measurement. However, for PRO endpoints, if 
an evaluable assessment is only available after randomization but before the first dose of study 
treatment then this assessment will be used as baseline. For safety endpoints the last 
observation before the first dose of study treatment will be considered the baseline 
measurement unless otherwise specified. For assessments on the day of first dose where time 
is not captured, a nominal pre-dose indicator, if available, will serve as sufficient evidence that 
the assessment occurred prior to first dose.
Assessments on the day of the first dose, where neither time nor a nominal pre-dose indicator 
are captured, will be considered prior to the first dose if such procedures are required by the 
protocol to be conducted before the first dose.
If two visits are equally eligible to assess patient status at baseline (e.g. screening and baseline 
assessments both on the same date prior to first dose with no washout or other intervention in 


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the screening period), the average can be taken as a baseline value. For non-numeric 
laboratory tests (i.e. some of the urinalysis parameters) where taking an average is not 
possible the best value would be taken as baseline as this is the most conservative. In the 
scenario where there are two assessments on day 1, one with time recorded and the other 
without time recorded, the one with time recorded would be selected as baseline. Where safety 
data are summarized over time, study day will be calculated in relation to date of first study 
treatment.
In all summaries, change from baseline variables will be calculated as the post-treatment value 
minus the value at baseline. The percentage change from baseline will be calculated as (post-
baseline value - baseline value) / baseline value × 100. 
4.1.2
General Considerations for Safety and PRO Assessments
The following conventions will apply for visit windows on safety and ePRO:
∀
The time windows will be exhaustive so that data recorded at any time point has the 
potential to be summarized. Inclusion within the time window will be based on the actual 
date and not the intended date of the visit.
∀
All unscheduled visit data have the potential to be included in the summaries.
∀
The window for the visits following baseline will be constructed in such a way that the 
upper limit of the interval falls half way between the 2 visits (the lower limit of the first 
post-baseline visit will be Day 2). If an even number of days exists between 2 consecutive 
visits then the upper limit will be taken as the midpoint value minus 1 day. An example is 
provided in Appendix A.
∀
For summaries showing the maximum or minimum values, the maximum/minimum value 
recorded on-treatment will be used (regardless of where it falls in an interval).
∀
Listings should display all values contributing to a time point for a patient.
∀
For visit windows with more than one record
-
If there is more than one value per patient within a time window then the closest value 
to the scheduled visit date will be summarized, or the earlier, in the event the values 
are equidistant from the nominal visit date. If there are two values recorded on the 
same day and CTCAE grades are available then the record with the highest toxicity 
grade should be used. Alternatively, if there are two records recorded on the same day 
and the toxicity grade is the same (or is not calculated for the parameter) then the 
average of the two records should be used. The listings will highlight the value for the 
patient that contributed to the summary table, wherever feasible. Note: in summaries 
of extreme values all post-baseline values collected are used including those collected 
at unscheduled visits regardless of whether or not the value is closest to the scheduled 
visit date. 


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∀
For summaries at a patient level, all values will be included, regardless of whether they 
appear in a corresponding visit-based summary, when deriving a patient level statistic 
such as a maximum. 
Imputation Rules
Missing safety data will generally not be imputed. However, safety assessment values of the 
form of ‘< x’ (i.e. below the lower limit of quantification) or ‘> x’ (i.e. above the upper limit 
of quantification) will be imputed as ‘x’ in the calculation of summary statistics but displayed 
as ‘< x’ or ‘> x’ in the listings. Additionally, AEs that have missing causality (after data 
querying) will be assumed to be related to durvalumab or placebo.
For the handling of partial date of birth and missing/partial start and/or stop dates of AEs, 
medications/therapies, deaths and subsequent anti-cancer therapies (including radiotherapy), 
refer to Appendix B.
The original incomplete or missing dates will be presented in the listings.
All AEs will be considered as treatment-emergent unless the opposite can be clearly stated. 
Imputation will be done only in the context of identifying TEAEs.
All medications/therapies will be considered as concomitant unless the opposite can be clearly 
stated.
4.2
Analysis Methods
Only descriptive summaries or listings will be produced. The following table (Table 5) details 
the statistical analysis. Where listings are specified, these will be produced on the FAS only 
and will include the PD-L1 TC≥1% analysis set status.
Table 5 
Statistical Analyses to be Conducted 
Endpoints 
Notes
Disease-free survival (DFS)
Primary analysis using descriptive summaries based on 
Investigator assessments (RECIST 1.1) for the FAS. 
Listing only for PD-L1 ≥1% analysis set.
Overall survival (OS)
Listing only.
Progression-free survival (PFS)
Listing only.  
 
 
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Endpoints 
Notes
 
 
Change from baseline in PRO 
endpoints 
 
Listing only. 
Time to deterioration 
 
Listing only. 
DFS Disease-free survival; 
 
; 
 
; FAS Full analysis set; OS Overall 
survival; PFS Progression-free survival; 
; RECIST Response Evaluation Criteria 
in Solid Tumors.
4.2.1
Multiplicity 
Under CSP V2.0, no methods for multiplicity control will be performed and the analyses of all 
endpoints will be considered exploratory.
4.2.2
Disease-Free Survival (DFS) 
4.2.2.1
Primary Analysis of DFS
Disease-free survival, using Investigator assessment according to RECIST 1.1, will be 
summarized, for the FAS. This will include the number (%) of patients with event or 
censored, along with the reason for event/censoring. Kaplan-meier curves will also be 
produced.
DFS data on the PD-L1 ≥1% analysis set will be listed only.
Supportive Summaries
Additionally, a summary of time to MRD+ emergence during surveillance may be provided 
and this may also be included in the DFS supportive listing.
The location of the disease recurrence (local/regional, distant or second primary NSCLC) will 
be summarized by treatment group.
Additionally, summary statistics will be presented for the number of days from censoring to 
DCO for all censored patients. A summary of the duration of follow-up will be summarized 
using time from randomization to date of censoring (date last known to have not had disease 
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recurrence or died) in censored patients only (patients who have not had disease recurrence or 
died), presented by treatment group.
A summary table of first subsequent cancer therapies relative to recurrence by treatment group 
will be provided.
All the collected RECIST 1.1 data will be listed.
4.2.2.2
Subgroup Analyses
No subgroup analyses will be performed.
4.2.3
Overall Survival (OS) 
Overall survival will be listed only, for the FAS.
4.2.4
4.2.5
 
4.2.6
Data Cut-Offs
Following implementation of CSP V2.0, the DCO will occur after the last patient has either 
discontinued the study or has signed consent (ICF3) to receive open-label durvalumab, 
whichever occurs later. This will be followed by DBL and the primary DFS analysis. The 
study will then be concluded.
Details regarding the approach used for removing post-DCO data from SAS datasets can be 
found in the AstraZeneca Oncology Guidance on Data Cut-off Processing and Clean file/ 
DBL Considerations document as well as the DCO Specifications for this study.
4.2.7
 
∀
∀
∀
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∀
 
4.2.8
4.2.9
Safety
Safety and tolerability data from all cycles of treatment will be combined. The safety analysis 
set will be used for reporting of safety according to actual treatment group as defined in 
Section 2.1.3. 
4.2.9.1
Adverse Events (AEs)
All AEs, both in terms of current MedDRA PT and CTCAE grade, will be summarized 
descriptively by count (n) and percentage (%) for each treatment group. Any AE occurring 
before study treatment (i.e. before the administration of the first dose of durvalumab/placebo) 
will be included in the AE listings, but will not be included in the summary tables (unless 
otherwise stated). These will be referred to as ‘pre-treatment’. However, any AE occurring 
before the administration of the first dose of study treatment on study day 1 that increases in 
severity after the first dose will be regarded as treatment-emergent and thus will be included in 
the majority of summary tables.
Adverse events observed up until 90 days following discontinuation of study treatment (i.e. 
the last dose of durvalumab/placebo) or until the initiation of the first subsequent anti-cancer 
therapy (including radiotherapy, except for palliative radiotherapy) following discontinuation 
of study treatment (whichever occurs first) will be used for the reporting of the AE summary 
tables. This will more accurately depict AEs attributable to study treatment only, as a number 
of AEs up to 90 days following discontinuation of study treatment are likely to be attributable 
to subsequent therapy.
Any AEs that occur between the start of subsequent anti-cancer therapy and up until 90 days 
following discontinuation of study treatment will be flagged in the data listings.
All reported AEs will be listed along with the date of onset, date of resolution (if AE is 
resolved) and Investigator’s assessment of severity and relationship to durvalumab/placebo. 
Frequencies and percentages of patients reporting each PT will be presented (i.e. multiple 
events per patient will not be accounted for apart from on the episode level summaries).
Summary information (the number and percentage of patients by system organ class (SOC) 
and PT separated by treatment group) will be tabulated for:
∀
All AEs
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∀
All AEs possibly related to study treatment (as determined by the reporting Investigator)
∀
AEs with maximum CTCAE grade 3 or 4
∀
AEs with maximum CTCAE grade 3 or 4, possibly related to study treatment (as 
determined by the reporting Investigator)
∀
SAEs with outcome of death
∀
SAEs with outcome of death possibly related to study treatment (as determined by the 
reporting Investigator)
∀
All SAEs
∀
All SAEs possibly related to study treatment (as determined by the reporting Investigator)
∀
AEs leading to discontinuation of study treatment
∀
AEs leading to discontinuation of study treatment, possibly related to study treatment (as 
determined by the reporting Investigator)
∀
AEs leading to dose interruption of study treatment
An overall summary of the number and percentage of patients in each category will be 
presented, as well as an overall summary of the number of episodes in each category. 
Summaries of the number and percentage of patients with AEs will be provided by maximum 
reported CTCAE grade, SOC, PT and treatment group. In addition, a truncated AE table of 
most common AEs and another table showing most common AEs with maximum CTCAE 
grade 3 or 4, showing all events that occur in at least 5% of patients overall will be 
summarized by PT, by decreasing frequency in the total column (the total column will not be 
displayed in the AE tables). This cut-off may be modified after review of the data. When 
applying a cut-off (i.e. x%), the raw percentage should be compared to the cut-off, no 
rounding should be applied first (i.e. an AE with frequency of 4.9% will not appear if a cut-off 
is 5%). 
In addition, all AEs will be listed (including listings for AEs that required treatment with 
steroids, immunosuppressants, or endocrine treatment, grade changes for AEs of CTCAE 
grade ≥ 3, and grade changes for AEs of CTCAE grade ≥ 3 that required treatment with 
steroids, immunosuppressants, or endocrine treatment). Listings of key patient information for  
SAEs, and AEs leading to discontinuation of durvalumab/placebo or SoC will also be 
provided.
Deaths
A summary of all deaths will be provided with number and percentage of patients in the FAS 
by treatment group, categorized as:
∀
Total number of deaths (regardless of date of death)


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∀
Death related to disease under investigation only, as determined by the Investigator
∀
Death related to disease under investigation and an SAE with outcome of death
(a) AE onset prior to subsequent anti-cancer therapy, defined as an AE with onset date 
(or pre-treatment AEs that increase in severity) on or after the date of first dose of 
study treatment and up to and including the earlier of 90 days following the date of 
last dose of study treatment or the date of initiation of the first subsequent anti-cancer 
therapy 
(b) AE onset after start of subsequent anti-cancer therapy, defined as an AE with onset 
date more than 90 days following the date of last dose of study treatment or after the 
date of initiation of the first subsequent anti-cancer therapy (whichever occurs first)
∀
SAE with outcome of death only
(a) AE onset prior to subsequent anti-cancer therapy, defined as an AE with onset date 
(or pre-treatment AEs that increase in severity) on or after the date of first dose of 
study treatment and up to and including the earlier of 90 days following the date of 
last dose of study treatment or the date of initiation of the first subsequent anti-cancer 
therapy 
(b) AE onset after start of subsequent anti-cancer therapy, defined as an AE with onset 
date more than 90 days following the date of last dose of study treatment or after the 
date of initiation of the first subsequent anti-cancer therapy (whichever occurs first)
∀
Death after end of safety follow-up period (last dose of study treatment 
[durvalumab/placebo] + 90 days) and not due to disease under investigation
∀
Unknown reason for death
∀
Other deaths
All deaths will be listed along with time from first and last dose, primary and secondary 
causes, and relationship to disease using the FAS.
4.2.9.2
AEs of Special Interest and Possible Interest
Preferred terms used to identify AESI/AEPI will be listed before DBL and documented in the 
Trial Master File. Grouped summary tables of certain MedDRA PTs will be produced and 
may also show the individual PTs which constitute each AESI grouping. Groupings will be 
based on PTs provided by the medical team prior to DBL, and a listing of the PTs in each 
grouping will be provided.
Summaries of the above-mentioned grouped AE categories will include number (%) of 
patients who have:
∀
Any AESI/AEPI


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∀
Any AESI/AEPI by SOC, PT and maximum CTCAE grade
∀
Any AESI/AEPI of maximum CTCAE grade 3 or 4
∀
Any serious AESI/AEPI
∀
Any serious AESI/AEPI with outcome of death
∀
Any AESI/AEPI possibly related to study treatment
∀
Any AESI/AEPI leading to concomitant medication use (high dose steroids)
∀
Any AESI/AEPI leading to concomitant medication use (endocrine therapy)
∀
Any AESI/AEPI leading to concomitant medication use (other immunosuppressants)
An overall AESI/AEPI summary will be presented, including number and percentage of 
patients in each of these categories. Any AESI/AEPI presented by outcome will also be 
provided.
In addition, a listing of key patient information for AESI/AEPI will be provided.
Immune-mediated Adverse events (imAEs)
The imAEs (as classified by the Sponsor) will be summarized in the similar manner as for the 
summaries for AESI/AEPI described above. Time to onset and resolution of imAE will also 
be summarized. Further details are covered in the latest version of the imAE charter.
4.2.9.3
Laboratory Assessments
Data obtained up until the 90 days following discontinuation of study treatment (i.e. 
durvalumab/placebo) or until the initiation of subsequent anti-cancer therapy (including 
radiotherapy, except for palliative radiotherapy) following discontinuation of study treatment 
(whichever occurs first) will be used for reporting. This will more accurately depict laboratory 
toxicities attributable to study treatment only as some toxicities up to 90 days following 
discontinuation of the study treatment are likely to be attributable to subsequent therapy. Any 
data post 90 days after the last dose of the study treatment will not be summarized.
Data summaries will be provided in SI units.
Shift tables for laboratory values by worst CTCAE grade will be produced, and for specific 
parameters separate shift tables indicating hyper- and hypo- directionality of change will be 
produced. The laboratory parameters for which CTCAE grade shift outputs will be produced 
are:
∀
Hematology: Hemoglobin (low and high); Leukocytes (low and high); Lymphocytes (low 
and high - count, absolute); Neutrophils (low - count, absolute); Platelets (low)


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∀
Clinical chemistry: Alanine aminotransferase (ALT) (high), Aspartate aminotransferase 
(AST) (high), Alkaline phosphatase (ALP) (high), Total Bilirubin (high), Albumin (low), 
Magnesium (hypo and hyper), Sodium (hypo and hyper), Potassium (hypo and hyper), 
Corrected Calcium (hypo and hyper), Glucose (low), Creatinine (high), GGT (high), 
Amylase (high), Lipase (high)
In addition, all laboratory data will be listed.
Liver Enzyme Elevations and Hy's Law
The following summaries will include the number (%) of patients who have:
∀
Elevated ALT, AST, and Total bilirubin on-treatment
-
ALT ≥ 3× – ≤ 5×, > 5× – ≤ 8×, > 8× – ≤ 10×, > 10× – ≤ 20×, and > 20× ULN 
on-treatment
-
AST ≥ 3× – ≤ 5×, > 5× – ≤ 8×, > 8× – ≤ 10×, > 10× – ≤ 20×, and > 20× ULN 
on-treatment
-
Total bilirubin ≥ 2× – ≤ 3×, > 3× – ≤ 5×, > 5× ULN on-treatment
-
ALT or AST ≥ 3× – ≤ 5×, > 5× – ≤ 8×, > 8× – ≤ 10×, > 10× – ≤ 20×, > 20× ULN 
on-treatment
-
ALT or AST ≥ 3× ULN and Total bilirubin ≥ 2× ULN on-treatment (Potential Hy’s 
law): The onset date of ALT or AST elevation should be prior to or on the date of 
Total Bilirubin elevation
Individual patient data where ALT or AST (i.e. ≥ 3× ULN) plus Total Bilirubin (i.e. ≥ 2× 
ULN) are elevated at any time will be listed also.
Assessment of Thyroid Function Test Results
The following summaries will include the number and percentage of patients who have 
elevated or low thyroid stimulating hormone (TSH).
∀
TSH > ULN
∀
TSH > ULN with TSH ≤ ULN at baseline
∀
TSH > 3 × ULN
∀
TSH > 3 × ULN with TSH ≤ ULN at baseline
∀
TSH > 10 × ULN
∀
TSH > 10 × ULN with TSH ≤ ULN at baseline


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∀
TSH < LLN
∀
TSH < LLN with TSH ≥ LLN at baseline
In addition, summaries will include shift tables comparing baseline value to maximum 
on-treatment value and baseline value to minimum on-treatment value. Thyroid function test 
data will be listed also.
Assessment of Renal Function Test Abnormalities
In addition to the analysis for serum creatinine, the number and percentage of patients with 
creatinine clearance (CrCl) rate on-treatment (derived per Section 3.3.5) meeting the 
following categories will be presented:
∀
Normal: CrCl ≥ 90 mL/min
∀
Mild Impairment: CrCl ≥ 60 - < 90 mL/min
∀
Moderate Impairment: CrCl ≥ 30 - < 60 mL/min
∀
Severe Impairment: CrCl ≥ 15 - < 30 mL/min
∀
Kidney Failure: CrCl < 15 mL/min
4.2.9.4
Electrocardiograms
Since ECGs are only collected as clinically indicated, abnormalities in ECG data obtained at 
any time during the study will be listed only.
4.2.9.5
Vital Signs
All vital signs data (SBP, DBP, pulse rate, temperature, respiratory rate and weight) will be 
listed only. 
4.2.10
Demographics and Baseline Characteristics
The following will be summarized for all patients in the FAS and PD-L1 TC ≥1% analysis set 
(unless otherwise specified) by treatment group:
∀
Patient disposition (all patients, including screening failures [split by whether or not 
ICF2a was signed] and reason for screening failure, and status in regards to the 
surveillance period) 
∀
Important protocol deviations (FAS only)
∀
Inclusion in analysis sets (all patients)


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∀
Demographics (age, age group [< 50, ≥ 50 - < 65, ≥ 65 - < 75 and ≥ 75 years], sex, race 
and ethnicity) 
∀
Patient characteristics at baseline (height, weight, weight group [< 70, 70-90, > 90 kg], 
body mass index [BMI], BMI group [< 18.5, ≥ 18.5 - < 25, ≥ 25 - < 30, ≥ 30 kg/m2])
∀
Patient recruitment by region, country and center
∀
Previous disease-related treatment modalities (chemotherapy, radiation therapy and 
immunotherapy) (FAS only)
∀
Disease characteristics at baseline (Easter Cooperative Oncology Group [ECOG] 
performance status, primary tumor location, histology type [squamous, non-squamous, 
other], tumor grade, and overall disease classification)
∀
Extent of disease at baseline 
∀
TNM classification at baseline
∀
Disease related medical history (past and current) (FAS only)
∀
Relevant surgical history (FAS only)
∀
Nicotine use, categorized ([never, former, current])
∀
Stratification factors as per IWRS and eCRF
The data mentioned above will also be presented in listings. Additionally, a listing of 
EGFR/ALK results will also be provided.
4.2.11
Concomitant and Other Treatments
Information on any medications or therapies from first screening to 90 days after the last dose 
of study treatment (i.e. durvalumab/placebo) will be recorded in the eCRF. Thereafter, only 
subsequent regimens of anti-cancer therapy will be recorded in the eCRF.
Other anti-cancer therapies, investigational agents, and radiotherapy should not be given once 
the patient has completed curative intent therapy and while they are randomized and on study 
drug. 
Medications received prior to, concomitantly, or post-study treatment will be coded using the 
World Health Organization drug dictionary (WHODD) Anatomical Therapeutic Chemical 
(ATC) classification codes. Concomitant medications/therapies will be summarized for the 
FAS by ATC classification codes.
For the purpose of inclusion in prior and/or concomitant medication or therapy summaries, 
incomplete medication or radiotherapy start and stop dates will be imputed as detailed in 
Section 4.1.2.


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Prior, concomitant and post-study treatment medications and therapies are defined based on 
imputed start and stop dates as follows:
∀
Prior medications/therapies are those taken prior to study treatment with a stop date prior 
to the first dose of study treatment.
∀
Concomitant medications/therapies are those that started prior to study treatment and are 
ongoing at the first dose date of study treatment, or that started on or after the first dose 
date of study treatment but on or before the last dose date of study treatment.
∀
Post-study treatment medications/therapies are those with a start date after the last dose 
date of study treatment.
The following summaries will be produced for the FAS:
∀
Summary of allowed concomitant medications 
∀
Summary of disallowed concomitant medications 
∀
Summary of subsequent anti-cancer therapies (including radiotherapy)
All concomitant and other treatment data will be listed.
Missing coding terms should be listed and summarized as ‘Not coded’.
4.2.12
Exposure
Exposure will be summarized for the safety analysis set.
The following summaries will be produced by treatment group:
∀
Total exposure
∀
Actual exposure
∀
Number of, and reasons for, interruptions and delays of study treatment
∀
Cumulative exposure over time for study treatment
∀
Number of treatment cycles received
∀
RDI 
Exposure of durvalumab/placebo over time will be plotted in a line graph. The plot will show 
percentage of patients still on treatment against time since first dose.
For patients on study treatment at the time of the DFS analysis, the DCO date will be used to 
calculate exposure.


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4.2.13
Coronavirus Disease 2019 (COVID-19)
Summaries of data relating to patients diagnosed with COVID-19 and the impact of 
COVID-19 on study conduct (eg, missed visits, delayed or discontinued study treatment [i.e. 
durvalumab/placebo], and other protocol deviations) may be generated. For AE and deaths, 
summaries of COVID-19 related events including infections and deaths maybe produced.
Supportive listings may be produced.
4.3
Surveillance Period
For the purpose of the CSR, data collected during the surveillance period may be included in 
listings for patients in the FAS only, and will be flagged to distinguish between data collected 
in the surveillance period and the treatment period. 
Additional exploratory summaries and analyses may be performed on top of the summary of 
time to MRD+ emergence mentioned in Section 4.2.2.1.
5.
INTERIM ANALYSES
5.1
Interim Efficacy Analysis
Prior to CSP V2.0, an interim analysis of OS was to be performed at the time of the DFS 
primary analysis. 
Under CSP V2.0, no interim analyses will be performed.
5.2
Independent Data Monitoring Committee (IDMC)
This study will use an external IDMC to assess ongoing safety analyses in an unblinded 
manner. The committee will first meet to review the safety data from the study from a DCO 
approximately 12 months after the first patient has been dosed with IP or after approximately 
50 patients have received at least 1 dose of IP (whichever occurs first). The frequency of 
subsequent reviews will be determined by the IDMC, but will be no more frequent than every 
6 months.
This committee will be composed of therapeutic area experts, who are not employed by 
AstraZeneca and are free from conflict of interest.
Following the reviews, the IDMC will recommend whether the study should continue 
unchanged, be stopped, or be modified in any way based on the safety data that has been 
reviewed. Once the IDMC has reached a recommendation, a report will be provided to 


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AstraZeneca. The report will include the recommendation and any potential protocol 
amendments, and will not contain any unblinding information.
The final decision to modify or stop the study will sit with the sponsor. The sponsor or IDMC 
may call additional meetings if at any time there is concern about the safety of the study.
Full details of the IDMC procedures and processes can be found in the IDMC Charter (v17, 07 
April 2022). The safety of all AstraZeneca/MedImmune clinical studies is closely monitored 
on an ongoing basis by AstraZeneca/MedImmune representatives in consultation with the 
Patient Safety Department. Issues identified will be addressed; this could involve, for instance, 
amendments to the Clinical Study Protocol and letters to Investigators.
Following the decision to stop recruitment, a decision was made on 21 November 2022 
(during IDMC#1) to have no further IDMCs. A final safety report following DBL will be 
provided to the IDMC members.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
The following are changes from the planned analyses described in version 2 of the CSP.
Overall visit response table updated to more accurately reflect RECIST 1.1 evaluations and 
responses applicable to this study.
Except that change, this SAP has been produced in line with section 10.4 of CSP V2.0, which 
states:
“Under CSP v2.0, as a result of the decision by AstraZeneca to close enrollment to the study 
and end study assessments early, all analyses of the objectives and endpoints listed in Section 
3 will be descriptive only and considered exploratory. Further details will be included in the 
SAP.”


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7.
REFERENCES
 
 
Cockcroft and Gault 1976
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976; 16(1):31-41.
 user guide: basic information on how to use the 
 
 version 3.0, September 2019. Available from: 
 
 
 
Litwin et al 1998
Litwin MS, Lubeck DP, Henning JM, Carroll PR. Differences in urologist and patient 
assessments of health related quality of life in men with prostate cancer: results of the 
CaPSURE database. J Urol 1998;159:1988-92.
Sprangers and Aaronson 1992
Sprangers MA, Aaronson NK. The role of health care providers and significant others in 
evaluating the quality of life of patients with chronic disease: a review. J Clin Epidemiol 
1992;45:743-60.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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8.
APPENDICES


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APPENDIX A Visit Windows
For example, the visit windows for vital signs data (with 4 weeks between scheduled 
assessments) are:
Day 29, visit window 2 - 42
Day 57, visit window 43 - 70
Day 85, visit window 71 - 98
Day 113, visit window 99 - 126
Day 141, visit window 127 - 154
Day 169, visit window 155 - 182
Day 197, visit window 183 - 210
Day 225, visit window 211 - 238
Day 253, visit window 239 - 266
Day 281, visit window 267 - 294
Day 309, visit window 295 - 322
Day 337, visit window 323 - 350
Day 365, visit window 351 - 378
Day 393, visit window 379 - 406
Day 421, visit window 407 - 434
Day 449, visit window 435 - 462
Day 477, visit window 463 - 490
Day 505, visit window 491 - 518
Day 533, visit window 519 - 546
Day 561, visit window 547 - 574
Day 589, visit window 575 - 602
Day 617, visit window 603 - 630
Day 645, visit window 631 - 658
Day 673, visit window 659 - 686
Day 701, visit window 687 - 714
Day 729, visit window 715 - 742
Note: The same rules should be followed if a patient has more than 26 cycles due to delayed 
durvalumab/placebo. Also, due to the differing assessment schedules the visit windows will be 
different for the different endpoints.


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APPENDIX B Missing/Partial Dates Imputation
Imputation of partial date of birth
Patients with a partial date of birth will have an assumed date of birth of 1st January [given 
year]) for calculation of age at randomization.
Imputation of partial start/end dates for AEs and medications/therapies
In practice, for AEs and medications/therapies, original incomplete or missing start dates will 
be imputed as below:
∀
Missing day: impute the 1st of the month unless month is same as month of first dose of 
study treatment (i.e. durvalumab/placebo) then impute first dose date;
∀
Missing day and month: impute 1st January unless year is the same as year of first dose of 
study treatment (i.e. durvalumab/placebo) then impute first dose date;
∀
Completely missing: impute first dose date unless the end date suggests it could have 
started prior to this in which case impute the 1st January of the same year as the end date.
When imputing a start date, ensure that the new imputed date is sensible i.e. is prior to the end 
date of the AE or medication.
Original incomplete or missing stop dates for AEs and medications/therapies will be imputed 
as below:
∀
Missing day: impute as the earlier of either the DCO or the last day of the month unless 
month is the same as month of last dose of study treatment (i.e. durvalumab/placebo) then 
consider the last dose date;
∀
Missing day and month: impute as the earlier as either the DCO or 31st December unless 
year is the same as year of last dose of study treatment (i.e. durvalumab/placebo) then 
consider the last dose date;
∀
Completely missing: 
∀
AE: since there is no ongoing flag recorded in eCRF, then assume that AE is still 
present (i.e. do not impute a date);
∀
Medication/therapy: if the ongoing flag is missing then assume that medication is still 
being taken (i.e. do not impute a date). If the medication has stopped and start date of 
medication is prior to first dose of study treatment (i.e. durvalumab/placebo) then 
impute as the day before the first dose date.If the medication has stopped and start 
date of medication is on or after first dose of study treatment (i.e. 
durvalumab/placebo) but before or on the last dose of study treatment (i.e. 


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durvalumab/placebo) then impute the earlier of either the DCO or the day after the 
last dose date.
When imputing a stop date, ensure that the new imputed date is sensible i.e. is after the start 
date of the AE or medication/therapy.
Duration of AEs or medications/therapies will not be derived using imputed dates.
Imputation of partial death dates
If a patient is known to have died where only a partial death date is available then the date of 
death will be imputed as the latest of the last date known to be alive + 1 day from the database 
and the imputed death date using the following:
∀
For missing day only – using the 1st of the month
∀
For missing day and month – using the 1st of January
∀
If there is evidence of death but the date is entirely missing, it will be treated as missing, 
i.e. censored at the last known alive date.
Imputation of partial start dates of subsequent anti-cancer therapy (including radiotherapy)
∀
For missing day only – using the 1st of the month
∀
For missing day and month – using the 1st of January
If the imputed start date for a subsequent anti-cancer therapy (including radiotherapy) results 
in a start that date that is not after the date of last dose of study treatment (i.e. 
durvalumab/placebo), this will be flagged and discussed with the clinical team.
Other parameters
∀
No other imputation will be made.


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: d910mc00001-sap-ed-2
Document Title:
Statistical Analysis Plan Edition 2
Document ID:
Doc ID-004502317
Version Label:
2.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
23-Mar-2023 12:21 UTC
Content Approval
22-Mar-2023 14:08 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
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