Conditions: Non-small Cell Lung Cancer
Keywords: Radiation therapy Phase II Palliative Radiotherapy
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 102
Healthy volunteers: no

Brief summary:
This is a Phase II open-label, single-arm, multicenter, international study to evaluate the clinical activity of durvalumab in patients with Stage III unresectable NSCLC who are deemed to be ineligible for chemotherapy per Investigator assessment. Patients will be enrolled into 2 cohorts according to radiotherapy pretreatment dose (Cohort A: standard radiation therapy \[60 gray (Gy) ± 10% or hypofractionated bioequivalent dose (BED)\]; Cohort B: palliative radiation therapy \[40 to \< 54 Gy or hypofractionated BED\])

Detailed description:
This is a Phase II open-label, single-arm, multicenter, international study to evaluate the clinical activity of durvalumab in patients with Stage III unresectable NSCLC who have an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 2 and who were treated with radiotherapy but are ineligible for chemotherapy. Patients will be enrolled into 2 cohorts according to the dose of radiotherapy received prior to study entry (Cohort A: Standard Radiotherapy \[60 Gy ± 10% or hypofractionated BED\]; Cohort B: Palliative Radiotherapy \[40 to \< 54 Gy or hypofractionated BED\]). Patients must not have progressed following radiation therapy, and radiation therapy must be completed within 6 weeks (42 days) prior to first study drug administration. The last dose of radiation therapy is defined as the day of the last radiation treatment session. All patients will receive 1500 mg durvalumab via IV infusion every 4 weeks (q4w) for up to a maximum of 12 months (up to 13 doses/cycles)

Arms:
arm 1: Patients received standard radiotherapy \[60 gray (Gy) ± 10% or hypofractionated BED\] prior to study entry. arm 2: Patients received palliative radiotherapy \[40 to \< 54 Gy or hypofractionated BED\] prior to study entry.

Interventions: intervention 1: Durvalumab
Intervention descriptions: intervention 1: All patients will receive 1500 mg durvalumab via IV infusion q4w for up to a maximum of 12 months.

Protocol document:
Prot_002.pdf: 
A Phase II, Open-label, Multicenter, International Study of 
Durvalumab Following Radiation Therapy in Patients with 
Stage III, Unresectable Non- Small Cell Lung Cancer Who 
Are Ineligible for Chemotherapy (DUART)
ClinicalTrials.gov Identifier: NCT04249362 
Protocol Amendment No. 1: Final 2.0, 18 August 2023 
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Clinical Study Protocol 
Drug Substance
Durvalumab
Study Code
D4194C00009
Version
2.0
Date
18 August 2023
A Phase II, Open-label, Multicenter, International Study of Durvalumab 
Following Radiation Therapy in Patients with Stage III, Unresectable 
Non-Small Cell Lung Cancer Who Are Ineligible for Chemotherapy (DUART)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
EudraCT / EU CT Number: 2019-004336-31




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SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
CSP Version 2.0
18-Aug-2023
CSP Version 1.0
05-Nov-2019
CSP Version 2.0 (18-August-2023)
This modification is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union and in the EU Clinical Trial Regulation Article 2, 2 (13) as it neither significantly impacts 
the safety or physical/mental integrity of patients nor the scientific value of the study. 
Overall Rationale for the Modification
This CSP was amended to clarify initial intent to allow continuation of the treatment with 
durvalumab for patients who may benefit from it, based on Investigator’s opinion, after the 
individual patient reached end of scheduled visits, but before the study reached last patient last 
visit/final data cut off date and to update language related to sample size, data analysis, and 
follow-up of patients after discontinuation of study treatment for clarification. Text was also 
updated to comply with regulatory requirements.
The updates are summarized below. Other minor editorial updates were made throughout. 
Administrative changes, such as formatting, updates to abbreviations, and punctuation 
corrections, are not presented in this summary.








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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................1
VERSION HISTORY ...........................................................................................................2
TABLE OF CONTENTS......................................................................................................7
1
PROTOCOL SUMMARY ................................................................................12
1.1
Schedule of activities ........................................................................................12
1.2
Synopsis ...........................................................................................................20
1.3
Schema .............................................................................................................25
2
INTRODUCTION ............................................................................................25
2.1
Study rationale..................................................................................................26
2.2
Background.......................................................................................................27
2.2.1
Immunotherapies ..............................................................................................27
2.2.2
Durvalumab......................................................................................................28
2.3
Benefit/risk assessment .....................................................................................29
2.3.1
Potential benefits...............................................................................................29
2.3.2
Overall risks......................................................................................................30
2.3.2.1
Durvalumab......................................................................................................30
2.3.3
Overall benefit/risk ...........................................................................................31
3
OBJECTIVES AND ENDPOINTS...................................................................31
4
STUDY DESIGN .............................................................................................33
4.1
Overall design...................................................................................................33
4.2
Scientific rationale for study design ..................................................................34
4.2.1
Rationale for safety endpoints...........................................................................34
4.2.2
Rationale for efficacy endpoints........................................................................34
4.2.3
Rationale for other study exploratory endpoints ................................................35
4.2.4
Rationale for treatment duration........................................................................35
4.2.5
Timing of treatment with durvalumab relative to prior radiation therapy ...........36
4.3
Justification for dose.........................................................................................36
4.3.1
Durvalumab monotherapy dose rationale ..........................................................36
4.3.2
Rationale for fixed-dosing.................................................................................37
4.4
End of study definition......................................................................................38
5
STUDY POPULATION ...................................................................................39
5.1
Inclusion criteria ...............................................................................................39
5.2
Exclusion criteria ..............................................................................................41
5.3
Lifestyle restrictions..........................................................................................43
5.4
Patient enrollment.............................................................................................45
5.5
Procedures for handling incorrectly enrolled patients ........................................46
5.6
Screen failures ..................................................................................................46






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9.3.1
Safety analysis set.............................................................................................86
9.4
Outcome measures for analyses.........................................................................86
9.5
Statistical analyses ............................................................................................88
9.5.1
Analysis of the primary variable........................................................................89
9.5.2
Analysis of the secondary variables...................................................................89
9.5.2.1
Safety variables.................................................................................................89
9.5.2.2
Efficacy variables .............................................................................................90
9.5.2.3
Patient-reported outcomes.................................................................................90
9.6
Interim analysis.................................................................................................95
9.6.1
Steering committee ...........................................................................................95
9.7
Data management by AstraZeneca or delegate ..................................................95
10
REFERENCES .................................................................................................96
11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...................................................................................... 102
LIST OF TABLES
Table 1
Schedule of activities for screening and treatment period .........................13
Table 2
Schedule of activities for patients who have discontinued study drug or 
completed treatment with study drug........................................................18
Table 3
Study objectives and endpoints ................................................................32
Table 4
Highly effective methods of contraception ( < 1% failure rate).................45
Table 5
Study Treatment ......................................................................................47
Table 6
Prohibited concomitant medications.........................................................53
Table 7
Supportive medications............................................................................55
Table 8
Clinical chemistry....................................................................................64
Table 9
Hematology .............................................................................................64
Table 10
Urinalysis ................................................................................................65
Table 11
Precision around varying incidence of Grade 3 and Grade 4 Possibly-
Related Adverse Events ...........................................................................86
Table 12
...............91
Table 13
 
................................................................................................94
Table 14
Summary of imaging modalities for tumor assessment........................... 129
Table 15
Evaluation of target lesions .................................................................... 134
Table 16
Evaluation of nontarget lesions .............................................................. 135
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Table 17
Overall visit response............................................................................. 136
LIST OF FIGURES
Figure 1
Study design ............................................................................................25
Figure 2
Durvalumab monotherapy dosing schedule ..............................................49
LIST OF APPENDICES
Appendix A
Regulatory, ethical, and study oversight considerations.......................... 103
Appendix B
Adverse event definitions and additional safety information................... 110
Appendix C
................................................... 116
Appendix D
................................................................................................. 119
Appendix E
Actions required in cases of increases in liver biochemistry and evaluation 
of Hy’s Law........................................................................................... 123
Appendix F
Guidelines for evaluation of objective tumor response using RECIST 1.1 
Criteria (Response Evaluation Criteria in Solid Tumors)........................ 128
Appendix G
...................................................................... 140
Appendix H
Abbreviations ........................................................................................ 146
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1
PROTOCOL SUMMARY
1.1
Schedule of activities
The procedures for the screening and treatment periods in this study are presented in Table 1, 
and the procedures for the follow-up period are presented in Table 2.
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 schedule of activities (SoA; Table 1 and Table 2). 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 (Table 1 and Table 2).

Patients may delay dosing under certain circumstances.

Dosing may be delayed per the Dosing Modification and Toxicity Management 
Guidelines (see Section 8.4.5.1), due to either immune-mediated adverse events 
(imAEs) or non-imAEs.

If dosing must be delayed for reasons other than treatment-related toxicity, dosing will 
resume as soon as feasible.

Dosing intervals of subsequent cycles may be shortened as clinically feasible in order to 
gradually align treatment cycles with the schedule of tumor efficacy (Response 
Evaluation Criteria in Solid Tumors [RECIST]) and patient-reported outcomes (PRO) 
assessments. Subsequent time between 2 consecutive doses cannot be less than 22 days, 
based on the half-life of durvalumab (see the current Investigator’s Brochure [IB] for 
durvalumab).
One cycle of treatment with durvalumab is equal to 28 calendar days.
If imaging procedures were performed for alternate reasons prior to signing consent, these can be 
used for screening purposes with consent of the patient. However, all screening imaging results 
must have been obtained within 28 days prior to the first dose.
PRO and tumor efficacy (RECIST) assessment dates are not affected by dose delays and remain 
as originally scheduled, as they are based on the date of the first dose (not the date of therapy).
All other scheduled assessments must be performed relative to the start of the dosing cycle such 
that all laboratory procedures, etc, required for dosing should be performed within 3 calendar 
days prior to dosing.


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Table 1
Schedule of activities for screening and treatment period
Screening
C1 a
C2 a
C3 a
C4 a
C5 to C13 or PD 
(12 months) a
For details, see 
Section
Week
-4 to -1
0
q4w ± 3 days unless dosing needs to be held for toxicity reasons
Day
-28 to -1
1 a
q28d ± 3 days unless dosing needs to be held for toxicity reasons
Informed Consent
Informed consent: study procedures b
X
5.1
Consent: genetic sample and analysis 
(optional)
X
5.1
Study procedures
Physical exam (full)
X
8.2.2
Targeted physical exam (based on 
symptoms)
X
X
X
X
X
8.2.2
Assessment of early toxicities (phone 
call) c
X
X
X
8.2.5
Vital signs (temperature, respiration 
rate, blood pressure, and pulse), body 
weight, and height) d
X
X
X
X
X
X
8.2.3
ECG e
X
As clinically indicated
8.2.4
Concomitant medications
< ----------------------------------------------------------------------------------------------------------------------------- > 
6.4
Demography, including baseline 
characteristics and tobacco use
X
5.1
Pulmonary function testing (FEV1) f
X
8.2.7
Eligibility criteria
X
X
5.1, 5.2
Laboratory Assessments
Clinical chemistry g
X
X h
X
X
X
X
Table 8
Hematology g
X
X h
X
X
X
X
Table 9
Coagulation
X i
As clinically indicated
Table 9
TSH j, (reflex free T3 or free T4 k)
X
X
X
X
X
X
Table 8








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should be imaged based on signs and symptoms of individual patients, including new lesions at follow-up. If an unscheduled assessment was performed and the 
patient has not progressed, every attempt should be made to perform the subsequent assessments at their scheduled visits (relative to the date of IP treatment 
initiation). All confirmatory scans should be recorded in the database. For patients who are clinically stable and being treated through radiological progression, 
the follow-up scan performed after a RECIST 1.1-defined PD should be performed preferably at the next (and no later than the next) scheduled imaging visit, and 
no less than 4 weeks after the prior assessment of PD. For these patients the assessments should continue as indicated here. Special Confirmation of Radiological 
Progression criteria apply for tumor assessments on the follow-up scan (Appendix F).
Note: If a patient has a delay to an infusion of study drug, the efficacy and 
should be conducted relative to the date of first dose administration.
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Table 2
Schedule of activities for patients who have discontinued study drug or completed treatment with study drug
Time since last dose of durvalumab
Evaluation
Day (± 3)
Months (± 1 week)
12 months and 
every 3 months
(± 2 weeks)
For details, 
see Section
30
2
3
4
6
8
10
Physical examination (full)
X
8.2.2
Vital signs
X
8.2.3
Body weight
X
X
X
8.2.3
Pregnancy test a
X
As clinically indicated
8.2.1
AE/SAE assessment
X
X
X
8.3
Concomitant medications
X
X
X
6.4
WHO/ECOG PS b
At timepoints consistent with tumor assessments; at 30, 60, and 90 days after last dose; and then at 
initiation of subsequent anticancer therapy
8.2.6
Subsequent anticancer therapy c,d
Survival status e
X
X
X
X
X
X
X
8.1.1
Hematology
X
X
X
8.2.1
Clinical chemistry
X
X
X
8.2.1
Urinalysis
As clinically indicated
8.2.1
TSH (reflex free T3 or free T4) f
X
X
X
8.2.1
 
X
X
X
8.1.2.1, 
8.1.2.2, 
8.1.2.3, 
9.5.2.3
Tumor assessment as per local institutional 
standard care (RECIST 1.1) h
Additional scans to be completed per standard practice post progression. Patients who permanently 
discontinue IP for reasons other than objective RECIST 1.1 disease progression should continue to have 
RECIST 1.1 assessments performed q8w ± 1 week beginning 8 weeks after IP treatment initiation for the 
first 48 weeks (relative to the first dose) and q12w ± 1 week thereafter until clinical 
progression/deterioration or RECIST 1.1-defined radiological progression plus one or more additional 
follow-up scans for confirmation of progression until confirmed radiological progression, the end of 
study, death, study discontinuation, or Sponsor decision (whichever comes first).
8.1, 
Appendix F
AE = Adverse event; CT = Computed tomography; eCRF = Electronic case report form; 
 
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1.2
Synopsis
International Coordinating Investigator
Fondazione IRCCS Policlinico San Matteo
Viale Camillo Golgi 19
Pavia, Italy
Protocol title:
A Phase II, Open-label, Multicenter, International Study of Durvalumab Following Radiation 
Therapy in Patients with Stage III, Unresectable Non-Small Cell Lung Cancer Who Are 
Ineligible for Chemotherapy (DUART)
Rationale:
Durvalumab (MEDI4736) is a human monoclonal antibody (mAb) of the immunoglobulin G 
(IgG) 1 kappa subclass that blocks the interaction of programmed cell death ligand 1 (PD-L1) 
(but not programmed cell death ligand-2) with programmed cell death receptor (PD-1) on T cells 
and cluster of differentiation (CD)80 (B7.1) on immune cells. It is being developed by 
AstraZeneca/MedImmune for use in the treatment of cancer. Results of early studies with 
durvalumab in advanced cancers are consistent with a class effect of early and sustained tumor 
control that has been observed previously with other inhibitors of the immune-checkpoint 
pathway. As radiation therapy is known to upregulate PD-L1, using durvalumab subsequent to 
radiation therapy could potentially provide better clinical outcomes in this population. Results 
from the PACIFIC Study in patients with Stage III unresectable non-small cell lung cancer 
(NSCLC) following concurrent chemoradiation therapy (cCRT) demonstrated a significant 
increase in median progression-free survival (PFS) and a significant increase in overall survival 
(OS) among patients who received durvalumab compared with placebo. Safety results from this 
study demonstrated that durvalumab monotherapy was well tolerated and had a manageable 
safety profile in this patient population. However, many patients with Stage III unresectable 
NSCLC are unable to undergo chemotherapy; these patients are therefore faced with fewer 
treatment options. The main goal of this study is to evaluate the safety and tolerability of 
maintenance treatment with durvalumab following radiation therapy in this population.
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Objective
Endpoint/variable
Primary objective
To assess the safety and tolerability profile of 
durvalumab as defined by Grade 3 and Grade 4 PRAEs 
within 6 months from the initiation of durvalumab 
treatment
Grade 3 and Grade 4 PRAEs
Secondary objectives
To assess the efficacy of durvalumab treatment in 
terms of PFS and OS 
Median PFS according to RECIST 1.1as assessed by 
the Investigator
PFS6 and PFS12 according to RECIST 1.1 as assessed 
by the Investigator
Median OS and OS12
To further assess the efficacy of durvalumab treatment 
in terms of ORR and DoR
ORR according to RECIST 1.1as assessed by the 
Investigator
DoR according to RECIST 1.1as assessed by the 
Investigator
To assess the efficacy of durvalumab treatment in 
terms of lung cancer mortality
Lung cancer mortality
To further assess the safety and tolerability profile of 
durvalumab treatment, including all AEs
AEs, SAEs, AESIs, imAEs, physical examinations, 
vital signs including BP, pulse, ECGs, and laboratory 
findings including clinical chemistry, hematology, and 
urinalysis
Exploratory objectives 
 
 
 
 
 
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radiation therapy, and radiation therapy must be completed within 6 weeks (42 days) prior to first 
durvalumab administration. The last dose of radiation therapy is defined as the day of the last 
radiation treatment session.
Approximately 148 patients are screened to achieve 102 patients treated with durvalumab and 
60 evaluable patients.
Note: "Screened" means a patient’s or their legally acceptable representative’s, agreement to 
participate in a clinical study following completion of the informed consent process. Potential 
patients who are screened for the purpose of determining eligibility for the study, but are not 
randomized/assigned in the study, are considered “screen failures”, unless otherwise specified by 
the protocol. 
Treatments and treatment duration
All patients will receive 1500 mg durvalumab via intravenous (IV) infusion every 4 weeks (q4w) 
for 12 months (13 doses/cycles). The last administration of durvalumab will be on week 48 
unless there is clinical progression, confirmed radiological progression, unacceptable toxicity, 
withdrawal of consent, or another discontinuation criterion is met. (Please note: If a patient’s 
weight falls to 30 kg or below, the patient should receive weight-based dosing equivalent to 
20 mg/kg of durvalumab q4w after consultation between Investigator and Study Physician, until 
the weight improves to > 30 kg, at which point the patient should resume the fixed-dosing of 
durvalumab 1500 mg q4w).
Progression during treatment
During the treatment period, patients who are clinically stable at an initial RECIST 1.1-defined 
progressive disease (PD) may continue to receive study treatment at the discretion of the 
Investigator and patient. A follow-up scan is to be collected after the initial RECIST 1.1-defined 
PD, preferably at the next (and no later than the next) scheduled imaging visit, and no less than 
4 weeks after the prior assessment of PD; this follow-up scan is evaluated using the 
Confirmation of Radiological Progression criteria. Patients with confirmed PD who continue to 
receive durvalumab at the discretion of the Investigator and patient (following consultation with 
AstraZeneca) can receive treatment for the remainder of the 12-month treatment period, and 
tumor assessments should continue on their regular imaging schedule for the duration of 
treatment.
Follow-up of patients after discontinuation of study drug
Patients who have discontinued study treatment due to toxicity or symptomatic deterioration, 
clinical progression, or who have commenced subsequent anticancer therapy, will be followed up 
for adverse events (AEs) and with PRO-questionnaires for 90 days after investigational product 
(IP) discontinuation, and thereafter followed up with tumor assessments until 


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RECIST 1.1-defined radiological PD plus an additional follow-up scan or until death (whichever 
comes first).
Survival
All patients in the study should be followed up for survival at months 2, 3, 4, 6, 8, 10, and 12 
following treatment discontinuation or completion, and then every 12 weeks until death, 
withdrawal of consent, or the end of the study, as per the SoA.
Steering Committee
If required, a Steering Committee (SC) will be assembled by AstraZeneca for the executive 
oversight and supervision of the study. The SC will consist of oncology experts and a statistician 
who serve their role through regular scheduled meetings or teleconferences and, if necessary, 
additional ad hoc meetings. Details of the SC remit, procedures, processes, and meeting 
frequency will be outlined in an SC Charter.
Interim analysis
No formal interim analyses are planned for this study.
Statistical methods
The primary objective of this study is to assess the safety and tolerability of durvalumab which is 
defined as Grade 3 and Grade 4 possibly related adverse events (PRAEs), as assessed by the 
Investigator, observed within 6 months after the initiation of durvalumab treatment. In addition, 
safety and tolerability of durvalumab will be characterized for the cohorts of patients who 
received Standard Radiotherapy (60 Gy ± 10% or hypofractionated BED) and patients who 
received palliative radiotherapy (40 to < 54 Gy or hypofractionated BED).
Safety data will be summarized descriptively overall, by seriousness, by causality and by 
maximum National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) Grade. The exact 95% confidence intervals (CIs) around the incidence of Grade 3 and 
Grade 4 PRAEs will be reported for patients overall and separately for each cohort.
The median PFS, median OS, and median time to NSCLC-related death, together with their 
corresponding 95% CIs, will be calculated using Kaplan-Meier product limit methods. The 
proportion of patients who are progression-free at 6 and 12 months and the proportion of patients 
who are alive at 12 months will be presented. In addition, the objective response rate (ORR), 
based on Investigator assessments, together with the corresponding 95% CIs will be reported.
A total of approximately 102 patients are treated with the study drug in 2 cohorts: approximately 
59 patients in the Standard Radiotherapy Cohort and approximately 43 patients in the Palliative 
Radiotherapy Cohort. It is estimated that a sample size of a minimum 60 patients would be 
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PRAEs occurring within 6 months after initiation of durvalumab treatment, which is the primary 
endpoint. With a sample size of 60 patients, the exact binomial 95% CI for an observed 
incidence rate of 12% would be 5% to 23%. If the underlying/true incidence rate was 12% as 
reported in PACIFIC, on repeated implementations of this study, observing an incidence rate less 
than 5% or greater than 18.3% would be approximately 5% for each region/tail. Furthermore, if 
there are 30 patients in each cohort (Standard Radiotherapy and Palliative Radiotherapy) and the 
true incidence of Grade 3 and Grade 4 PRAEs occurring within 6 months after initiation of 
durvalumab treatment is 12%, the precision will be approximately ± 13.0% (95% CI: 3.1, 29.1) 
in each cohort.
1.3
Schema
The general study design is summarized in Figure 1.
Figure 1
Study design
BED = bioequivalent dose; DoR = Duration of response; Durva = durvalumab; ECOG = Eastern Cooperative 
Oncology Group; Gy = gray; m = Month; mOS = median overall survival; mPFS = median progression-free 
survival; NSCLC = Non-small cell lung cancer; ORR = Overall response rate; OS12 = Overall survival at 
12 months; PD = Progressive disease; PFS6, PFS12 = Progression-free survival at 6, 12 months, respectively; 
PRAE = Possibly related adverse event; PS = Performance status; q4w = Every 4 weeks; RT = radiation therapy
2
INTRODUCTION
Lung cancer has been the most common cancer in the world for several decades, and by 2012, 
there were an estimated 1.8 million new cases, representing 12.9% of all new cancers. It was also 
the most common cause of death from cancer, with 1.59 million deaths (19.4% of the total) 


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(GLOBOCAN 2012). NSCLC represents approximately 80% to 85% of all lung cancers and 
30% of patients present with Stage III disease. Standard treatment for patients with a good 
performance status (PS) and unresectable Stage III NSCLC had been platinum-based doublet 
chemotherapy and radiotherapy administered concurrently with cCRT. A meta-analysis of 
concurrent versus sequential CRT demonstrated better outcomes with concurrent therapy, but 
even with cCRT, 5-year OS ranges between 15% and 32% (Antonia et al 2017, 
Aupérin et al 2010).
More recently, the PACIFIC Study (D4191C00001) demonstrated that the addition of 
durvalumab as sequential therapy to platinum-based CRT significantly improves PFS (median 
PFS 17.2 months with durvalumab compared to 5.6 months with placebo, hazard ratio [HR] of 
0.51) and OS (HR of 0.68) (Antonia et al 2018). Given the potential for further clinical benefit, 
the Sponsor is currently evaluating the efficacy and safety of durvalumab given concurrently 
with platinum-based CRT in patients with locally-advanced, unresectable NSCLC (Stage III) in 
PACIFIC2 (D933KC00001).
However, a significant proportion of patients with Stage III unresectable NSCLC are ineligible 
for chemotherapy for a number of reasons, including comorbidities, poor PS, or elderly age; 
these patients are therefore faced with fewer treatment options. A common regimen for these 
patients is radiotherapy alone; however, it is associated with disappointing results in terms of OS 
(Driessen et al 2016; Miller et al 2018). Using durvalumab subsequent to radiation therapy could 
potentially provide better clinical outcomes in this population.
2.1
Study rationale
Over the last decade, there has been an increasing interest in studying the therapeutic potential of 
immune therapy for different types of tumors. In particular, nonclinical and clinical studies have 
indicated that blockade of immune checkpoints can have a positive effect on antitumor 
immunity.
Results of early studies with durvalumab in advanced cancers are consistent with a class effect of 
early and sustained tumor control that has been observed previously with other inhibitors of the 
immune-checkpoint pathway. A consistent observation across these studies is the long durability 
of benefits with immune-checkpoint inhibitors. However, not all patients benefit from immune-
checkpoint inhibitors as monotherapy. Hence, studies that follow established treatments (such as 
radiation therapy) with immune-checkpoint inhibitors are needed in order to expand the patient 
population who might benefit from immune-checkpoint inhibitors.
Radiation has been shown to induce immunogenic cell death. Cell death enhances the ability of 
the immune system to recognize and respond to the tumor through enhanced antigen release and 
presentation (tumor specific T-cell activation; Formenti and Demaria 2013, Weichselbaum 
et al 2017). In addition, ionizing radiation causes upregulation of various proinflammatory 


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signals and cytokines, which play a key role in immune regulatory pathway, leading to improved 
antitumor immunity. Twyman-Saint Victor et al also showed that radiation enhanced the 
diversity of the T-cell receptor repertoire of intratumoral T cells (Twyman-Saint Victor et al 
2015). Additionally, radiotherapy has been shown to upregulate the expression of PD-L1 (Butts 
et al 2014, Deng et al 2014, Zhang et al 2008b), and therefore may confer greater sensitivity to 
PD-L1-directed therapy.
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).
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling 
T-cell activation. The PD-1 receptor (CD279) is expressed on the surface of activated T cells
(Janssen et al 2008a, Janssen et al 2008b, Keir et al 2008). It has 2 known ligands: PD-L1 
(B7-H1; CD274) and 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 (Pazdur 2008, 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.


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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 nonclinical and clinical studies of 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 (Antonia et al 2017, Antonia et al 2018, ASTRO 2017, 
Aupérin et al 2010, Basch et al 2009, Bergman et al 1994, Herdman et al 2011, Hirano et al 
2005, IASLC 2016, Iwai et al 2002, Okudaira et al 2009, Topalian et al 2012,Zhang et al 2008a) 
with responses that tend to be more pronounced in patients with tumors that express PD-L1 
(Pickard et al 2007, Powles et al 2014, Rizvi et al 2015, Segal et al 2015). In addition high 
mutational burden (eg, in bladder carcinoma; Aaronson et al 1993, Alexandrov et al 2013) may 
contribute to the responses seen with immune therapy.
Nonclinical data have 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 
Food and Drug Administration 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 nonsquamous 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 IgG1 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. It is being developed by AstraZeneca/MedImmune for use in the treatment of cancer. 
(MedImmune is a wholly owned subsidiary of AstraZeneca; AstraZeneca/MedImmune will be 
referred to as AstraZeneca throughout this document.) The proposed mechanism of action 
(MOA) for durvalumab is interference in the interaction of PD-L1 with PD-1 and CD80 (B7.1). 
Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune 
responses, including those that may result in tumor elimination. In vitro studies demonstrate that 
durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T cells resulting in the 
restored proliferation of interferon gamma (IFN-γ) (Sprangers and Aaronson 1992, Stewart et al 
2015). In vivo studies have shown that durvalumab inhibits tumor growth in xenograft models 
via a T-cell-dependent mechanism (Sprangers and Aaronson 1992, 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 
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To date, durvalumab has been given to more than 5000 patients as part of ongoing studies either 
as monotherapy or in combination with other anticancer agents. Details on the safety profile of 
durvalumab monotherapy are summarized in Section 4.3.1 and Section 8.3.12. Refer to the 
current durvalumab IB for a complete summary of nonclinical and clinical information including 
safety, efficacy, and pharmacokinetics (PK).
2.3
Benefit/risk assessment
The majority of the safety and efficacy data currently available for durvalumab are based on the 
first-in-human, single-agent study (Study CD-ON-MEDI4736-1108; hereafter referred to as 
Study 1108) in patients with advanced solid tumors, the study of durvalumab monotherapy in 
NSCLC (ATLANTIC Study [NCT02087423]), the study of durvalumab monotherapy in NSCLC 
following completion of platinum-based chemotherapy concurrent with radiation therapy 
(PACIFIC Study [NCT02125461]), and the study of durvalumab with or without tremelimumab 
as first line treatment for patients with advanced or metastatic NSCLC (MYSTIC Study 
[NCT02453282]). Data from these studies have demonstrated clinical activity of durvalumab 
therapy in patients with NSCLC. Details pertaining these studies are provided in the current 
durvalumab IB.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of durvalumab may also be found in the IB.
2.3.1
Potential benefits
The efficacy of durvalumab was evaluated in the Phase III PACIFIC Study, a multi-center, 
randomized, double-blind, placebo-controlled study in patients with unresectable Stage III 
NSCLC who completed at least 2 cycles of concurrent platinum-based chemotherapy and 
definitive radiation within 42 days prior to initiation of the study drug and had a World Health 
Organization (WHO) PS 0 or 1 (Antonia et al 2017, Antonia et al 2018). A total of 713 patients 
were randomized 2:1 to receive durvalumab 10 mg/kg or placebo intravenously every 2 weeks 
for up to 12 months or until unacceptable toxicity or confirmed RECIST 1.1-defined progression. 
The prespecified interim PFS analysis based on 81% of total planned events demonstrated a 
statistically significant improvement in PFS of 16.8 months (95% CI: 13.0, 18.1) with 
durvalumab versus 5.6 months (95% CI: 4.6, 7.8) with placebo (stratified HR: 0.52; 
95% CI: 0.42, 0.65; p < 0.001). The PFS benefit in favor of durvalumab was observed 
irrespective of PD-L1 expression before CRT (PD-L1 expression < 25%, HR: 0.59; 95% CI: 
0.43, 0.82; PD-L1 expression ≥ 25%, HR: 0.41; 95% CI: 0.26, 0.65). The response rate was 
higher with durvalumab than with placebo (28.4% versus 16.0%; p < 0.001), and the median 
duration of response (DoR) was longer (72.8% versus 46.8% of the patients had an ongoing 
response at 18 months).
As of the time of the PACIFIC OS analysis, the median time to death or distant metastasis was 
28.3 months in the durvalumab group and 16.2 months in the placebo group (stratified HR, 0.53; 


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95% CI, 0.41 to 0.68) (Antonia et al 2018). The 24-month OS rate was 66.3% (95% CI, 61.7 to 
70.4) in the durvalumab group, as compared with 55.6% (95% CI, 48.9 to 61.8) in the placebo 
group (two-sided P 0.005). As of 31 January 2019 (third data cutoff [DCO]), 3-year data 
demonstrated a durvalumab survival benefit over placebo that was consistent with the OS 
primary analysis, with a 31% reduction in the risk of death (HR: 0.69; 95% CI, 0.55 to 0.86). The 
Kaplan-Meier estimate of the median OS was 29.1 months in the placebo group, while it was not 
yet reached in the durvalumab group. The 12-, 24-, and 36-month OS rates with durvalumab and 
placebo were 83.1% versus 74.6%, 66.3% versus 55.3%, and 57.0% versus 43.5%, respectively 
(Gray et al 2019).
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 
hypothyroidism, type I diabetes mellitus, and diabetes insipidus), hepatitis/increases in 
transaminases, nephritis/increases in creatinine, pancreatitis/increases in amylase and lipase, 
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, Guillian-Barre syndrome, myasthenia gravis).
For information on all identified and potential risks with durvalumab, please always refer to the 
current version of the durvalumab IB.
In monotherapy clinical studies, AEs at an incidence of > 20% include events such as fatigue, 
cough, decreased appetite, dyspnea, and nausea. Approximately 10% of patients discontinued the 
drug due to an AE. In the PACIFIC Study in patients with Stage III NSCLC following cCRT, 
AEs (all causality) experienced during the study with an incidence of > 10% (durvalumab vs 


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placebo) were cough (35.4% vs 25.2%); fatigue (23.8% vs 20.5%); dyspnea (22.3% vs 23.9%); 
radiation pneumonitis (20.2% vs 15.4%); diarrhea (18.3% vs 18.8%); pyrexia (14.7% vs 9%); 
decreased appetite (14.3% vs 12.8%); nausea (13.9% vs 13.2%); pneumonia (13.1% vs 7.7%); 
pneumonitis (12.6% vs 7.7%); arthralgia (12.4% vs 11.1%); pruritus, rash and upper respiratory 
tract infection (12.2% each vs 4.7%, 7.3% and 9.8%, respectively); constipation (11.8% vs 
8.5%); hypothyroidism (11.6% vs 1.7%); headache (10.9% vs 9.0%); asthenia (10.7% vs 
13.2%); and back pain (10.5% vs 11.5%). Combined events of pneumonitis or radiation 
pneumonitis occurred in 33.9% vs 24.8% of patients, including CTCAE Grade 3 pneumonitis or 
radiation pneumonitis in 3.4% vs 2.6% of patients; no patients in either treatment group reported 
Grade 4 events of pneumonitis or radiation pneumonitis.
Please see the current version of the IB for a detailed summary of the monotherapy data 
including AEs, serious adverse events (SAEs), and 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
The clinical activity associated with potentiating the proinflammatory effects of radiation therapy 
suggests that giving durvalumab following radiation therapy may have clinical benefits, 
including increasing the response rate to radiation therapy.
The safety of durvalumab following radiation therapy is further supported by results from the 
PACIFIC Study, which showed that durvalumab administered within 42 days of completion of 
CRT had a well tolerated and manageable safety profile that was consistent with the established 
safety profile to date. It is therefore reasonable to assume that immunotherapy administered 
within 42 days of completion of radiation therapy will also be well tolerated.
Therefore, the overall benefit-risk assessment supports the proposed study to evaluate the 
efficacy and safety of administration of durvalumab following radiation therapy.
3
OBJECTIVES AND ENDPOINTS
The study objectives and corresponding endpoints/variables are listed in Table 3.






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For details on what is included in the efficacy and safety endpoints, see Section 3 Objectives and 
Endpoints.
Patients will receive study treatment for 12 months or until RECIST 1.1-defined radiological 
progression by Investigator unless there is evidence of an unacceptable toxicity, or if the patient 
requests to stop the study treatment. See Section 6.1.3 for detailed criteria.
Patients who have discontinued study treatment due to toxicity or symptomatic deterioration, 
clinical progression, or who have commenced subsequent anticancer therapy, will be followed up 
for AEs and with PRO-questionnaires for 90 days after study treatment discontinuation, and 
thereafter followed up with tumor assessments until RECIST 1.1-defined radiological PD plus an 
additional follow-up scan or until death (whichever comes first).
4.2
Scientific rationale for study design
4.2.1
Rationale for safety endpoints
This study is designed to evaluate the safety of durvalumab monotherapy, using a fixed-dosing 
regimen, in unresectable Stage III NSCLC patients who are ineligible for chemotherapy and who 
have not progressed following radiation therapy. This study is designed to complement and 
expand the safety database from the ongoing Phase III PACIFIC Study and PACIFIC-5 Study 
(NCT03706690) and the ongoing Phase II PACIFIC-6 Study (NCT03693300). Given the 
potential for radiotherapy to increase the likelihood of anti-PD-L1–mediated pneumonitis, a need 
for additional safety data on the use of durvalumab under this context exists, including in the 
sub-population of WHO/ECOG PS 2 patients, who have not been representatively included in 
pivotal studies.
In the PACIFIC Study, the majority of imAEs with durvalumab occurred during the first 
6 months of treatment (see the current version of the durvalumab IB). This timing is consistent 
with published literature using anti-PD-1 or anti-CTLA-4 agents, which indicates that most of 
the imAEs occur within 3 to 6 months of the initiation of treatment (Topalian et al 2012, Weber 
et al 2017). This study will assess the safety of durvalumab within the first 6 months of treatment 
as defined by Grade 3 and Grade 4 PRAEs, including the evaluation of the nature of toxicities 
(SAEs, AEs, Adverse Events of Special Interest [AESIs], imAEs), interventions and treatment, 
and outcome of treatment.
4.2.2
Rationale for efficacy endpoints
The secondary aim of this study is to determine the efficacy of durvalumab 1500 mg q4w in 
terms of ORR, PFS, and OS. PFS has been found to be correlated with OS in previous CRT 
studies (Mauguen et al 2013). Although the OS benefit has exceeded the PFS benefit in other 
studies of immune-checkpoint inhibitors in advanced-stage NSCLC (Borghaei et al 2015), there 
are certain settings in which the utility of survival as an endpoint may potentially be confounded 
by subsequent therapies. Specifically, there are currently a number of molecules targeting the 


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PD-1/PD-L1 pathway in late-stage development for the treatment of first-, second-, and/or 
third-line metastatic NSCLC. It is anticipated that these agents may be approved or become 
available for use through expanded-access programs or additional clinical studies while this 
study is ongoing. This poses challenges in being able to fully characterize effects on OS if 
patients subsequently receive these immunotherapeutic agents.
Antitumor activity will be assessed according to RECIST 1.1 guidelines, with the understanding 
that in the context of postradiation changes, tumor assessment may be difficult and may need to 
be repeated over time to reach a clear determination regarding responses and PD (see 
Section 8.1). The tumor-based efficacy analyses will be conducted by programmatically deriving 
each efficacy endpoint based on RECIST 1.1 criteria. PFS will be programmatically derived 
from Investigators’ tumor data from all scans based upon RECIST 1.1.
4.2.3
Rationale for other study exploratory endpoints
 
 
 
 
 
4.2.4
Rationale for treatment duration
Treatment in this study will continue for 12 months or until RECIST 1.1-defined PD and 
Investigator determination that the patient is no longer benefiting from treatment with IP, or until 
another discontinuation criterion is met (see Section 7.1). This guidance is supported by data 
from the PACIFIC Study, in which patients were treated for up to 12 months with durvalumab, 
and no new safety signals were observed after 6 months of treatment (Antonia et al 2017). The 
median duration of treatment in the PACIFIC Study was 40.1 weeks (range, 1 to 54) in the 
durvalumab group, suggesting that durvalubab treatment was tolerable in this patient population 
(Antonia et al 2018). Numerous Phase III studies are currently evaluating durvalumab treatment 
until PD for patients with a variety of malignancies. Although the results of these studies are not 
yet available, no new safety signals have been identified as a result of the longer duration. In 
order to balance the patient burden associated with monthly visits until disease progression with 
the potential for additional clinical benefit with prolonged treatment duration, durvalumab will 
be administered for 12 months in this study.
CCI
CCI
CCI


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4.2.5
Timing of treatment with durvalumab relative to prior radiation therapy
Nonclinical data show that ionizing radiation up-regulates PD-L1 expression (Deng et al 2014, 
Zhang et al 2008b). In addition, radiotherapy releases new antigens leaving the cancer to act as 
an in situ vaccine that can elicit tumor-specific T cells. Thus, starting durvalumab as close as 
possible to the completion of radiation therapy, when antigen release and PD-L1 expression are 
most likely to be at their maximum, will hopefully result in the most optimal benefit. The timing 
for durvalumab treatment initiation will be aligned with what has been tested in the PACIFIC 
Study (ie, 42 days after the end of cCRT).
4.3
Justification for dose
This study will use a fixed dose for durvalumab treatment (1500 mg q4w IV). Based on an 
average body weight of 75 kg, a fixed dose of 1500 mg of durvalumab q4w is equivalent to a 
weight-based dose of 20 mg/kg q4w.
4.3.1
Durvalumab monotherapy dose rationale
A durvalumab dose of 20 mg/kg q4w is supported by in vitro data, nonclinical activity, clinical 
PK/pharmacodynamics, biomarkers, and activity data from Study 1108) in patients with 
advanced solid tumors and from a phase I study performed in Japanese patients with advanced 
solid tumor (D4190C00002).
PK/Pharmacodynamic data
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging 
from 0.1 to 10 mg/kg every 2 weeks (q2w) or 15 mg/kg every 3 weeks (q3w), durvalumab 
exhibited nonlinear (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 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; EuroQoL 2013, 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 area under the plasma concentration versus time curve at steady state 
(4 weeks). Median peak drug concentration at steady state is expected to be higher with 
20 mg/kg q4w (~1.5 fold) and median trough drug concentration at steady state is expected to be 
higher with 10 mg/kg q2w (~1.25 fold). Clinical activity with the 20 mg/kg q4w dosing regimen 


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is anticipated to be 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 antidrug 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 (AUC) and modest 
differences in median peak and trough levels at steady state, the observation that both regimens 
maintain complete sPD-L1 suppression at trough, and the available clinical data, the 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.
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.
4.3.2
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 (Litwin et al 1998, Mauguen et al 2013, Narwal et 
al 2013, Ng et al 2006, Wang et al 2009, Zhang et al 2012). Wang and colleagues investigated 
12 monoclonal antibodies 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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4.4
End of study definition
For the purpose of Clinical Trial Transparency the definition of the end of the study differs under 
Food and Drug Administration and European regulatory requirements:

European Union requirements define study completion as the last visit of the last subject for 
any protocol related activity.

Food and Drug Administration requirements defines two completion dates:

Primary Completion Date – the date that the final patient is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome 
measure, whether the clinical study concluded according to the pre-specified protocol or 
was terminated. In the case of clinical studies with more than one primary outcome 
measure with different completion dates, this term refers to the date on which data 
collection is completed for all of the primary outcomes.

Study Completion Date – the date the final patient is examined or receives an 
intervention for purposes of final collection of data for the primary and secondary 
outcome measures and AEs (eg, last patient’s last visit), whether the clinical study 
concludes according to the pre-specified protocol or is terminated.
A patient is considered to have completed the study if they have completed all phases of the 
study including the last visit or the last scheduled procedure shown in the SoA.
Patients may be withdrawn from the study if the study itself is stopped. The study may be 
stopped if, in the judgment of AstraZeneca, study patients are placed at undue risk because of 
clinically significant findings.
In the event that a rollover or safety extension study is available at the time of the final DCO and 
database closure, patients currently receiving treatment with durvalumab may be transitioned to 
such a study, and the current study would reach its end. The rollover or safety extension study 
would ensure treatment continuation with visit assessments per its protocol. Any patient who 
would be proposed to move to such a study would be given a new ICF.
See Appendix A 6 for guidelines for the dissemination of study results.
At the DCO, the clinical study database will close to new data. However, patients will be 
permitted to continue to receive durvalumab beyond the closure of the database for the remainder 
of the 12-month treatment period if, in the opinion of the Investigator, they are continuing to 
receive benefit from durvalumab (refer to Section 6.1.3 for details on patient management 
following the final DCO as well as following study completion). For patients who do continue to 
receive durvalumab beyond the time of the DCO, Investigators will continue to report all AEs 
and SAEs to AstraZeneca Patient Safety until 90 days after durvalumab is discontinued, in 
accordance with Section 8.4.1. If an Investigator learns of any SAEs, including death, at any time 


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after a patient has completed the study, and he/she considers there is a reasonable possibility that 
the event is causally related to the study drug, the Investigator should notify AstraZeneca Patient
Safety. Any SAE or nonserious AE ongoing at the time of this DCO is to be followed up at the 
discretion of the Investigator and per local practice and in alignment with the Dosing 
Modification and Toxicity Management Guidelines (see Section 8.4.5.1), unless the event is 
considered by the Investigator to be unlikely to resolve or the patient is lost to follow-up.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to receive IP treatment. Under no circumstances can there be exceptions to this 
rule. Patients who do not meet the entry requirements are screen failures, refer to Section 5.4.
In this protocol, “enrolled” patients are defined as those who sign informed consent.
For procedures for withdrawal of incorrectly enrolled patients see Section 5.5.
5.1
Inclusion criteria
Patients are eligible to be included in the study only if all of the following inclusion criteria 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 informed consent form (ICF) and in this protocol.
2
Provision of signed and dated, written ICF prior to any mandatory study specific procedures, 
sampling, and analyses.
3
Provision of signed and dated written genetic ICF prior to collection of sample for genetic 
analysis (optional).
The ICF process is described in Appendix A 3.
Age
4
Age ≥ 18 years at the time of screening.
Type of patient and disease characteristics
5
Histologically- or cytologically-documented NSCLC with locally-advanced, unresectable 
Stage III disease (according to the IASLC Staging Manual Version 8 [IASLC 2016]).
(a) Imaging to rule out distant metastasis is required.


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(b) Endobronchial ultrasound with biopsy is encouraged in patients with suspected 
lymph node involvement.
6
Deemed ineligible for chemotherapy per Investigator assessment (eg, comorbidities, poor 
PS, etc).
7
Receipt of radiation therapy that was completed within 42 days prior to first IP dose 
administration in the study.
8
Patients must have received a total dose of radiation of 40 to 66 Gy (standard or 
hypofractionated BED). Note that patients will be assigned to Cohort A (standard radiation 
therapy [60 Gy ± 10% or hypofractionated BED]) or Cohort B (palliative radiation therapy 
[40 to < 54 Gy or hypofractionated BED]) based upon total dose of radiation received. Sites 
are encouraged to adhere to mean organ radiation dosing as follows:
(a) Mean lung dose < 20 Gy and/or V20 < 35%;
(b) Mean esophagus dose < 34 Gy;
(c) Heart V45 < 35% or V30 < 30%. Heart V45 < 35% or V30 < 30%.
Note: Sites should be aware of the recent RTOG 0617 Study data (Bradley et al 
2015) demonstrating that doses higher than 60 Gy may be associated with greater 
toxicity and worse efficacy.
(d) Patients with WHO/ECOG PS 2 or chronic lung disease (pulmonary emphysema 
or chronic obstructive pulmonary disease) must have received a V20 < 25%.
9
Patients must not have progressed following radiation therapy, as per Investigator assessed 
RECIST 1.1 criteria.
(a) Patients with measurable disease and/or nonmeasurable and/or no evidence of disease 
assessed at baseline by computed tomography (CT)/magnetic resonance imaging (MRI) 
will be eligible for this study.
(b) Prior irradiated lesions may be considered measurable and selected as target lesions 
(TLs) providing they fulfill the other criteria for measurability.
10 WHO/ECOG PS of ≤ 2.
11 No prior exposure to immune-mediated therapy including, but not limited to, anti-CTLA-4, 
anti-PD-1, anti-PD-L1, and antiprogrammed cell death ligand 2 (anti-PD-L2) antibodies, 
excluding therapeutic anticancer vaccines.
12 Adequate organ and marrow function as defined below:

Hemoglobin ≥ 9.0 g/dL

Absolute neutrophil count ≥ 1.0 × 109/L

Platelet count ≥ 75 × 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.


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
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)
13 Must have a life expectancy of at least 12 weeks.
Weight
14 Body weight > 30 kg at enrollment and first IP dose administration
Sex
15 Male or female
5.2
Exclusion criteria
Medical conditions
1
Patients with locally-advanced NSCLC whose disease has progressed following radiation 
therapy.
2
Mixed small cell lung cancer and NSCLC histology.
3
History of allogeneic organ transplantation.
4
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
5
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 


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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
6
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 durvalumab and of low potential risk for recurrence

Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of 
disease

Adequately treated carcinoma in situ without evidence of disease
7
History of leptomeningeal carcinomatosis
8
History of active primary immunodeficiency
9
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 (known positive hepatitis B virus surface antigen (HBsAg) result), 
hepatitis C, or human immunodeficiency virus (HIV; positive HIV 1/2 antibodies). 
Patients with a past or resolved hepatitis B virus infection (defined as the presence of 
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive 
for hepatitis C antibody are eligible only if polymerase chain reaction is negative for 
hepatitis C virus ribonucleic acid (RNA).
10 Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the
exception of alopecia, vitiligo, lymphopenia, and the laboratory values defined in the 
inclusion criteria

Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Study Physician

Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab may be included only after consultation with the Study 
Physician
11 Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients
Prior/concomitant therapy
12 Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab. Note: 
Patients, if enrolled, should not receive live vaccine while receiving durvalumab and up to 
30 days after the last dose of durvalumab.
13 Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of durvalumab. Note: Local surgery of isolated lesions for palliative intent is 
acceptable.


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14 Current or prior use of immunosuppressive medication within 14 days before the first dose 
of durvalumab. The following are exceptions to this criterion:

Intranasal, inhaled, topical steroids, or local steroid injections (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
15 Participation in another clinical study with an IP administered in the last 4 weeks
16 Concurrent enrollment in another clinical study, unless it is an observational 
(noninterventional) clinical study or during the follow-up period of an interventional study
17 Prior randomization or treatment in a previous durvalumab clinical study regardless of 
treatment arm assignment
Other exclusions
18 Patients who refuse chemotherapy by their own decision. 
19 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site)
20 Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from screening 
to 90 days after the last dose of durvalumab monotherapy
21 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
22 Genetics research study (optional):

Exclusion criteria for participation in the optional (DNA) genetics research component 
of the study include:
o
Previous allogeneic bone marrow transplant
o
Nonleukocyte-depleted whole blood transfusion within 120 days of genetic sample 
collection
5.3
Lifestyle restrictions
The following restrictions apply while the patient is receiving durvalumab and for the specified 
times before and after:
1
Female patient of childbearing potential

Female patients of childbearing potential who are not abstinent and intend to be 
sexually active with a non-sterilized male partner must use at least one highly effective 
method of contraception (Table 4) from the time of screening throughout the total 


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duration of the drug treatment and the drug washout period (90 days after the last dose 
of durvalumab monotherapy). Non-sterilized male partners of a female patient of 
childbearing potential must use a male condom plus spermicide throughout this period. 
Cessation of birth control after this point should be discussed with a responsible 
physician. Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. Female patients should refrain from breastfeeding 
throughout this period.
2
Male patients with a female partner of childbearing potential

Non-sterilized male patients who are not abstinent and intend to be sexually active with 
a female partner of childbearing potential must use a male condom plus spermicide 
from the time of screening throughout the total duration of the drug treatment and the 
drug washout period (90 days after the last dose of durvalumab monotherapy). Periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable methods 
of contraception. Male patients should refrain from sperm donation throughout this 
period.

Female partners (of childbearing potential) of male patients must also use a highly 
effective method of contraception throughout this period (Table 4).
Please note, females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or 
post-menopausal.
Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause. The following age-specific requirements apply:

Women < 50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal treatments
and if they have luteinizing hormone and follicle-stimulating hormone levels in the 
postmenopausal range for the institution.

Women ≥ 50 years of age would be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses > 1 year ago, had 
chemotherapy-induced menopause with last menses > 1 year ago.

Women who are surgically sterile (ie, bilateral salpingectomy, bilateral oophorectomy, or 
complete hysterectomy) are eligible.
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 4. Note 
that some contraception methods are not considered highly effective (eg, male or female condom 
with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; 
non-copper containing intrauterine device; progestogen-only oral hormonal contraceptive pills 


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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).
Table 4
Highly effective methods of contraception ( < 1% failure rate)
Barrier/intrauterine methods
Hormonal methods

Copper T intrauterine device

Levonorgestrel-releasing intrauterine system 
(eg, Mirena®) a

Implants: Etonogestrel-releasing implants 
(eg, Implanon® or Norplant®)

Intravaginal Devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®)

Injection: Medroxyprogesterone injection 
(eg, Depo-Provera®)

Combined Pill: Normal and low dose 
combined oral contraceptive pill

Patch: Norelgestromin/ethinylestradiol-
releasing transdermal system (eg, Ortho 
Evra®)

Minipill: Progesterone based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only highly 
effective progesterone based pill 
a
This is also considered a hormonal method
3
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
Patient enrollment
All patients will be centrally assigned to study drug using an interactive voice/web response 
system (IVRS/IWRS). Before the study is initiated, the telephone number and call-in directions 
for the IVRS and/or the log-in information and directions for the IWRS will be provided to each 
site.
Investigators should keep a record (ie, the patient screening log) of patients who entered 
screening.
At screening/baseline (Days -28 to -1), the Investigators or suitably trained delegate will:

Obtain signed informed consent before any study specific procedures are performed. If 
laboratory or imaging procedures were performed for alternate reasons prior to signing 


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consent, these can be used for screening purposes with consent of the patient. However, all 
screening laboratory and imaging results must have been obtained within 28 days of the first 
dose, with the exception of PFTs, which must have been obtained within 8 weeks of study 
enrollment.

Obtain a unique 7-digit enrollment number (E-code), through the IVRS/IWRS in the 
following format (ECCNNXXX: CC being the country code, NN being the center 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 electronic case report forms 
(eCRFs).

Determine patient eligibility (see Sections 5.1 and 5.2).

Obtain signed informed consent for genetic research study (optional).
Patients will begin treatment on Day 1. Patients must not be treated unless all eligibility criteria 
have been met.
If a patient withdraws from participation in the study, then his or her enrollment code cannot be 
reused. Withdrawn patients will not be replaced.
5.5
Procedures for handling incorrectly enrolled 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 not to meet all the eligibility criteria must not be initiated on treatment, 
and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is 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.
5.6
Screen failures
Screen failures are patients who do not fulfill the eligibility criteria for the study, and therefore 
must not be dosed. These patients should have the reason for study withdrawal recorded as 
“screen failure” (ie, patient does not meet the required inclusion/exclusion criteria). This reason 
for study withdrawal is only valid for screen failures (ie, not dosed patients). Patients may be 
rescreened a single time, but they may not be re-assigned IP treatment. If a patient who has failed 
screening is rescreened, a new E-code must be assigned. Patients will reconfirm their consent to 
participate in the study by re-signing and dating their original consent form(s), next to their 
initial signature and date.


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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 publishing requirements 
and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any AEs/SAEs.
6
STUDY TREATMENTS AND CONCOMITANT THERAPY
Study treatments are all pre-specified, IPs and NIPs, medical devices and other interventions (eg, 
surgical and behavioral) intended to be administered to the study patients during the study 
conduct. Study treatment in this study refers to durvalumab monotherapy.
6.1
Treatments administered
AstraZeneca will supply durvalumab. Details of study treatment are described in Table 5. Dose 
modifications are described in Section 6.5.
Table 5
Study Treatment
Durvaluamab
Study treatment name:
Durvalumab
Type:
Biologic
Dosage formulation: a
500-mg vial solution for infusion after dilution, 50 mg/mL
Unit dose strength:
500 mg (50 mg/mL)
Route of administration:
IV infusion
Use:
Experimental
IP and NIP:
IP
DosageRegimen: b
1500 mg; 20 mg/kg in patients who weigh ≤ 30 kg; q4w c
Packaging and labeling:
Study treatment will be provided in 500 mg vials. Each vial will be labeled in 
accordance with GMP Annex 13 and per country regulatory requirement. d
Sourcing:
AstraZeneca
GMP = Good Manufacturing Practice; IP – investigational procuct; IV = Intravenous; NIP = non-investigational 
product; q4w = Every 4 weeks.
Note: Cycles of durvalumab are 28 days.
a
Refer to Section 6.1.1.1 for detailed formulation and preparation instructions for durvalumab.
b
Detailed instructions for durvalumab administration are provided below. Refer to Section 6.1.1.1 for details on 
duration of treatment.
c
If a patient’s weight falls to 30 kg or below, the patient should receive weight-based dosing equivalent to 
20 mg/kg of durvalumab q4w until the weight improves to > 30 kg, at which point the patient should start 
receiving the fixed-dosing of durvalumab 1500 mg q4w.
d
Label text prepared for durvalumab will show the product name as “MEDI4736” or “durvalumab” depending 
upon the agreed product name used in the approved study master label document. All naming conventions are 
correct during this transitional period.


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6.1.1.1
Durvalumab
Durvalumab will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution. The solution contains 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. The label-claim volume is 10.0 mL. Investigational product vials are 
stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Investigational product should be 
kept in original packaging until use to prevent prolonged light exposure.
Preparation of durvalumab doses for administration with an IV bag
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
designated durvalumab manager using aseptic technique and following local practices and site 
requirements. Total time from needle puncture of the durvalumab vial to the start of 
administration should not exceed:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
A dose of 1500 mg (for patients > 30 kg in weight) will be administered using an IV bag 
containing 0.9% sodium chloride for injection or 5% 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 30.0 mL (ie, 1500 mg) of durvalumab 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 patient weight falls to ≤ 30 kg, weight-based dosing at 20 mg/kg will be administered using an 
IV bag containing 0.9% sodium chloride for injection or 5% 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.
The use of elastometric pumps and use of a pneumatic tube for transport of either a vial or a final 
prepared product have not been studied; please contact AstraZeneca before using.
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the infusion 
according to institutional policy to ensure the full dose is administered. Infusion time does not 
include the final flush time.
If the final product is stored at both refrigerated and ambient temperatures, the total time must 
not exceed 24 hours otherwise a new dose must be prepared from new vials. Durvalumab does 
not contain preservatives, and any unused portion must be discarded immediately after use.


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6.1.2
Dose and treatment regimens
6.1.2.1
Durvalumab monotherapy
All patients will receive 1500 mg durvalumab via IV infusion q4w for 12 months 
(13 doses/cycles), starting on Week 0. The last administration of durvalumab will be on week 
48 unless there is clinical progression, RECIST 1.1-defined radiological progression, 
unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. See 
Figure 2. (Please note, if a patient’s weight falls to 30 kg or below, the patient should receive 
weight-based dosing equivalent to 20 mg/kg of durvalumab 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 1500 mg q4w).
The durvalumab infusion time is 1 hour ± 10 minutes; however, if there are interruptions, the 
total allowed time must not exceed 8 hours with the infusion back maintained at room 
temperature, otherwise a new dose must be prepared from new vials.
Figure 2
Durvalumab monotherapy dosing schedule
PD = Progression of disease; q4w = Every 4 weeks.
a
Or until discontinuation of study drug due to any of the reasons listed in Section 7.1.
6.1.3
Duration of treatment and criteria for treatment through progression
Treatment will be administered beginning on Day 1 for 12 months for durvalumab monotherapy 
or until clinical progression or RECIST 1.1-defined radiological progression (refer to 
Appendix F) unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met.
During the treatment period, patients who are clinically stable at an initial RECIST 1.1-defined 
PD may continue to receive study treatment at the discretion of the Investigator and patient as 
long as they are deemed to be receiving clinical benefit. A follow-up scan is to be collected after 
the initial RECIST 1.1-defined PD, 4-8 weeks after the prior assessment of PD; this follow-up 
scan is evaluated using the post-progression evaluation criteria outlined in Appendix F. Patients 
with confirmed PD who continue to receive durvalumab at the discretion of the Investigator and 
patient (following consultation with AstraZeneca) can receive treatment for the remainder of the 
12-month treatment period, and image acquisitions and tumor assessments should continue on 
their regular imaging schedule for the duration of treatment.


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Patients with rapid tumor progression or with symptomatic progression that requires urgent 
medical intervention (eg, central nervous system metastasis, respiratory failure due to tumor 
compression, or spinal cord compression) will not be eligible for continuing durvalumab.
For all patients who are treated through progression, the Investigator should ensure that:

The patient does not have any significant, unacceptable, or irreversible toxicities that 
indicate continuing treatment will not further benefit the patient. The patient must not have 
experienced a toxicity that required permanent discontinuation of study treatment.

There is absence of clinical symptoms or signs indicating clinically significant disease 
progression accompanied by a decline in WHO/ECOG PS to > 2.

There is absence of rapid disease progression or threat to vital organs or critical anatomical 
sites (eg, central nervous system metastasis, respiratory failure due to tumor compression, or 
spinal cord compression) requiring urgent alternative medical intervention.

The patient still fulfills the eligibility criteria for this study (see Section 5.1 and 5.2) with the 
exception of inclusion criteria 9, 11, and 14 and exclusion criterion 17.

Patient agrees to re-consenting to be treated through progression.
Patients will not be permitted to continue treatment with durvalumab if progression occurs after 
confirmed response (CR or PR as defined by RECIST 1.1) in the TLs (regardless of the 
appearance of new lesions) (ie, the response and progression events both occurred in the TL 
while receiving durvalumab).
Patients who AstraZeneca and the Investigator determine may not continue treatment after 
RECIST 1.1-defined PD will be followed up for survival. Patients who have discontinued 
treatment due to toxicity or symptomatic deterioration, or who have commenced subsequent 
anticancer therapy, will be followed up with tumor assessments until RECIST 1.1-defined PD 
plus an additional follow-up scan or until death (whichever comes first) and followed for 
survival (refer to Section 7.1.2).
Treatment after final overall survival data cutoff
At the time of the DCO, the analysis portion of the clinical study will have been completed and 
all patients remaining in the study will be considered to have completed the analysis portion of 
the study. At the time of DCO, the clinical study database will be closed to new data.
Patients in OS follow-up (progressed and have discontinued treatment) will be considered to 
have completed the study.
Patients who are receiving treatment at the time of DCO may continue receiving IP until 
12 months if the Investigator judges that they are gaining clinical benefit. 


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All patients will receive efficacy scans and follow-up care in accordance with standard local 
clinical practice. Data should be recorded on patient charts but will not otherwise be reported for 
the purposes of this study.
For patients who are continuing to receive treatment with durvalumab following the final DCO 
and database closure, it is recommended that the patients continue the scheduled site visits and 
Investigators monitor the patients’ safety laboratory results prior to and periodically during 
treatment with durvalumab in order to manage AEs in accordance with the durvalumab Dosing 
Modification and Toxicity Management Guidelines (see Section 8.4.5.1).
Following the DCO, SAE reporting applies only to patients who are active on IP and within 
90 days after the last dose; in all other cases, only a Statement of Death notification is to be sent 
to AstraZeneca. No OS data will be recorded in the study database after DCO for the study. 
Investigators will report SAEs to AstraZeneca Patient Safety via paper case report forms (CRFs) 
until 90 days after the last dose of study drug, in accordance with Section 8.4.1. Any SAE or 
nonserious AE ongoing at the time of the DCO is to be followed up at the discretion of the 
Investigator and per local practice and in alignment with the Dosing Modification and Toxicity 
Management Guidelines (see Section 8.4.5.1), unless the event is considered by the Investigator 
to be unlikely to resolve, or the patient is lost to follow-up. Data will not be captured for the 
purposes of this study outside of being recorded in the patients’ source documents.
Different drug supply options will be available depending on the country, and these will be 
proposed to the patient when the most appropriate alternatives for continued treatment have been 
agreed between AZ and the Investigator. Options may include the participation in a new rollover 
study or, if the study drug has been locally approved for use in this disease indication, patients 
may be discontinued and switched to the marketed product, in accordance with local laws. In the 
event that a rollover or safety extension study is available at the time of the final DCO and 
database closure, patients currently receiving treatment with durvalumab may be transitioned to 
such a study, and the current study would reach its end. The rollover or safety extension study 
would ensure treatment continuation with visit assessments per its protocol. Any patient who 
would be proposed to move to such a study would be given a new ICF.
Continued Access to Study treatment
As described in Section 4.4, the study will remain open until all patients have discontinued study 
treatment and completed their last expected visit/contact.
Before the study reaches the final DCO, AstraZeneca will continue to supply durvalumab to 
patients who were enrolled to receive durvalumab until completion of a patient’s current 
12-month treatment period or until meeting any other discontinuation criteria, as defined in 
Section 7.1. Patients should be followed according to the institution's standard of care 


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assessments. No further data collection is required, except for reporting of AEs and SAEs, 
however drug dispensation data may be collected in electronic data capture (EDC).
AstraZeneca can continue to supply durvalumab in the continued access phase of this study and 
after completion of the 12-month treatment period while, in the opinion of the Investigator, the 
patient is benefiting from durvalumab therapy. 
In the event that product development reaches a point where alternative product supply options 
become available, then these alternative product supply options will be discussed by 
AstraZeneca with the Investigator. AstraZeneca will work with the Investigator to transition the 
patient(s) to alternative supply, where possible.
6.1.4
Storage
The Investigator, or an approved representative (eg, pharmacist), will ensure that all durvalumab 
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
Not applicable.
6.3
Treatment compliance
The administration of durvalumab should be recorded in the appropriate sections of the eCRF.
Any change from the dosing schedule, dose interruptions, and dose discontinuations should be 
recorded in the eCRF.
Treatment compliance will be ensured by reconciliation of site drug accountability logs.
The IP Storage Manager is responsible for managing the durvalumab from receipt by the study 
site until the destruction or return of all unused durvalumab.
6.4
Concomitant therapy
The Investigator must be informed as soon as possible about any medication taken from the time 
of screening until the end of the clinical treatment phase of the study including the follow-up 
period following the last dose of study drug.


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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 must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose, unit, 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 6 and 
Table 7. Refer also to the Dosing Modification and Toxicity Management Guidelines (see 
Section 8.4.5.1).
Table 6
Prohibited concomitant medications
Prohibited medication/class of drug:
Usage:
Any investigational anticancer therapy other 
than those under investigation in this study
Should not be given concomitantly while the patient 
is on-study treatment.
mAbs against CTLA-4, PD-1, or PD-L1 other 
than those under investigation in this study
Should not be given concomitantly while the patient 
is on-study treatment.
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal 
therapy for cancer treatment other than those 
under investigation in this study
Should not be given concomitantly while the patient 
is on-study treatment. (Concurrent use of hormones 
for noncancer-related conditions [eg, insulin for 
diabetes and hormone replacement therapy] is 
acceptable. Local treatment of isolated lesions, 
excluding TLs, for palliative intent is acceptable [eg, 
by local surgery or radiotherapy]).
Live attenuated vaccines 
Should not be given through 30 days after the last 
dose of durvalumab.


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Prohibited medication/class of drug:
Usage:
Immunosuppressive medications including, 
but not limited to, systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-α blockers

Should not be given concomitantly, or used 
for premedication prior to the I-O infusions
The following are allowed exceptions:

Use of immunosuppressive medications for 
the management of durvalumab-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 nonimmunotherapy related events 
experienced by the patient (eg, chronic obstructive 
pulmonary disease, radiation, nausea, etc).
EGFR TKIs

Should not be given concomitantly

Should be used with caution in the 90 days 
post-last dose of durvalumab
Increased incidences of pneumonitis (with third 
generation EGFR TKIs) and increased incidence of 
transaminase increases (with first generation EGFR 
TKIs) have been reported when durvalumab has been 
given concomitantly.
Herbal and natural remedies which may have 
immune-modulating effects
Should not be given concomitantly unless agreed by 
the Sponsor.
AE = adverse event; CTLA-4 = cytotoxic T-lymphocyte-associated antigen-4; EGFR = epidermal growth factor 
receptor; mAB = monoclonal antibody; PD-1 = programmed cell death receptor ; PD-L1 = programmed cell death 
ligand 1; TKI = tyrosine kinase inhibitor; TL = target lesion.


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Table 7
Supportive medications
Supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) 
deemed necessary to provide adequate 
prophylactic or supportive care, except for 
those medications identified as “prohibited,” 
as listed above 
To be administered as prescribed by the Investigator
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy 
to NTL, etc])
Should be used, when necessary, for all patients
Inactivated viruses, such as those in the 
influenza vaccine
Permitted
NTL = nontarget lesion.
6.4.1
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the patient’s 
safety and well-being, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the CRF.
6.4.2
Durvalumab drug-drug interactions
There is no information to date on drug-drug interactions with durvalumab either nonclinically or 
in patients. As durvalumab is a monoclonal antibody and therefore a protein, it will be degraded 
to small peptides and amino acids and will be eliminated by renal and reticuloendothelial 
clearance. It is therefore not expected that durvalumab will induce or inhibit the major drug 
metabolizing cytochrome P450 pathways. As a result, there are no expected pharmacokinetic 
drug-drug interactions. The MOA 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.
6.4.3
Rescue medication
As a result of imAEs that could potentially be experienced by patients on durvalumab, steroids, 
and other immunosuppressant rescue medication has to be made available to this patient 
population. The 2 products that fall into the category of immunosuppressants are infliximab 
(eg, for colitis) and mycophenolate (eg, for hepatitis). AstraZeneca supply chain will be 
responsible for sourcing these 2 rescue medications to the sites if countries cannot source rescue 
medications locally or if local regulations prevent the use of infliximab and mycophenolate in 
this indication, as they are considered off-label for management of immunotherapy related 


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toxicities. These rescue medications must be receipted, controlled, and administered by the 
pharmacist and stored according to the labeled storage conditions, with temperature excursions 
reported accordingly by the pharmacist.
6.5
Dose modification
Dose delays are permitted for durvalumab (see Dosing Modification and Toxicity Management 
Guidelines in Section 8.4.5.1). However, dose reduction is not permitted.
6.6
Treatment after the end of the study
After the final analysis, AstraZeneca will continue to supply open-label drug to patients 
receiving durvalumab up to completion of a patient’s 12-month treatment period (see 
Section 6.1.3).
7
DISCONTINUATION OF TREATMENT AND PATIENT
WITHDRAWAL
7.1
Discontinuation of study treatment
An individual patient will not receive any further treatment (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 8.4.5.1)

Pregnancy or intent to become pregnant

Noncompliance 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

Clinical progression or confirmed radiological progression (refer to Appendix F) and 
Investigator determination that the patient is no longer benefiting from treatment with IP.
7.1.1
Follow-up of patients post discontinuation of study treatment
All patients who discontinue the study treatment will be followed up for safety assessments 
(AEs) and with 
 90 days after their last dose of study treatment and for 
CCI


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survival follow-up. Additional assessments to be performed at the time of the 90-day safety 
follow-up are detailed in the SoA (Table 2).
Patients who have discontinued study treatment prior to objective RECIST 1.1-defined 
radiological progression will be followed up with tumor assessments according to the SoA 
(Table 2) until RECIST 1.1-defined PD or death, regardless of whether or not the patient started 
a subsequent anticancer therapy, unless they have withdrawn all consent to study-related 
assessments.
Subsequent anticancer therapy (including radiation therapy) will be assessed and recorded from 
the end of treatment with study treatment through the safety and survival follow-up period or 
until death for patients who have discontinued study treatment, including at PD.
7.1.2
Follow-up for survival
Patients will be followed up for survival status as indicated in the SoA (Table 2) until death, 
withdrawal of consent, or the end of the study. 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. Additional assessments, including subsequent anticancer therapy, are to be recorded at 
the time of survival follow-up and are detailed in the SoA (Table 2).
7.1.3
Procedures for discontinuation of study 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. 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 in Table 1 and Table 2).
Patients who permanently discontinue drug for reasons other than objective RECIST disease 
progression should continue to have RECIST scans performed every 8 weeks (q8w) ± 1 w for the 
first 48 weeks (relative to the date of the first dose), and then every 12 weeks ± 1 w thereafter 
until RECIST 1.1-defined radiological PD plus an additional follow-up scan or death (whichever 
comes first) as defined the SoAs (Table 1 and Table 2).


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If a patient is discontinued for RECIST 1.1-defined progression, then the patient should have 
1 additional follow-up scan performed preferably at the next (and no later than the next) 
scheduled imaging visit, and no less than 4 weeks after the prior assessment of PD.
All patients will be followed for survival until the end of the study.
Patients who decline to return to the site for evaluations should be contacted by telephone as 
indicated in the SoAs (Table 1 and Table 2) as an alternative.
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IVRS/IWRS.
7.2
Lost to follow-up
Patients will be considered lost to follow-up only if no contact has been established by the time 
the study is completed (see Section 4.4), such that there is insufficient information to determine 
the patient’s status at that time. Patients who refuse to continue participation in the study, 
including telephone contact, should be documented as “withdrawal of consent” rather than “lost 
to follow-up.” Investigators should document attempts to re-establish contact with missing 
patients throughout the study period. If contact with a missing patient is re-established, the 
patient should not be considered lost to follow-up and evaluations should resume according to 
the protocol.
In order to support key end points of PFS and OS analyses, the survival status of all patients in 
the full analysis and the safety analysis sets should be re-checked, this includes those patients 
who withdrew consent or are classified as “lost to follow-up.”

Lost to Follow-up – site personnel should check hospital records, the patients’ current 
physician, and a publicly available death registry (if available) to obtain a current survival 
status. (The applicable CRF 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 CRF modules will be updated.)
7.3
Withdrawal from the study
Patients are free to withdraw from the study at any time (treatment and assessments) without 
prejudice to further treatment.
Patients who withdraw consent for further participation in the study will not receive any further 
durvalumab 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 


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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, they will be specifically asked if they are withdrawing consent to:

All further participation in the study including any further follow-up (eg, survival contact 
telephone calls)

Withdrawal to the use of any samples (see Section 8.8.6)
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA (Table 1 and Table 2).
The Investigator will ensure that data are recorded on the eCRFs. The 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 patient should continue or discontinue study treatment.
Adherence to the study design requirements, including those specified in the SoA (Table 1 and 
Table 2), is essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as applicable.
Procedures conducted as part of the patient’s routine clinical management (eg, blood count and 
imaging assessments) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA (Table 1 and Table 2).
8.1
Efficacy assessments
The key efficacy endpoints are: median PFS; proportion of patients progression-free at 6 and 
12 months (PFS6 and PFS12, respectively); median OS; proportion of patients alive at 


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12 months (OS12); and median time to NSCLC-related death, from first IP dose administration; 
ORR and DoR. Efficacy assessments of PFS, ORR, and DoR will be derived (by AstraZeneca) 
using Investigator assessments according to RECIST 1.1.
Tumor assessments utilize images from CT (preferred) or MRI, each preferably with IV contrast, 
of the chest and abdomen (including the entire liver and both adrenal glands) collected during 
screening/baseline and at regular (follow-up) intervals during study treatment. Any other areas of 
disease involvement should be additionally imaged based on the signs and symptoms of 
individual patients. It is important to follow the tumor assessment schedule as closely as possible 
(refer to Table 1 and Table 2). If an unscheduled assessment is performed and the patient has not 
progressed, every attempt should be made to perform the subsequent assessments at the next 
scheduled visit. Treatment continues for 12 months or until disease progression (clinical 
progression/deterioration ± radiological progression by RECIST 1.1), and scanning/tumor 
assessments continue throughout treatment. An additional follow-up scan is requested following 
progression if clinically feasible.
The RECIST 1.1 guidelines (Appendix F) provide a method of assessment of change in tumor 
burden in response to treatment. Screening/baseline imaging should be performed no more than 
28 days before start of study treatment, and ideally should be performed as close as possible to 
and prior to the start of study treatment. The RECIST 1.1 assessments of baseline images 
identify TLs (defined as measurable) and nontarget lesions (NTLs). On-study images are 
evaluated for TLs and NTLs chosen at baseline, and for new lesions when they appear. This 
allows determination of follow-up TL response, NTL lesion response, the presence of 
unequivocal new lesions, and overall timepoint responses (CR, PR, SD, PD, or Not Evaluable 
[NE]).
For all patients who are treated through progression, a follow-up scan is to be collected after the 
initial RECIST 1.1-defined PD, 4-8 weeks after the prior assessment of PD; this follow-up scan 
is evaluated using the post-progression criteria outlined in Appendix F. If the subsequent scan 
confirms the immediate prior radiological PD, no additional scans are required unless the patient 
is allowed to continue study treatment; however, if the subsequent scan does not confirm the 
immediate prior radiological PD, scanning should continue until the next RECIST 1.1-defined 
PD which in turn will require a subsequent scan evaluated using the post-progression criteria 
outlined in Appendix F.
8.1.1
Survival assessments
Assessments for survival must be made as shown in Table 2. Survival information may be 
obtained via telephone contact with the patient or the patient’s family, or by contact with the 
patient’s current physician. The details of first and subsequent therapies for cancer, after 
discontinuation of treatment, will be collected.


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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.
8.1.2
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. COAs can be reported by patients (PRO), clinicians (ClinRo), or observers (ObsRo).
 
 
The following PROs will be collected as detailed in SoA (Table 1, Table 2): 
 
 
 
 
 
 
8.1.2.1
 
 
 
 
 
 
 
 
8.1.2.2
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI






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The following laboratory variables will be measured:
Table 8
Clinical chemistry
Albumin
Lipase b
Alkaline phosphatase a
Magnesium c
ALT a
Potassium
Amylase b
Sodium
AST a
Total bilirubin a
Bicarbonate c
Total protein
Calcium 
TSH d
Chloride c
T3 free e (reflex)
Creatinine c
T4 free e (reflex)
Gamma glutamyltransferase c
Urea or blood urea nitrogen, depending on local practice
Glucose
Lactate dehydrogenase
ALT = alanine aminotransferase; AST = aspartate aminotransferase; T3 = triiodothyronine; T4 = thyroxine; 
TSH = thyroid-stimulating hormone.
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 one of these 
parameters is routinely measured, either lipase or amylase is acceptable.
c
Bicarbonate (where available), chloride, creatinine clearance, gamma glutamyltransferase, and magnesium 
testing are to be performed at baseline, on Day 1 (unless all screening laboratory clinical chemistry assessments are 
performed within 3 days prior to Day 1), and if clinically indicated.
d
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 1.
e
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE related 
to the endocrine system.
Table 9
Hematology
Absolute neutrophil count a
Absolute lymphocyte counta
Hemoglobin
Platelet count
Total white cell count
Coagulation
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 Cycle 1 Day 1 and as clinically 
indicated.
a
Can be recorded as absolute counts or as percentages. Absolute counts will be calculated by Statistical 
Programming if entered as percentage. Total white cell count therefore has to be provided.


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Table 10
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.
Note: Microscopy is preferred to investigate white blood cells and the high power field should be used 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 (TBL) ≥ 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 (see the SoAs).
Any clinically significant abnormal laboratory values should be repeated as clinically indicated 
and recorded on the eCRF. Situations in which laboratory safety results should be reported as 
AEs are described in Section 8.3.7.
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
Physical examinations
Physical examinations will be performed according to the assessment schedules (see the SoAs). 
Full physical examinations will include assessments of the head, eyes, ears, nose, and throat and 
the respiratory, cardiovascular, gastrointestinal, urogenital, musculoskeletal, neurological, 
dermatological, hematologic/lymphatic, and endocrine systems. Height will be measured at 
screening only. Targeted physical examinations are to be utilized by the Investigator on the basis 
of clinical observations and symptomatology. Situations in which physical examination results 
should be reported as AEs are described in Section 8.3.7.
8.2.3
Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the SoAs. Body weight is also recorded at each visit along with vital signs.


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First infusion
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, pulse, temperature, and respiration rate will be collected from patients before, during, and 
after the first 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, pulse, temperature, and respiration rate
measurements should follow the principles as described above or be taken more frequently if 
clinically indicated. A 1-hour observation period is recommended after the first infusion of 
durvalumab.
Subsequent infusions
BP, pulse, and other vital signs should be measured, collected/recorded in eCRF prior to the start 
of the infusion. Patients should be carefully monitored and BP and other vital signs should be 
measured during and postinfusion 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.
8.2.4
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.
In case of clinically significant ECG abnormalities, including a QTcF (QT interval corrected for 
heart rate using Fridericia’s formula) value > 470 ms, 2 additional 12-lead ECGs should be 
obtained over a brief period (eg, 30 minutes) to confirm the finding.
Situations in which ECG results should be reported as AEs are described in Section 8.3.7.


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8.2.5
Early patient review for safety
Patients should be contacted 2 weeks (± 1 day) after receiving the first 3 cycles of durvalumab 
monotherapy (Cycle 1 Day 14 ± 1, Cycle 2 Day 14 ± 1, and Cycle 3 Day 14 ± 1) of study drug(s) 
to ensure early identification and management of toxicities.
8.2.6
World Health Organization/Eastern Cooperative Oncology Group 
performance status
WHO/ECOG PS 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.
8.2.7
Other safety assessments
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormality suggestive 
of pneumonitis/ILD is observed, toxicity management as described in detail in the Dosing 
Modification and Toxicity Management Guidelines (see Section 8.4.5.1) will be applied. The 
results of the full diagnostic workup (including high-resolution computed tomography [HRCT], 
blood and sputum culture, hematological parameters, etc) will be captured in the eCRF. It is 
strongly recommended to perform a full diagnostic workup, to exclude alternative causes such as 
lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage. 
In the presence of confirmatory HRCT scans where other causes of respiratory symptoms have 
been excluded, a diagnosis of pneumonitis (ILD) should be considered and the Dosing 
Modification and Toxicity Management Guidelines should be followed.
Pneumonitis (interstitial lung disease) 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


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
Signs and symptoms (cough, shortness of breath, and pyrexia, etc) including 
auscultation for lung field will be assessed

SpO2

Saturation of peripheral oxygen (SpO2)

Other items

When pneumonitis (ILD) is suspected during study treatment, the following markers 
should be measured where possible:
(i)
ILD Markers (KL-6, SP-D) and β-D-glucan
(ii) Tumor markers: Particular tumor markers which are related to disease progression.
(iii) Additional clinical chemistry: C-reactive protein (CRP), lactate dehydrogenase 
(LDH)
Pulmonary function testing
At screening, pulmonary function will be assessed by measurement of forced expiratory volume.
8.3
Collection of adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative).
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs see 
Section 8.3.3.
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.
8.3.2
Time period and frequency for collecting AE and SAE information
AEs and SAEs will be collected from the time of the patient signing the ICF until 90 days after 
the last dose of durvalumab. If an event that starts after the defined safety follow-up period noted 
above is considered to be due to a late onset toxicity to study drug, then it should be reported as 
an AE or SAE as applicable.


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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 patients. However, 
if the Investigator learns of any SAE, including a death, at any time after a patient’s last visit and 
he/she considers the event to be reasonably related to the study treatment or study participation, 
the Investigator should notify the Sponsor.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All AEs, SAEs, and AESIs (as defined in Section 8.3.12) will be 
followed until resolution, stabilization, the event is otherwise explained, or the patient is lost to 
follow-up.
Any AEs that are unresolved at the patient’s last AE assessment in the study are followed up by 
the Investigator for as long as medically indicated (this may be beyond the 90 days after the last 
dose of durvalumab), but without further recording in the CRF. AstraZeneca retains the right to 
request additional information for any patient with ongoing AE(s)/SAE(s) at the end of the study, 
if judged necessary.
8.3.4
Adverse event data collection
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

The maximum CTCAE grade reported

Changes in CTCAE Grade (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 the AE met criteria for SAE


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
Date the Investigator became aware of the SAE

Seriousness criteria

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Whether an autopsy was performed

Causality assessment in relation to study procedure(s)

Causality assessment in relation to other medication, as explained in Section 8.3.5

Description of the SAE
The grading scales found in the revised NCI CTCAE version 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).
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 an 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 it would be an SAE if it satisfies the criteria shown in Appendix B 2.
8.3.5
Causality collection
The Investigator will assess causal relationship between IP and each AE, and answer “yes” or 
“no” to the question “Do you consider that there is a reasonable possibility that the event may 
have been caused by the 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 to the Clinical 
Study Protocol (CSP).
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 


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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 study report (CSR). Deterioration as compared to baseline in 
protocol-mandated laboratory tests 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.
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 nonmandated parameters 
should be reported as AE(s).
Deterioration of a laboratory value that is unequivocally due to disease progression should not be 
reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE unless unequivocally related to 
the disease under study (see Section 8.3.9).
8.3.8
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥ 3×ULN together with TBL ≥ 2×ULN may need to be reported as 
SAEs. Please refer to Appendix E for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s Law.
8.3.9
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to the 
disease for which the IP is being studied. It may be an increase in the severity of the disease 
under study and/or increases in the symptoms of the disease. The development of new or 
progression of existing metastasis to the primary cancer under study should be considered as 
disease progression and not an AE. Events which are unequivocally due to disease progression 
should not be reported as an AE during the study.


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8.3.10
New malignancies
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 nonserious AE. For 
example, if the tumor 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 tumors, 
which do not spread remotely after a routine treatment that does not require hospitalization, may 
be assessed as nonserious; examples include Stage 1 basal cell carcinoma and Stage 1A1 cervical 
cancer removed via cone biopsy.
The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (ie, it is not the tumor for which entry into the study is a criterion and that is 
being treated by the IP under study and is not the development of new or progression of existing 
metastasis to the tumor under study). 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.
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 study drug, 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 coinvolvement 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 postmortem may be helpful in 
the assessment of the cause of death, and if performed, a copy of the post-mortem results 
should be forwarded to AstraZeneca Patient Safety or its representative within the usual 
timeframes.
Deaths occurring after the protocol-defined safety follow-up period after the administration of 
the last dose of study drug should be documented in the Statement of Death page. If the death 
occurred as a result of an event that started post the defined safety follow-up period and the event 


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is considered to be due to a late onset toxicity to study drug then it should also be reported as an 
SAE.
8.3.12
Adverse events of special interest
An AESI is one of scientific and medical interest specific to understanding of the IP and may 
require close monitoring. An AESI may be serious or nonserious. 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 MOA and where there is no clear alternate etiology. 
Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to support 
an imAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin, or other etiologic causes of the imAE.
If the Investigator has any questions in regards to an event being an imAE, the Investigator 
should promptly contact the Study Physician.
AESI/imAEs observed with anti-PD-L/PD-1 agents such as durvalumab include pneumonitis, 
hepatitis, diarrhea/colitis, intestinal perforation, endocrinopathies (hypo- and hyper-thyroidism, 
adrenal insufficiency, hypophysitis/hypopituitarism and Type 1 diabetes mellitus), nephritis, 
rash/dermatitis, myocarditis, myositis/polymyositis, pancreatitis and rare/less frequent imAEs 
including neuromuscular toxicities such as myasthenia gravis and Guillain-Barre syndrome.
Other inflammatory responses that are rare/less frequent with a potential immune-mediated 
etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and other events 
involving the eye and skin, hematological, and rheumatological events, vasculitis, noninfectious 
meningitis, and noninfectious encephalitis. It is possible that events with an inflammatory or 
immune-related mechanism could occur in nearly all organs.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological etiology are also considered AESIs.
Further information on these risks (eg, presenting symptoms) can be found in the current version 
of the durvalumab IB. More specific guidelines for their evaluation and treatment are described 
in detail in the Dose Modification and Toxicity Management Guidelines (see Section 8.4.5.1). 
These guidelines have been prepared by the Sponsor to assist the Investigator in the exercise of 


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his/her clinical judgment in treating these types of toxicities. These guidelines apply to AEs 
considered causally related to the study drug/study regimen by the reporting Investigator.
8.3.13
Safety data to be collected following the final DCO of the study
For patients continuing to receive durvalumab treatment after final DCO and database closure, it 
is recommended that the patients continue the scheduled site visits and Investigators monitor the 
patient’s safety laboratory results prior to and periodically during treatment with durvalumab in 
order to manage AEs in accordance with the durvalumab Dose Modification and Toxicity 
Management Guidelines (see Section 8.4.5.1). All data after 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
Prompt notification by the Investigator to AstraZeneca of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a study 
treatment under clinical investigation are met.
AstraZeneca has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. 
AstraZeneca will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/Independent IECs, and Investigators.
For all studies except those utilizing medical devices, Investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary.
Adherence to European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations.
An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from AstraZeneca will review and then file 
it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to 
local requirements.All SAEs must be reported, whether or not considered causally related to the 
IP. All SAEs will be recorded in the CRF.


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If any SAE occurs during the study, Investigators or other site personnel will 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 
one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For a fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel will 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.
Once the Investigators or other site personnel indicate an AE is serious in the 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 the SAE
via secure method to the appropriate AstraZeneca representative.
When the EDC is temporarily not accessible, the AstraZeneca Study Representative should 
confirm that the Investigator/site staff enters the SAE in the AstraZeneca EDC when access 
resumes.
For further guidance on the definition of an SAE, see Appendix B.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
IP.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca unless the 
pregnancy is discovered before the study patient has received any study drug.
If a pregnancy is reported, 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.
8.4.2.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the IP should be discontinued 
immediately.


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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 durvalumab monotherapy.
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 durvalumab monotherapy 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/IRB 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 and will enter follow-up (see the 
SoAs).


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8.4.3
Reporting of Overdose
The 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 IP or AstraZeneca NIP occurs in the course of the study, the Investigator or 
other site personnel inform 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 within one or 
5 calendar days for overdoses associated with an SAE (see Section 8.4.1) and within 30 days
for all other overdoses.
8.4.4
Medication Error, Drug Abuse, and Drug Misuse
8.4.4.1
Timelines
If an event of medication error, drug abuse, or drug misuse occurs during the study, then the 
Investigator or other site personnel informs the appropriate AstraZeneca representatives within 
one calendar day, ie, immediately but no later than 24 hours of when they become aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is completed within one (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, drug abuse, or misuse (see Section 8.3.2) and within 
30 days for all other events.
8.4.4.2
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IP or AstraZeneca NIMP that either causes harm to the patient or has 
the potential to cause harm to the patient.
The definition of a medication error can be found in Appendix B 8.
8.4.4.3
Drug Abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect.
The full definition and examples of drug abuse can be found in Appendix B 8.


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8.4.4.4
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study patient) of IP or AstraZeneca 
NIP for medicinal purposes outside of the authorised product information, or for unauthorised 
IPs or AstraZeneca NIPs, outside the intended use as specified in the protocol and includes 
deliberate administration of the product by the wrong route.
The full definition and examples of drug misuse can be found in Appendix B 8.
8.4.5
Management of IP-related toxicities
The following general guidance should be followed for management of toxicities.

Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity if required).

If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of the assigned IP along with appropriate continuing supportive 
care. If medically appropriate, dose modifications are permitted.

All dose modifications should be documented with clear reasoning and documentation of the 
approach taken.
All toxicities will be graded according to NCI CTCAE, Version 5.0.
8.4.5.1
Specific toxicity management and dose modification information – durvalumab
Comprehensive toxicity management guidelines (TMGs) have been developed to assist 
Investigators with the recognition and management of toxicities associated with use of the 
immune-checkpoint inhibitor, durvalumab (PD-L1 inhibitor). Given the similar underlying 
mechanisms of toxicities observed with these 2 compounds, these guidelines are applicable to the 
management of patients receiving either drug as monotherapy or in combination. Additionally, 
these guidelines are applicable when durvalumab is used alone or in combination and is 
administered 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 nonimmune-mediated reactions that may be observed with checkpoint inhibitor 
monotherapy or in combination checkpoint inhibitor regimens, with specific instructions for 
checkpoint inhibitor-specific dose modifications (including discontinuation) and treatment 
interventions. Investigators are advised, however, to use local practice guidelines and consult 
local references for the management of toxicities observed with other anticancer treatment.
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),” and is provided to the investigative site as an Annex document and is 
maintained within the Site Master File. In addition, a current version of TMGs is available 


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through the following link: https://tmg.azirae.com. Please contact the clinical study associate for 
information on how to gain access to this website.
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered potentially 
immune-related. In addition, there are certain circumstances in which durvalumab should be 
permanently discontinued (see Section 7.1 of this protocol and the TMGs). Following the first 
dose of IP, subsequent administration of durvalumab can be modified based on toxicities 
observed as described in the Dosing Modification and TMGs. These guidelines have been 
prepared by the Sponsor to assist the Investigator in the exercise of his/her clinical judgment in 
treating these types of toxicities. These guidelines apply to AEs considered causally related to 
durvalumab monotherapy by the reporting Investigator.
8.5
Pharmacokinetics
Not applicable.
8.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7
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A comprehensive statistical analysis plan (SAP) will be prepared and finalized within 3 months 
of the first enrolled patient and any subsequent amendments will be documented, with final 
amendments completed prior to reporting of the data. The aim of the study is to assess the safety 
and tolerability of durvalumab after radiotherapy with standard radiation therapy [60 Gy ± 10%] 
or hypofractionated BED or palliative radiation therapy [40 to < 54◦Gy]) or hypofractionated 
BED.
9.2
Sample size estimate
The primary objective of this study is to assess the safety and tolerability of durvalumab which is 
defined as Grade 3 and Grade 4 PRAEs observed within 6 months after the initiation of 
durvalumab treatment. In addition, safety and tolerability of durvalumab will be characterized for 
the cohorts of patients who received Standard Radiotherapy (60 Gy ± 10%) or hypofractionated 
BED and patients who received palliative radiotherapy (40 to < 54 Gy) or hypofractionated 
BED.
A total of approximately 102 patients are treated with durvalumab in 2 cohorts: approximately 
59 patients in the Standard Radiotherapy Cohort and approximately 43 patients in the Palliative 
Radiotherapy Cohort. It is estimated that a sample size of a minimum 60 patients would be 
required to provide an adequate level of confidence in the estimated incidence of Grade 3 and 4 
PRAEs occurring within 6 months after initiation of durvalumab treatment, which is the primary 
endpoint. With a sample size of 60 patients, the exact binomial 95% CI for an observed 
incidence rate of 12% would be 5% to 23%. If the underlying/true incidence rate was 12% as 
reported in PACIFIC (D4194C00006), on repeated implementations of this study, observing an 
incidence rate less than 5% or greater than 18.3% would be approximately 5% for each 
region/tail. 
Furthermore, if there are 30 patients in each cohort (Standard Radiotherapy and Palliative 
Radiotherapy) and the true incidence of Grade 3 and Grade 4 PRAEs occurring within 6 months 
after initiation of durvalumab treatment is 12%, , the precision will be approximately ± 13.0% 
(95% CI: 3.1, 29.1) in each cohort.
An illustration of the precision around the varying incidence rate of Grade 3 and Grade 4 PRAEs 
for the patients overall and for each cohort (Standard Radiotherapy and Palliative Radiotherapy) 
is provided in Table 11.


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Table 11
Precision around varying incidence of Grade 3 and Grade 4 Possibly-
Related Adverse Events
Sample size
Grade 3 and Grade 4 PRAE Incidence Rate
10 %
12 %
15 %
60
3.8-20.5
(± 8.4)
5.0-23.0
(± 9.0)
7.1-26.6
(± 9.7)
30
2.1-26.5
(± 12.2)
3.1-29.1
(± 13.0)
4.7-32.7
(± 14.0)
AE = adverse event; CI = confidence interval; n = number of patients; PRAE = possibly related adverse event; 
RT = radiation therapy.
9.3
Definitions of analysis sets
All analyses will be performed on the safety analysis set.
9.3.1
Safety analysis set
The safety analysis set will consist of all patients who received at least one dose of study 
treatment. Safety and efficacy data will be summarized using the safety analysis set.
9.4
Outcome measures for analyses
1
AE: Number and proportion of patients with AEs in total and by causality and severity
2
AE: Number and proportion of patients with Grade 3 and Grade 4 AEs in total and by 
causality
3
SAE: Number and proportion of patients with SAEs in total and by causality and severity
4
AEs leading to death: Number and proportion of patients with AEs leading to death
5
AEs leading to treatment interruption or discontinuation: Number and proportion of 
patients with AEs leading to treatment interruption and/or discontinuation
6
AESI: Defined as an AE of scientific and medical interest specific to understanding of the 
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. In order to further characterize safety objectives related to AESIs, 
outcome measures will be assessed, which may include (and are not necessarily limited to) 
the following:
(a) Number and proportion of patients with AESIs, by predefined type (or newly defined by 
this study) in total and by seriousness, severity and causality, including immune-
relatedness;


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(b) Number and proportion of patients who received steroids, immunosuppressants, and/or 
hormone replacement therapy to manage AESIs;
(c) Time from start of durvalumab to the onset of an AESI predefined type, all 
interventions of AESIs by type of intervention (including intervention with steroids, 
immunosuppressants, and/or hormone replacement therapy), and time from onset of an 
AESI type to resolution;
(d) Duration of the intervention with steroids, immunosuppressants, and/or hormone 
replacement therapy until the resolution of AESI;
(e) The imAEs will be assessed as a subset of AESIs. An imAE is defined as an AESI that 
is associated with drug exposure and is consistent with an immune-mediated MOA and 
where there is no clear alternate etiology.
(f) Laboratory findings, vital signs, and other safety parameters associated with AESIs will 
be summarized as part of the AESI outcome measures.
7
PFS: Defined as the time from the first date of treatment until the date of objective disease 
progression or death (by any cause in the absence of progression) regardless of whether the 
patient withdraws from IP or receives another anticancer therapy prior to progression.
8
PFS (days) = Date of event or Censor date – treatment start date + 1
9
Patients who have not progressed or died at the time of analysis will be censored at the time 
of the latest date of assessment from their last evaluable assessment. However, if the patient 
progresses or dies after 2 or more missed visits, the patient will be censored at the time of 
the latest evaluable assessment prior to the 2 missed visits. If the patient has no evaluable 
visits or does not have baseline data, he/she will be censored at Day 1 unless he/she dies 
within 2 visits of baseline, in which case the date of death is the event date.
10 OS: Defined as the time from the first date of treatment until death due to any cause.
11 OS (days) = Death date or Censor date - treatment start date + 1
12 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.
13 Lung cancer mortality (NSCLC-related death): Defined as the time from the date of 
treatment start until death due to lung cancer.
Time to NSCLC-related deaths (days) = NSCLC-related death date or Censor date -
treatment start date + 1
Any patient not known to have died due to lung cancer will be censored based on the last 
recorded date on which the patient was known to be alive or died due to reason other than 
lung cancer.
14 ORR: Based on Investigator−assessed response to treatment of CR and PR, per RECIST1.1.
15 DoR: Defined as the time from the date of first documented response per RECIST1.1 until 
the first date of documented progression per RECIST1.1 or death in the absence of disease 
progression.


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16 DoR (days) = Date of PFS event or censoring – Date of first response + 1
17 The end of response should coincide with the date of progression or death from any cause 
used for the PFS endpoint. If a patient does not progress following a response, then the 
patients’ DoR will be censored at the PFS censoring time. DoR will not be defined for those 
patients who do not have a documented response.
18
 
 
 
 
 
19
 
 
20 Treatment duration: Defined as Treatment end date - Treatment start date + 1; will be 
summarized.
In addition, demographics, medical history, comorbidities, diagnosis (eg, stage and histology), 
and prior therapeutic management of NSCLC will be reported. Specific details of planned 
analyses will be described in the SAP.
9.5
Statistical analyses
Descriptive statistics will be used for all variables. Continuous variables will be summarized by 
the number of observations (n), mean, standard deviation, median, quartiles (Q1 and Q3), 
minimum, and maximum. Categorical variables will be summarized by frequency counts and 
percentages for each category.
For all summaries of AEs, only treatment-emergent AEs will be included. Treatment-emergent 
AEs are defined as events present at baseline that worsen in intensity after administration of IP or 
events absent at baseline that emerge after administration of IP, for the period extending to 90 
days after the last dose of IP. Baseline will be the last assessment of the variable under 
consideration prior to the first IP dose administration.
A data analysis is planned to be performed once all patients had the opportunity to receive 
treatment for 6 months, ie, the DCO for this primary analysis would be expected 6 months after 
the last patient has received first dose of durvalumab. The data from this analysis would be 
published to support the real-world use of durvalumab.
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9.5.1
Analysis of the primary variable
Safety data will be summarized descriptively overall, by seriousness, by causality, and by 
maximum NCI CTCAE Grade. The exact 95% CIs around the incidence of Grade 3 and Grade 4 
PRAEs will be reported for patients overall and separately for each cohort.
9.5.2
Analysis of the secondary variables
9.5.2.1
Safety variables
Adverse events
Total SAEs, AESIs, AEs leading to death, and AEs leading to study drug interruption or 
discontinuation will be summarized by Medical Dictionary for Regulatory Activities (MedDRA) 
by system organ class and preferred term, causality, and maximum NCI CTCAE Grade. Deaths 
from all causes will be also summarized.
Data from all cycles of will be combined in the presentation of safety data. AEs (both in terms of 
MedDRA preferred term and CTCAE Grade) will be listed individually by patient. Any AE 
occurring before treatment with IP will be included in the data listings but will not be included in 
the summary tables of AEs. Any AE occurring within 90 days of discontinuation of IP may be 
included in the AE summaries, but the majority of the AE summaries will omit the AEs observed 
after a patient has received further therapy for cancer. Further details will be provided in the 
SAP. Any AE that occurs after a patient has received further therapy for cancer (following 
discontinuation of IP) will be flagged in the data listings.
A separate data listing of AEs occurring more than 90 days after discontinuation of IP will be 
produced. These events will not be included in AE summaries.
For the change from baseline summaries for vital signs, laboratory data, ECGs, and physical 
examination, the baseline value will be the latest result obtained prior to the first IP dose 
administration.
The QTcF will be derived during creation of the reporting database using the reported ECG 
values (RR and QT) using the following formula:
QTcF = QT/RR^(1/3) where RR is in seconds
Corrected calcium product will be derived during creation of the reporting database using the 
following formula:
Corrected calcium (mmol/L) = Total calcium (mmol/L) + ([40 – Albumin (G/L)] × 0.02)


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The denominator used in laboratory summaries will include only 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 
predose and at least one postdose value recorded.

If a CTCAE criterion does not consider changes from baseline, to be evaluable, the patient 
need only have one postdose value recorded.
The denominator in vital signs data should include only those patients with recorded data.
9.5.2.2
Efficacy variables
Efficacy data will be reported for patients overall and separately for the cohorts of Standard
Radiotherapy and Palliative Radiotherapy whenever possible.
Progression-free survival
The median PFS together with the corresponding 95% CIs will be reported using Kaplan-Meier 
product limit methods. In addition, the proportion of patients who are progression-free at 6 and 
12 months will be presented.
Overall survival
The median OS together with the corresponding 95% CIs will be reported using the Kaplan-
Meier product limit methods. In addition, the proportion of patients who are alive at 12 months 
will be reported.
Lung cancer mortality (NSCLC-related deaths)
The median time to NSCLC-related death together with the corresponding 95% CIs will be 
reported using the Kaplan-Meier product limit methods.
Objective response rate
The ORR, based on Investigator assessments (following RECIST 1.1 criteria; see Appendix F), 
together with the corresponding 95% CIs will be reported.
Duration of response
The average DoR will also be calculated for responders. If appropriate, CIs will be used to 
characterize the precision of the estimate.
9.5.2.3
Patient-reported outcomes
 
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Table 12
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n
 
 
 
 
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SUBGROUP ANALYSIS
Summaries for endpoints of interest by subgroup will be detailed in the SAP.
9.6
Interim analysis
No formal interim analysis is planned for this study.
9.6.1
Steering committee
If required, a SC will be assembled by AstraZeneca for the executive oversight and supervision 
of the study. The SC will consist of oncology experts and a statistician who serve their role 
through regular scheduled meetings or teleconferences and, if necessary, additional ad hoc 
meetings. Details of the SC remit, procedures, processes, and meeting frequency will be outlined 
in an SC Charter.
9.7
Data management by AstraZeneca or delegate
Data management will be performed by a Contract Research Organization according to the Data 
Management Plan.
Any data collected through third party sources will be obtained and reconciled against study 
data. Data queries will be raised for inconsistent, impossible, or missing data. All entries to the 
study database will be available in an audit trail. The data will be validated as defined in the Data 
Management Plan. Quality control procedures will be applied to each stage of data handling to 
ensure that all data are reliable and have been processed correctly. The Data Management Plan 
will also clarify the roles and responsibilities of the various functions and personnel involved in 
the data management process. When all data have been coded, validated, signed, and locked, 
clean file will be declared, and the final database will be locked.
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10
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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 as amended at 64th WMA General Assembly, Fortaleza, Brazil, 
October 2013 and Council for International Organizations of Medical Sciences
(CIOMS) International Ethical Guidelines

Applicable ICH GCP Guidelines

Applicable laws and regulations

The protocol, revised protocol, ICF, IB, 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 revised protocol will require IRB/IEC and applicable Regulatory Authority approval 
before implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study patients.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
contract research organization, but the accountability remains with AstraZeneca.

The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR 312.120, ICH guidelines, the IRB/IEC,
European Regulation 536/2014 for clinical studies (if applicable), European Medical Device 
Regulation 2017/745 for clinical device research (if applicable), and all other applicable 
local regulations.
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
Regulatory Reporting Requirements for Serious Breaches of Protocol or GCP
Prompt notification by the Investigator to AstraZeneca of any (potential) serious breach of the 
protocol or regulations is essential so that legal obligations and ethical obligations are met.


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
A “serious breach” means a breach likely to affect to a significant degree the safety and 
rights of a patient or the reliability and robustness of the data generated in the clinical trial.
AstraZeneca will comply with country-specific regulatory requirements relating to serious 
breach reporting to the regulatory authority , IRB/IEC, and Investigators.

Where the EU Clinical Trials Regulation 536/2014 applies, AstraZeneca has in place 
processes to enter details of serious breaches into the European Medicines Agency Clinical 
Trial Information System (CTIS). It is important to note that redacted versions of serious 
breach reports will be available to the public via CTIS.
If any (potential) serious breach occurs in the course of the study, Investigators or other site 
personnel will inform the appropriate AstraZeneca representatives immediately.
In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches.
The investigator should have a process in place to ensure that:

The site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach.

A (potential) serious breach is promptly reported to AstraZeneca or delegated party, through 
the contacts (email address or telephone number) provided by AstraZeneca.
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.
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 requirements, where applicable, and the IRB/IEC or study center.


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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.
If a patient’s partner becomes pregnant during or 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.
A 4
Data protection
Patients will be assigned a unique identifier by AstraZeneca. Any patient records or datasets that 
are transferred to AstraZeneca will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred.

The patient must be informed that their personal study-related data will be used by 
AstraZeneca in accordance with local data protection law. The level of disclosure and use of 
their data must also be explained to the patient in the informed consent. 

The patient must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by AstraZeneca, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.

The patient must be informed that data will be collected only for the business needs. We will 
only collect and use the minimum amount of personal data to support our business activities 


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and will not make personal data available to anyone (including internal staff) who is not 
authorised or does not have a business need to know the information. 

The patient must be informed that in some cases their data may be pseudonymised. The 
General data Protection Regultaion defines pseudonymisation as the processing of personal 
data in such a way that the personal data can no longer be attributed to a specific individual 
without the use of additional information, provided that such additional information is kept 
separately and protected by technical and organisational measures to ensure that the personal 
data are not attributed to an identified or identifiable natural person.
Personal Data Breaches
A ‘personal data breach’ means a breach of security leading to the accidental or unlawful 
destruction, loss, alteration, unauthorised disclosure of, or access to, personal data transmitted, 
stored or otherwise processed.

In compliance with applicable laws, the Data Controller1 for the processing activity where 
the personal data breach occurred (AstraZeneca or respectively the site), will notify the data 
protection authorities without undue delay within the legal terms provided for such 
notification and within the prescribed form and content.

Whilst AstraZeneca has processes in place to deal with personal data breaches it is important 
that investigators that work with AstraZeneca have controls in place to protect patient data 
privacy.
The Investigator should have a process in place to ensure that:

Allow site staff or service providers delegated by the investigator/institution to identify the 
occurrence of a (potential) personal data breaches.

Any (potential) personal data breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (e-mail address or telephone number) provided by AstraZeneca.
AstraZeneca and the site must demonstrate that they:

Have taken all necessary steps to avoid personal data breaches and 

Have undertaken measures to prevent such breaches from occurring in the first place and to 
mitigate the impact of occurred data breaches (eg, applying encryption, maintaining and 
                                               
1 The data controller determines the purposes for which and the means by which personal data 
is processed, as defined by the European Commission


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keeping systems and IT security measures up-to-date, regular reviews and testing, regular 
training of employees, and developed security policies and standards).

Where possible, have developed an internal data breach reporting and investigation process 
and internal protocols with guidance on how to respond swiftly and diligently to the 
occurrence of a personal data breach.

Where it has not been possible to develop an internal data breach reporting and investigation 
process, the site follows AstraZeneca’s instructions.
Notification of personal Data Breach to patients:

Notification to patients is done by the site for the data breaches that occurred within the 
processing activities for which the site is the Data Controller and for data breaches occurred 
within the processing activities of AstraZeneca as the Data Controller, the notification is 
done in collaboration with the site and is performed by the site and/or Principal Investigator, 
acting on behalf of AstraZeneca, so that AstraZeneca has no access to the identifying 
personal information of the patients. The site and/or Principal Investigator shall conduct the 
notification by contacting the patients using the information that they gave for 
communication purposes in clinical research.

If a personal data breach occurs in a processor’s systems, engaged by AstraZeneca, the 
processor under contractual obligations with AstraZeneca promptly and in due course after 
discovering the breach notifies AstraZeneca and provides full cooperation with the 
investigation. In these cases, to the extent AstraZeneca is the Data Controller for the 
processing activity where the breach occurred, it will be responsible for the notification to 
data protection authorities and, if applicable, to patients. If the personal data breach needs to 
be notified to the patients, the notification to patients is done in collaboration with the site 
and is performed by the site and/or Principal Investigator, acting on behalf of the Sponsor, 
so that AstraZeneca has no access to the identifying personal information of the patients.

If a personal data breach involving an AstraZeneca's representative device (ie, Study 
Monitor laptop), AstraZeneca representative will provide will provide AstraZeneca with all 
of the information needed for notification of the breach, without disclosing data that allows 
AstraZeneca directly or indirectly to identify the patients. The notification will be done by 
AstraZeneca solely with the information provided by the Study Monitor and in no event with 
access to information that could entail a risk of re-identification of the patients. If the data 
breach must be notified to the data subjects, the notification will be done directly by the 
Study Monitor in collaboration with the site and/or Principal Investigator, acting on behalf 
of the Sponsor, so that AstraZeneca has no access to the identifying personal information of 
the patients. The contract between AstraZeneca and the Study Monitor shall expressly 
specify these conditions.

The contract between the site and AstraZeneca for performing the clinical research includes 
the provisions and rules regarding who is responsible for coordinating and directing the 
actions in relation to the breaches and performing the mandatory notifications to authorities 
and patients, where applicable.


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A 5
Committee 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
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS within 
a half a year from global End of Trial Date in all participating countries, due to scientific 
reasons, as otherwise statistical analysis is not relevant.
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and
http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical 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.
A 7
Data quality assurance
All patient data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for a minimum of 25 years after study archiving or as required by 
local regulations, according to the AstraZeneca Global retention and Disposal (GRAD) 
Schedule. No records may be destroyed during the retention period without the written approval 


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of the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
A 8
Source documents
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.
All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the reconstruction and evaluation 
of the study are defined as source documents. Source data are contained in source documents 
(original records or certified copies).
A 9
Publication policy
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments.
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
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.


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Appendix B
Adverse event definitions and additional safety information
B 1
Definition of adverse events
An adverse event (AE) 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 nonserious 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 events
A serious adverse event (SAE) is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfills one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability or incapacity

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the patient or may require medical 
treatment to prevent one of the outcomes listed above
AEs for malignant tumors reported during a study should generally be assessed as serious. 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 nonserious AE. For 
example, if the tumor 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 tumors, 
which do not spread remotely after a routine treatment that does not require hospitalization, may 
be assessed as nonserious; examples include Stage 1 basal cell carcinoma and Stage 1A1 cervical 
cancer removed via cone biopsy.
The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (ie, it is not the tumor for which entry into the study is a criterion and that is 


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being treated by the IP under study and is not the development of new or progression of existing 
metastasis to the tumor under study). 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.
B 3
Life-threatening
“Life-threatening” means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death. “Life-threatening” does not mean that had an AE occurred in a more severe form it might 
have caused death (eg, hepatitis that resolved without hepatic failure).
B 4
Hospitalization
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the patient was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study.
B 5
Important medical event or medical treatment
Medical and scientific judgment 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, hospitalization, 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 anemia requiring blood transfusion, etc) or convulsions 
that do not result in hospitalization

Development of drug dependency or drug abuse


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B 6
CTCAE Grade
The grading scales found in the revised National Cancer Institute CTCAE version 5.0 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.
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 an 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 an 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 etiology 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?


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Causality of “related” is made if following a review of the relevant data, there is evidence for a 
“reasonable possibility” of a causal relationship for the individual case. The expression 
“reasonable possibility” of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough information 
to make an informed judgment. With limited or insufficient information in the case, it is likely 
that the event(s) will be assessed as “not related.”
Causal relationship in cases where the disease under study has deteriorated due to lack of effect 
should be classified as no reasonable possibility.
B 8
Medication error, Drug Abuse, and Drug Misuse
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IP or AstraZeneca NIP that either causes harm to the patient or has 
the potential to cause harm to the patient.
A medication error is not lack of efficacy of the drug, but rather a human or process-related 
failure while the drug is in control of the study site staff or patient.
Medication error includes situations where an error:

Occurred

Was identified and intercepted before the patient received the drug

Did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to the 
patient

Drug not administered as indicated, eg, 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 refrigerator when it should be at room 
temperature

Wrong patient received the medication (excluding IRT/RTSM errors)

Wrong drug administered to patient (excluding IRT/RTSM errors)


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Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT/RTSM - including those which lead to one of the 
above listed events that would otherwise have been a medication error

Patient accidentally missed drug dose(s), eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Patient failed to return unused medication or empty packaging
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IP or AstraZeneca NIP for a perceived reward or desired 
non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the data entry site using the Drug Abuse Report Form. This form should be used both if the drug 
abuse happened in a study patient or if the drug abuse involves a person not enrolled in the study 
(such as a relative of the study patient).
Examples of drug abuse include but are not limited to:

The drug is used with the intent of getting a perceived reward (by the study patient or a 
person not enrolled in the study)

The drug in the form of a tablet is crushed and injected or snorted with the intent of getting 
high
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study patient) of IP or AstraZeneca 
NIP for medicinal purposes outside of the authorised product information, or for unauthorised 
IPs or AstraZeneca NIPs, outside the intended use as specified in the protocol and includes 
deliberate administration of the product by the wrong route.
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to the 
data entry site using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a study patient or if the drug misuse regards a person not enrolled in the 
study (such as a relative of the study patient).
Examples of drug misuse include but are not limited to:

The drug is used with the intention to cause an effect in another person


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
The drug is sold to other people for recreational purposes 

The drug is used to facilitate assault in another person

The drug is deliberately administered by the wrong route

The drug is split in half because it is easier to swallow, when it is stated in the protocol that 
it must be swallowed whole

Only half the dose is taken because the study patient feels that he/she is feeling better when 
not taking the whole dose

Someone who is not enrolled in the study intentionally takes the drug








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Appendix E
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately report 
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. Specific guidance on 
managing liver abnormalities can be found in the Dosing Modification and Toxicity 
Management Guidelines (see Section 8.4.5.1).
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a patient meets 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 AE 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 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 IP.
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
AEs and SAEs according to the outcome of the review and assessment in line with standard 
safety reporting processes.
E 2
Definitions
Potential Hy’s law
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN 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
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, other than the 
IP, can be found to explain the combination of increases, eg, elevated ALP indicating cholestasis, 
viral hepatitis, another drug.
For PHL and HL, the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified time frame within which the elevations 
in transaminases and TBL must occur.
E 3
Identification of potential Hy’s law cases
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any patient who meets any of the following identification criteria in isolation or in 
combination:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Notify the AstraZeneca representative

Determine whether the patient meets PHL criteria (see Appendix E 2 for definition) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory CRF
E 4
Follow-up
E 4.1
Potential Hy’s law criteria not met
If the patient does not meet PHL criteria the Investigator will:

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 (CSP).


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E 4.2
Potential Hy’s law criteria met
If the patient does meet PHL criteria the Investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study treatment 
(see Appendix E 6).

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 
PHL (meeting serious criteria for “important medical event”) with causality assessment 
“yes/related” according to CSP process for SAE reporting

For patients that met PHL criteria prior to starting study treatment, the Investigator is not 
required to submit a PHL SAE unless there is a significant change# in the patient’s condition

The Study Physician will contact the Investigator to provide guidance, discuss, and agree on 
an approach for the study patients’ follow-up (including any further laboratory testing) and 
the continuous review of data

Subsequent to this contact the Investigator will:

Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated

Complete the follow-up SAE Form as required

Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician

Complete the 3 Liver eCRF Modules as information becomes available
#
A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Study Physician if there is any uncertainty.
E 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 is initially detected, the Study Physician
will contact 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 study treatment, 
and to ensure timely analysis and reporting to health authorities within 15 calendar days from the 
date PHL criteria was met. The AZ Global Clinical Lead or equivalent and Global Safety 
Physician will also be involved in this review together with other subject matter experts as 
appropriate.


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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 SAE: update the previously submitted PHL SAE eCRF 
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 study treatment:

Send updated SAE (report term ‘Hy’s Law’) according to AZ standard processes.

The “important medical event” serious criterion should be used if no other serious 
criteria apply.

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay of over 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. In this case, the 
Investigator will follow the instructions below:

Provide any further update to the previously submitted SAE of PHL (report term now ‘Hy’s 
Law case’), ensuring causality assessment is related to study treatment 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.
E 6
Actions required when potential Hy’s law criteria are met before 
and after starting study treatment
This section is applicable to patients with liver metastases who meet PHL criteria on-study 
treatment having previously met PHL criteria at a study visit prior to starting study treatment.


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At the first on-study treatment occurrence of PHL criteria being met, the Investigator will 
determine if there has been a significant change in the patient’s condition# compared with the 
last visit where PHL criteria were met#.

If there is no significant change, no action is required

If there is a significant change, notify the AstraZeneca representative, who will inform the 
central Study Team, then follow the subsequent process described in Appendix E 4.2.
#
A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Study Physician if there is any uncertainty.
E 7
Actions required for repeat episodes of potential Hy’s law
This section is applicable when a patient meets PHL criteria on-study treatment, and has already 
met PHL criteria at a previous on-study treatment visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence.
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found to be the 
disease under study (eg, chronic or progressing malignant disease, severe infection or liver 
disease), or did the patient meet PHL criteria prior to starting study treatment and at first 
on-study treatment visit, as described in Appendix E 6?
If No: Follow the process described in Appendix E 4.2 for reporting PHL as an SAE.
If Yes: Determine if there has been a significant change in the patient’s condition# compared 
with when PHL criteria were previously met.

If there is no significant change, no action is required

If there is a significant change, follow the process described in Appendix E 4.2 for reporting 
PHL as an SAE.
#
A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Study Physician if there is any uncertainty.


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Appendix F
Guidelines for evaluation of objective tumor response using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid 
Tumors)
Introduction
This appendix details the implementation of Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 guidelines (Eisenhauer et al 2009) for this study with regard to Investigator 
assessment of tumor burden including protocol-specific requirements for this study. Additional 
special guidance is provided for determination of Confirmation of Radiological Progression.
Definitions of measurable, nonmeasurable, target, and nontarget lesions
Measurable:
A lesion that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except 
lymph nodes which must have a short axis2diameter of ≥ 15 mm) with CT or MRI and which is 
suitable for accurate repeated measurements.
Nonmeasurable:

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)

Truly nonmeasurable lesions include the following: bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitic involvement 
of skin or lung, and abdominal masses/abdominal organomegaly identified by physical 
examination (manual palpation) that is not measurable by CT or MRI

Brain metastasis
Special cases:

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue components, 
can be considered measurable if the soft tissue component meets the definition of 
measurability. Blastic lesions are considered nonmeasurable.
                                               
2 The short axis is defined as the longest axis perpendicular to long axis
3 Lymph nodes with < 10 mm short axis diameter are considered nonpathological and should not be recorded or 
followed as NTLs.


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
Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if noncystic lesions are present in the 
same patient, these should be selected over cystic lesions as TLs.
Target lesions:
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative of 
all lesions involved suitable for accurate repeated measurement, should be identified as TLs at 
baseline. Lymph nodes, in any location (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.
A previously irradiated lesion may be selected as a TL provided it fulfills the criteria for 
reproducible measurability and is the only lesion available.
Tumor lesions selected for fresh screening biopsy should not be selected as TLs, unless imaging 
occurred at least ~2 weeks after biopsy, allowing time for healing.
Nontarget lesions (NTLs):
Additional measurable lesions not recorded as TLs and nonmeasurable lesions (or sites of 
disease) should be identified as NTLs at baseline.
Imaging modalities
A summary of the imaging modalities to be used for RECIST 1.1 assessment of TL, NTL, and 
new lesions is provided in Table 14.
Table 14
Summary of imaging modalities for tumor assessment
Target Lesions 
Nontarget Lesions
New Lesions
CT (preferred)
MRI
CT (preferred)
MRI
Plain X-ray
Chest X-ray
CT (preferred)
MRI
Plain X-ray
Chest X-ray
Bone scan
FDG-PET/CT
CT = Computed tomography; FDG-PET/CT = 18F-Fluoro-deoxyglucose positron emission tomography/CT; 
MRI = Magnetic resonance imaging.


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CT and MRI
CT and MRI, each preferably with IV contrast, are generally considered to generate the best 
currently available and reproducible anatomical images for measurement of TL, assessment of 
NTL, and identification of any new lesions.
It is recommended that IV contrast-enhanced CT examinations of the chest and abdomen 
(including the entire liver and both adrenal glands) will be used to assess tumor burden at 
baseline and follow-up visits. Any other areas of disease involvement (eg, pelvis, brain) should 
be additionally imaged based on the signs and symptoms of individual patients. In patients who 
are sensitive to intravenous CT contrast, a noncontrast CT examination of the chest and an MRI 
with intravenous MRI contrast of the abdomen is appropriate. In patients with severely 
compromised renal function, a noncontrast CT examination of the chest and abdomen is 
appropriate. For brain lesion assessment, MRI with IV contrast is the preferred method over IV 
contrast-enhanced CT. It is strongly recommended to maintain use of the same imaging modality 
(CT or MRI), acquisition protocol, facility, and scanner across all imaging time points per 
patient.
Clinical examination
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will not 
be used for RECIST assessments. Tumors identified by clinical examination will need to be 
assessed by correlative CT or MRI anatomical scans.
Chest X-ray
Chest X-ray assessment will not be used for assessment of TL. Chest X-ray can, however, be 
used to assess NTL and to identify the presence of new lesions.
Plain X-ray
Plain X-ray may be used as a method of assessment for bone NTL and to identify the presence of 
new bone lesions.
Ultrasound
Ultrasound examination will not be used for RECIST assessment of tumors as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation and may not 
provide an accurate assessment of true tumor size. Tumors identified by ultrasound will need to 
be assessed by correlative CT or MRI anatomical scan.
Endoscopy and laparoscopy
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated in 
the context of tumor assessment.
Tumor markers
Tumor markers on cytological or histological (biopsy) samples will not be used for tumor 
response assessments as per RECIST 1.1.


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Histology and cytology
Histology on tumor biopsy samples will not be used as part of the tumor response assessment as 
per RECIST 1.1.
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, pleural effusion) that appears or worsens during the study will not be used 
as part of the tumor response assessment in this study. An effusion that appears or significantly 
worsens (from trace to large) radiologically by CT/MRI anatomical scans will be considered to 
be disease progression due to new lesions or progression of NTLs, respectively.
Isotopic bone scan
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or X-ray 
at baseline should be recorded as NTL and followed by the same method as per baseline 
assessment.
Isotopic bone scans may be used as a method of assessment to identify the presence of new bone 
lesions at follow-up visits. New lesions 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 which cannot be verified with correlative imaging (CT, MRI, X-ray) of 
the same anatomical region shall not be the only trigger for a PD assessment at that timepoint.
FDG-PET/CT
18F-Fluoro-deoxyglucose positron emission tomography/CT (FDG-PET/CT) scans may be used 
as a method for identifying new lesions, according to the following algorithm: New lesions will 
be recorded where there is positive FDG uptake4 not present on baseline or prior FDG-PET scan 
or in a location corresponding to a new lesion on CT/MRI at the same follow-up visit. If there is 
no baseline or prior FDG-PET scan available, and no evidence of new lesions on CT/MRI scans 
then follow-up CT/MRI assessments should be continued, scheduled as per protocol or clinical 
indicated, in order to verify new lesions.
At present, low dose or attenuation correction CT portions of a combined FDG-PET/CT scan are 
of limited use in anatomically-based efficacy assessments, and it is therefore suggested that they 
should not substitute for dedicated diagnostic contrast-enhanced CT scans for tumor 
                                               
4 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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measurements by RECIST 1.1. In exceptional situations, if a site can document that the CT 
performed, as part of a PET/CT examination, is of identical diagnostic quality (with intravenous 
contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT can be used for 
RECIST 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.
Tumor response evaluation
Schedule of evaluation
The methods of assessment of tumor burden used at baseline CT/MRI scans of the chest and 
abdomen (including the entire liver and both adrenal glands) must be used at each subsequent 
follow-up assessment. Additional imaging may be performed based on the signs and symptoms 
of the patient, eg, new lesions at follow-up.
Baseline assessments should be performed no more than 28 days before the first dose, and 
ideally should be performed as close as possible to the first dose. Efficacy by RECIST 1.1 for all 
patients will be assessed according to the schedules of activities. If an unscheduled assessment is 
performed, and the patient has not progressed, every attempt should be made to perform the 
subsequent assessments at their scheduled imaging visits.
Target lesions
Documentation of TLs
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including lymph 
nodes collectively considered as a single organ), representative of all lesions involved should be 
identified as TL at baseline. Target lesions should be selected on the basis of their size (longest 
diameter for non-nodal lesions or short axis 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 measurement in which 
circumstance the next largest lesion that can be measured reproducibly should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes). All measurements should be recorded in 
millimeters. At baseline the sum of the diameters for all TL will be calculated and reported as the 
baseline sum of diameters. At follow-up visits the sum of diameters for all TL will be calculated 
and reported as the follow-up sum of diameters.
Special cases:

For TL measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis 
diameter.


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
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.

If a TL splits into 2 or more parts, then record the sum of the diameters of those parts.

If 2 or more TLs merge then the sum of the diameters of the combined lesion should be 
recorded for one of the lesions and 0 mm recorded for the other lesion(s).

If a TL is believed to be present and is faintly seen but too small to measure, a default value 
of 5 mm should be assigned. If an accurate measure can be given, this should be recorded, 
even if it is below 5 mm.

If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion.

When a TL has had any intervention eg, definitive radiotherapy, embolization, surgery, etc 
during the study, the size of the TL should still be provided where possible and the 
intervention recorded in the RECIST case report form. If a TL has been completely removed 
(surgery), the longest diameter should be recorded as 0 mm.


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Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TL (see Table 15).
Table 15
Evaluation of target lesions
Complete response (CR)
Disappearance of all TLs since baseline. Any pathological lymph 
nodes selected as TLs must have a reduction in short axis 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 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 also 
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.
CR = Complete response; NE = Not Evaluable; PR = Partial response; PD = Progression of disease; SD = Stable 
disease; TL = Target lesion.
Nontarget lesions
Evaluation of NTLs
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline. 
Measurements are not required for these lesions, but their status should be followed at 
subsequent visits. At each visit an overall assessment of the NTL response should be recorded by 
the Investigator. This section provides the definitions of the criteria used to determine and record 
overall response for NTL at the investigational site at each visit (see Table 16).


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


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Patients with “symptomatic deterioration” requiring discontinuation of treatment without 
objective radiologic evidence of disease progression at that time should continue to undergo 
tumor assessments where clinically feasible.
Evaluation of overall visit response
The overall visit response will be derived using the algorithm shown in Table 17.
Table 17
Overall visit response
Target lesions
Nontarget lesions
New lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
CR
NonCR/NonPD 
No
PR
CR
NE
No 
PR
PR
NonPD or NE
No
PR
SD 
NonPD or NE
No
SD
NE
NonPD or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = Complete response; NA = Not applicable (only relevant if there were no target and/or NTLs at baseline); 
NE = Not Evaluable; NTL = Nontarget lesion; PD = Progression of disease; PR = Partial response; SD = Stable 
disease.
Confirmation of Radiological Progression
A follow-up scan is collected after the initial RECIST 1.1-defined PD, preferably at the next (and 
no later than the next) scheduled imaging visit, and no less than 4 weeks after the prior 
assessment of PD, and the Confirmation of Radiological Progression criteria described below are 
applied for tumor assessments of this follow-up scan. Patients with confirmed radiological PD 
who continue to receive study treatment at the discretion of the Investigator and patient 
(following consultation with AstraZeneca) can receive treatment until no longer having clinical 
benefit, and will continue to have tumor assessments on their regular imaging schedule for the 
duration of treatment.
Confirmation of Radiological Progression guidelines are set for the following reasons:

For patient management and treatment decisions

In the absence of significant clinical deterioration, to promote the collection of additional 
scans after the first radiologic RECIST 1.1 assessment of PD in order to distinguish 
pseudoprogression from true radiologic progression.


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Confirmation of Radiological Progression criteria:
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 (acquired preferably at the next 
regularly scheduled imaging visit but no sooner than 4 weeks after the RECIST 1.1-defined PD 
scan):

≥ 20% increase in the sum diameters of TLs compared with the nadir at 2 consecutive visits, 
each with an absolute increase of at least 5 mm in sum of diameters compared to nadir (as 
per RECIST 1.1 definition)

and/or significant progression (worsening) of NTLs at the follow-up scan timepoint 
compared with the immediate prior timepoint (as per RECIST 1.1 definition)

and/or significant progression (worsening) of pre-existing new lesions at the follow-up scan 
timepoint compared with the immediate prior timepoint (unique definition)

and/or additional (brand) new unequivocal lesions at the follow-up scan timepoint (as per 
RECIST 1.1 definition)
NOTE: In order to have confirmed radiological progression, there should be 2 consecutive 
assessments meeting the PD definition: the first PD by RECIST 1.1 and the second PD using the 
Confirmation of Radiological Progression criteria (above). If the first assessment fulfilling the 
PD definition by RECIST 1.1 is not confirmed, in the absence of significant clinical 
deterioration, then the patient may continue with assessments until the next PD by RECIST 1.1, 
which will also require a follow-up scan evaluated using the Confirmation of Radiological 
Progression criteria. If the first PD (by RECIST 1.1) is not confirmed by the immediate next 
scan, then the Investigator should not change the PD assessment of the first scan.
Specifications for anatomical imaging
These notes are recommendations for use in clinical studies. The use of standardized protocols 
for CT and MRI allows comparability both within and between different studies, irrespective of 
where the examination has been undertaken.
CT scan
CT scans of the chest and abdomen (and pelvis when indicated) should be contiguous throughout 
all the anatomic region of interest.
The most critical CT image acquisition parameters for optimal tumor evaluation using 
RECIST 1.1 are anatomic coverage, contrast administration, slice thickness, and reconstruction 
interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumors is the chest, abdomen, 
and pelvis. Coverage should encompass all areas of known predilection for metastases in the 
disease under evaluation and should additionally investigate areas that may be involved based on 


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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 time points. This will enable better consistency not only of tumor 
measurements but also identification of new disease.
b. IV contrast administration: Optimal visualization and measurement of metastases in solid 
tumors requires consistent administration (dose and rate) of IV contrast as well as timing of 
scanning. Typically, most abdominal imaging is performed during the portal venous phase and 
(optimally) about the same time frame after injection on each examination. An adequate volume 
of a suitable contrast agent should be given so that the metastases are demonstrated to best effect 
and a consistent method is used on subsequent examinations for any given patient. It is very 
important that the same technique be used at baseline and on follow-up examinations for a given 
patient. For patients who develop contraindications to contrast after baseline contrast CT is done, 
the decision as to whether noncontrast CT or MRI (enhanced or nonenhanced) should be 
performed should also be based on the tumor type, anatomic location of the disease and should 
be optimized to allow for comparison to the prior studies if possible. Each case should be 
discussed with the radiologist to determine if substitution of these other approaches is possible 
and, if not, the patient should be considered not evaluable from that point forward. Care must be 
taken in measurement of TLs on a different modality and interpretation of nontarget disease or 
new lesions, since the same lesion may appear to have a different size using a new modality. 
Oral contrast is recommended to help visualize and differentiate structures in the abdomen.
If iodine contrast media is medically contraindicated at baseline or at any time during the course 
of the study then the recommended methods are: CT thoracic (chest) examination without 
contrast and abdominal (and pelvis) MRI with contrast. If MRI cannot be performed then CT 
without IV contrast is an option for the thorax and abdomen (and pelvis) examination. For brain 
imaging, MRI with IV contrast is the preferred method.
c. Slice thickness and reconstruction interval: It is recommended that CT scans be performed 
at 5 mm contiguous slice thickness and this guideline presumes a maximum 5 mm thickness in 
recommendations for measurable lesion definition. Exceptionally, particular institutions may 
perform medically acceptable scans at slice thicknesses greater than 5 mm. If this occurs, the 
minimum size of measurable lesions at baseline should be twice the slice thickness of the 
baseline scans.
All window settings should be included in the assessment, particularly in the thorax where lung 
and soft tissue windows should be considered. When measuring lesions, the TL should be 
measured on the same window setting for repeated examinations throughout the study. All 
images from each examination should be included in the assessment and not “selected” images 
of the apparent lesion.


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MRI scan
MRI has excellent contrast, spatial and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity 
and measurement. Furthermore, the availability of MRI is variable globally. The modality used 
at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. Generally, axial imaging of the abdomen and 
pelvis (and other anatomies [eg, neck]) with T1 and T2 weighted imaging along with 
gadolinium-enhanced imaging can be performed. The field of view, matrix, number of 
excitations, phase encoding steps, use of fat suppression and fast sequences should be optimized 
for the specific body part being imaged as well as the scanner utilized. CT of the chest is 
typically recommended over MRI due to significant motion artifacts (heart, major blood vessels, 
breathing) associated with MRI. It is beyond the scope of this appendix to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans. Body scans should be performed with breath-hold scanning techniques if 
possible.
For these reasons, CT is the imaging modality of choice.
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
Abbreviations
Abbreviation or 
special term
Explanation
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BED
bioequivalent dose
BP
blood pressure
C
cycle
cCRT
concurrent chemotherapy and radiotherapy
CD
cluster of differentiation
CI
confidence interval
CL
clearance
COA
Clinical Outcome Assessment
CR
complete response
CRF
case report form (electronic/paper)
CRP
C-reactive protein 
CRT
chemotherapy and radiotherapy
CSP
Clinical Study Protocol
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTIS
Clinical Trial Information System
CTLA-4
cytotoxic T-lymphocyte-associated antigen-4
DCO
data cutoff
DILI
drug induced liver injury
DoR
duration of response
DNA
deoxyribonucleic acid 
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
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eCRF
electronic case report form
EDC
electronic data capture
FDG-PET/CT
18F-Fluoro-deoxyglucose positron emission tomography/computed 
tomography
GCP
Good Clinical Practice
Gy
gray
HBsAg
hepatitus B virus surface antigen
HIV
human immunodeficiency virus
HL
Hy’s Law
HR
hazard ratio
HRCT
high-resolution computed tomography
IASLC
International Association for the Study of Lung Cancer
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
ICF
Informed Consent Form
IEC
independent ethics committee, synonymous to IRB
IFN-γ
interferon gamma
IgG
immunoglobulin G
IHC
immunohistochemistry
ILD
interstitial lung disease
imAE
immune-mediated adverse event
IP
Investigational Product
IRB
institutional review board, synonymous to ethics committee (EC) and 
independent ethics committee (IEC)
IRT
Interactive Response Technology
IV
intravenous
LDH
lactate dehydrogenase
mAb
monoclonal antibody
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RT-QPCR
reverse transcription quantitative polymerase chain reaction
RTSM
Randomisation and Trial Supply Management
SAE
serious adverse event 
SAP
statistical analysis plan
SC
Steering Committee
SD
stable disease
SoA
schedule of activities
sPD-L1
soluble programmed death ligand 1
SPO2
saturation of peripheral oxygen
T4
thyroxine
TBL
total bilirubin
TL
target lesion
TMG
toxicity management guidelines
ULN
upper limit of normal
WHO
World Health Organization


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: d4194C00009-csp-v2
Document Title:
D4194C00009 Clinical Study Protocol version 2
Document ID:
Doc ID-004099623
Version Label:
2.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
11-Sep-2023 16:00 UTC
Content Approval
12-Sep-2023 14:34 UTC
Management Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
PPD

SAP_003.pdf: 
A Phase II, Open-label, Multicenter, International Study of 
Durvalumab Following Radiation Therapy in Patients with 
Stage III, Unresectable Non- Small Cell Lung Cancer Who 
Are Ineligible for Chemotherapy (DUART) 
ClinicalTrials.gov Identifier: NCT04249362 
Statistical Analysis Plan Final 2.0, 12 Jan 2024
Statistical Analysis Plan  
Study Code D4194C00009 
Edition Number 2.0  
Date 12 January 2024 


Statistical Analysis Plan 
Study Code 
D4194C00009 
Edition Number 
2.0 
Date 
12 January 2024 
A Phase II, Open-label, Multicenter, International Study of Durvalumab 
Following Radiation Therapy in Patients with Stage III, Unresectable Non- 
Small Cell Lung Cancer Who Are Ineligible for Chemotherapy (DUART) 


Statistical Analysis Plan  
Study Code D4194C00009 
Edition Number 2.0  
Date 12 January 2024 
2
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ........................................................................................................... 1
TABLE OF CONTENTS ......................................................................................... 2
LIST OF TABLES ................................................................................................... 5
LIST OF ABBREVIATIONS .................................................................................. 6
AMENDMENT HISTORY ................................................................................... 10
1.
STUDY DETAILS ................................................................................................. 12
1.1
Study Objectives .................................................................................................... 12
1.1.1
Primary Objective .................................................................................................. 12
1.1.2
Secondary Objectives ............................................................................................. 12
1.1.3
Exploratory Objectives .......................................................................................... 13
1.2
Study Design .......................................................................................................... 14
1.2.1
Study Treatment ..................................................................................................... 15
1.2.2
Tumor Response Assessments ............................................................................... 16
1.2.3
Overall Survival Assessments ................................................................................ 17
1.3
Number of Patients ................................................................................................ 17
2.
ANALYSIS SETS ................................................................................................. 18
2.1
Definition of Analysis Sets .................................................................................... 18
2.1.1
Safety Analysis Set ................................................................................................ 18
2.2
Protocol Deviations ................................................................................................ 18
2.2.1
Important Protocol Deviations ............................................................................... 18
2.2.2
Monitoring of Protocol Deviations ........................................................................ 20
3.
ANALYSIS VARIABLES .................................................................................... 21
3.1
Derivation of RECIST Visit Responses ................................................................. 21
3.1.1
Site Investigator Assessments Using RECIST 1.1 ................................................ 22
3.1.1.1
Target Lesions ........................................................................................................ 22
3.1.1.2
Non-Target Lesions and New Lesions. .................................................................. 26
3.1.1.3
Overall Visit Response .......................................................................................... 28
3.2
Safety Variables ..................................................................................................... 28
3.2.1
Primary Safety Endpoint ........................................................................................ 28
3.2.2
Secondary Safety Endpoints .................................................................................. 28
3.2.3
Adverse Events ...................................................................................................... 29
3.2.3.1
Possibly-Related Adverse Events .......................................................................... 29
3.2.3.2
Adverse Events of Special Interest and AEs of Possible Interest .......................... 29
3.2.3.3
Immune-Mediated Adverse Event (ImAE) ............................................................ 30


Statistical Analysis Plan  
Study Code D4194C00009 
Edition Number 2.0  
Date 12 January 2024 
3
3.2.3.4
Confirmed/Suspected COVID-19 infections ......................................................... 30
3.2.4
Electrocardiograms ................................................................................................ 31
3.2.5
Vital Signs .............................................................................................................. 31
3.2.6
Laboratory Data ..................................................................................................... 31
3.2.7
Physical Examination ............................................................................................. 32
3.2.8
Exposure to Durvalumab ....................................................................................... 32
3.3
Efficacy Variables .................................................................................................. 34
3.3.1
Progression-Free Survival ...................................................................................... 34
3.3.2
Overall Survival ..................................................................................................... 35
3.3.3
Objective Response Rate ....................................................................................... 35
3.3.4
Best Objective Response ........................................................................................ 36
3.3.5
Duration of Response ............................................................................................. 36
3.3.6
Lung Cancer Mortality ........................................................................................... 37
3.4
 ............................................................................................ 37
3.4.1
 .................................................................................... 37
3.4.1.1
 ......................................................... 38
3.4.1.2
 ......................................................................................................... 40
3.4.2
 ........................................ 41
3.4.3
 .......................................................................... 41
3.5
Other Variables ...................................................................................................... 42
3.5.1
Baseline Characteristics ......................................................................................... 42
3.5.2
Prior and Concomitant Medications and Therapies ............................................... 42
3.5.3
............................................................................................................. 43
4.
ANALYSIS METHODS ....................................................................................... 43
4.1
General Principles .................................................................................................. 43
4.1.1
General Statistical Considerations ......................................................................... 43
4.1.2
General Considerations for Summary of Safety Data ............................................ 45
4.1.3
Handling of Missing Data ...................................................................................... 45
4.1.4
Definitions of Visit Windows ................................................................................ 46
4.1.4.1
Visit Windows for Safety and PRO Assessments .................................................. 46
4.1.4.2
Visit Windows for Tumor Assessments................................................................. 47
4.2
Study Population .................................................................................................... 48
4.2.1
Patient Disposition ................................................................................................. 48
4.2.2
Protocol Deviations ................................................................................................ 48
4.2.3
Demography and Baseline Characteristics ............................................................ 48
4.2.4
Previous and Concomitant Medications and Procedures ....................................... 49
4.2.5
Study Drug Administration .................................................................................... 49
4.3
Analysis of Primary Safety Endpoint..................................................................... 49
4.4
Analysis of Secondary Efficacy Endpoints ............................................................ 50
4.4.1
Progression-Free Survival ...................................................................................... 50
4.4.2
Overall Survival ..................................................................................................... 50
4.4.3
Objective Response Rate ....................................................................................... 50
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Statistical Analysis Plan  
Study Code D4194C00009 
Edition Number 2.0  
Date 12 January 2024 
4 
4.4.4 
Duration of Response ............................................................................................. 50 
4.4.5 
Time to Lung Cancer Mortality (NSCLC-Related Death)..................................... 51 
4.5 
Analysis of Secondary Safety Endpoints ............................................................... 51 
4.5.1 
Adverse Events ...................................................................................................... 51 
4.5.1.1 
Adverse Events of Special Interest and Possible Interest ...................................... 53 
4.5.1.2 
Immune-mediated Adverse events (imAEs) .......................................................... 54 
4.5.1.3 
COVID-19 related Adverse events ........................................................................ 54 
4.5.2 
Electrocardiograms ................................................................................................ 54 
4.5.3 
Vital Signs .............................................................................................................. 55 
4.5.4 
Laboratory Data ..................................................................................................... 55 
4.5.4.1 
Liver Enzyme Elevations and Hy's Law ................................................................ 55 
4.5.4.2 
Assessment of Thyroid Function Test Results ....................................................... 56 
4.5.4.3 
Assessment of Renal Function Test Abnormalities ............................................... 56 
4.5.5 
Exposure ................................................................................................................ 57 
4.6 
Analysis of Exploratory Endpoints ........................................................................ 57 
4.6.1 
 ......................................................... 57 
4.6.2 
......................................................................................................... 58 
4.6.3 
 .......................................................................... 58 
4.6.4 
............................................................................................................. 58 
4.6.5 
 .................................................................................................. 58 
5. 
INTERIM ANALYSES ......................................................................................... 58 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL ............................................... 58 
7. 
REFERENCES ...................................................................................................... 59 
8. 
APPENDIX ............................................................................................................ 61 
 
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Statistical Analysis Plan  
Study Code D4194C00009 
Edition Number 2.0  
Date 12 January 2024 
5 
LIST OF TABLES 
FIGURE 1 STUDY DESIGN .............................................................................................. 15 
TABLE 1    PRECISION AROUND VARYING INCIDENCE OF GRADE 3 AND 
GRADE 4 POSSIBLY-RELATED ADVERSE EVENTS .................................... 18 
TABLE 2  TARGET LESION VISIT RESPONSES .......................................................... 23 
TABLE 3  NTL VISIT RESPONSES ................................................................................. 27 
TABLE 4  OVERALL VISIT RESPONSES ...................................................................... 28 
TABLE 5  EXAMPLE DOSE INTENSITY SCENARIOS ................................................ 33 
TABLE 6  
 
 ........................................................................................ 39 
 
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Study Code D4194C00009 
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Date 12 January 2024 
6 
LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse event 
AEPI 
Adverse event of possible interest 
AESI 
Adverse event of special interest 
AJCC 
American Joint Committee on Cancer 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
Anti-HBc 
Hepatitis B core antibody 
AST 
Aspartate transaminase 
ATC 
Anatomical therapeutic chemical 
BED 
Bioequivalent dose 
BMI 
Body mass index 
BoR 
Best objective response 
BP 
Blood pressure 
cCRT 
Concurrent chemoradiation therapy 
CI 
Confidence interval 
COVID-19 
Corona virus disease-2019 
CR 
Complete response 
CrCl 
Creatinine clearance 
CRF 
Case Report Form 
CRT 
Chemoradiation therapy 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CT 
Computed tomography  
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Event 
 
 
DBL 
Database lock 
DBP 
Diastolic blood pressure 
DCO 
Data cut-off 
DoR 
Duration of response 
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Date 12 January 2024 
7 
Abbreviation or 
special term 
Explanation 
Dp 
Decimal place 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
  
  
 
 
 
 
 
 
 
Gy 
Gray 
HBsAg 
Hepatitis B virus surface antigen 
HIV 
Human immunodeficiency virus 
HL 
Hy’s Law 
 
 
IASLC  
International Association for the Study of Lung Cancer 
IASLC 2016 
IASLC Staging manual version 8 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International conference of harmonisation  
ICH 1995 
ICH guidelines version dated 1995 
ILD 
Interstitial lung disease  
imAE 
Immune-mediated adverse event 
IP 
Investigational product 
IPD 
Important protocol deviations 
IV 
Intravenous 
Kg 
Kilogram 
LD 
Longest diameter 
LLQ 
Lower limit of quantification 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
mOS 
Median overall survival 
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Date 12 January 2024 
8 
Abbreviation or 
special term 
Explanation 
MRI 
Magnetic resonance imaging 
MSSO 
Maintenance and Support Service Organization 
Msec 
Milliseconds 
NA 
Not applicable 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NED 
No evidence of disease 
NSCLC 
Non-Small Cell Lung Cancer 
NTL 
Non-target lesion 
OR 
Objective response 
ORR 
Objective response rate 
OS 
Overall survival 
OS12 
Proportion of patients alive at 12 months  
PD 
Progressive disease 
PD-L1 
Programmed cell death ligand 1 
PFS 
Progression-free survival 
PFS6 
Proportion of progression-free and alive patients at 6 months  
PFS12 
Proportion of progression-free and alive patients at 12 months 
 
 
 
 
PID 
Percentage intended dose 
PR 
Partial response  
PRAE 
Possibly related adverse event 
 
 
 
 
PS 
Performance status 
PT 
Preferred Term 
RDI 
Relative dose intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RT 
Radiation therapy 
q12w 
Every twelve weeks 
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Date 12 January 2024 
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Abbreviation or 
special term 
Explanation 
q4w 
Every four weeks 
 
 
 
 
 
 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RDI 
Relative dose intensity 
RECIST1.1 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
RS 
Raw score 
RTOG 
Radiotherapy Oncology Group 
RTOG 0617 
RTOG version 0617 
SAE 
Serious adverse event  
SAF 
Safety Analysis Set 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SBP 
Systolic blood pressure 
SC 
Steering Committee 
SD 
Stable disease / standard deviation 
SI 
International system (of units)  
simAE 
Suspected imAE 
SOC 
System Organ Class 
T3 
Tri-iodothyronine  
T4 
Thyroxine  
TEAE 
Treatment-emergent adverse event 
TL 
Target lesion 
 
 
TNM 
Tumor, node and metastasis 
PRAE 
Possibly related adverse event 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
WHO/ECOG PS 
World 
Health 
Organisation/Eastern 
Cooperative 
Oncology 
Group 
Performance Status 
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Statistical Analysis Plan  
Study Code D4194C00009 
Edition Number 2.0  
Date 12 January 2024 
10 
AMENDMENT HISTORY 
Date 
Brief description of change 
19th June 2020 
Initial version 1.0 
18 November 2020 Abbreviation for AEPI is added in list of abbreviations 
 
Updated from 3 to 4 general categories of IPD in section 2.2.1 
 
Text ‘and from time of the patients signed the informed consent and 30 days 
following last dose of the standard of care agents.’ removed from section 3.2.3 
 
Duration of dose delays updated in section 3.2.8 
 
Text added for unexpected questionnaires in section 3.4.1 
 
 
 
 
 
. 
 
Text added for previous disease-related radiotherapy and previous disease-
related cancer therapy in section 3.5.1 
 
Added text for definition of visit windows for survival follow-up (4.1.4.1) 
 
Units added for height, weight and bmi in section 4.2.3 
 
Changed to TEAE from AE in section 4.5.1 
 
Sign changed from >= to ≥  and =< to ≤ in section 4.2.3 and 4.5.4.2 in order to 
make it consistent. 
 
 
 
Section 5: Interim analysis text has been added 
11th February 2021 
In section 2.1.1 text for safety analysis is modified and patient reported safety 
analysis set (PROAS) is removed. 
PROAS removed from section 4.6 added updated text.  
PROAS removed from section 6 
New text added for rescreened patients in section 4.1.1 
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Statistical Analysis Plan  
Study Code D4194C00009 
Edition Number 2.0  
Date 12 January 2024 
11 
Date 
Brief description of change 
9th March 2021 
Section 3.2.3.3 updated based on AZ confirmation of internal adjudication of 
immune mediated AEs by AZ. Section 4.5.1.2 to remove wording for imAE 
charter 
7th May 2021 
 
 
 
 
 
 
 
Removed infection AEs (previous section 4.5.1.2) 
A new section 4.5.2 (Electrocardiogram) added to state that no summary or 
listing of ECG parameters will be presented.  
In section 6 (Changes of Analysis from Protocol) it is mentioned that ECG 
outputs will not be produced and only box plot for vitals will be presented. 
Section 4.5.5 (Therapy following discontinuation of Durvalumab) removed 
In section 4.2.1, more details added for last contact date. 
Cut-off for AE frequency has been changed from 5% to 2.5% in section 4.5.1 
Duration of AESI/AEPI and time to onset of first AESI/AEPI have been added 
in section 4.5.1.1 
Possibly related AESI/AEPI leading to discontinuation of study treatment has 
been added in section 4.5.1.1 
18th May 2021 and 
8th July 2021 
New text added for Covid-19 in section 3.2.3.4,  4.1.1, 4.2.1 and 4.2.2, 4.2.3, 
4.4.1, 0, 4.5.1.3 
8th July 2021 
 
06 Jul 2023 
Text added for Section 3.2.8 for dose delay 
06 Jul 2023 
Rules added for 2 missed visits for section 3.3.1  
06 Jul 2023 
Rules added for 2 missed visits for section 3.4.1.1 
06 Jul 2023 
Extra text added for handling of missing data in section 4.1.3 
05 January 2024 
Text and figure 1 updated in section 1.2 based on CSP V2.0  
05 January 2024 
Text updated for sample size section 1.3 based on CSP V2.0 
05 January 2024 
Text update for Section 5 
05 January 2024 
Removed the SOA tables (Tables 7 and 8) and referenced them in the protocol 
05 January 2024 
AJCC version and reference updated in section 7 
05 January 2024 
Signature page removed as it will be signed in Angel 
 
 
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Statistical Analysis Plan  
Study Code D4194C00009 
Edition Number 2.0  
Date 12 January 2024 
12 
1. 
STUDY DETAILS 
Results from the PACIFIC Study in patients with Stage III unresectable non-small cell lung 
cancer (NSCLC) following concurrent chemoradiation therapy (cCRT) demonstrated a 
significant increase in median progression-free survival (PFS) and a significant increase in 
overall survival (OS) among patients who received durvalumab compared with placebo. Safety 
results from this study demonstrated that durvalumab monotherapy was well tolerated and had 
a manageable safety profile in this patient population. However, many patients with Stage III 
unresectable NSCLC are unable to undergo chemotherapy; these patients are therefore faced 
with fewer treatment options. This study is being conducted to assess the safety and tolerability 
of maintenance treatment with durvalumab (MEDI4736) following radiation therapy in this 
population. DUART will also assess the efficacy as secondary objective and 
 as 
exploratory objective.  
1.1 
Study Objectives 
1.1.1 
Primary Objective 
Primary Objective 
Endpoint / Variable 
To assess the safety and tolerability profile of 
durvalumab as defined by Grade 3 and Grade 4 
possibly related adverse events (PRAEs) within 
six months from the initiation of durvalumab 
treatment 
Grade 3 or Grade 4 PRAEs 
Note: Toxicities will be classified as per CTCAE grading system NCI CTCAE version 5.0. 
PRAE: Possibly related adverse event; CTCAE: Common Terminology Criteria for Adverse Event; NCI: National Cancer 
Institute. 
1.1.2 
Secondary Objectives 
Secondary Efficacy Objectives 
Endpoints / Variables 
To assess the efficacy of durvalumab treatment 
in terms of progression-free survival (PFS) and 
overall survival (OS) 
Median PFS according to Response Evaluation 
Criteria in Solid Tumors version 1.1 
(RECIST 1.1) as assessed by the Investigator 
PFS6 and PFS12 according to RECIST 1.1 as 
assessed by the Investigator 
Median OS and OS12 
To further assess the efficacy of durvalumab 
treatment in terms of objective response rate 
(ORR) and duration of response (DoR) 
Objective response (OR) according to RECIST 
1.1 as assessed by the Investigator 
DoR according to RECIST 1.1 as assessed by the 
Investigator 
To assess the efficacy of durvalumab treatment 
in terms of lung cancer mortality 
Lung cancer mortality 
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Date 12 January 2024 
13 
Secondary Safety Objectives 
Endpoints / Variables 
To further assess the safety and tolerability 
profile of durvalumab treatment, including all 
adverse events (AEs) 
AEs, serious adverse events (SAEs), adverse 
events of special interest (AESIs), 
immune-mediated adverse events (imAEs), 
physical examinations, vital signs including 
blood pressure (BP) and pulse rate, 
electrocardiograms (ECGs) and laboratory 
findings including clinical chemistry, 
haematology and urinalysis 
Note: Analysis of OR and DoR will be based upon Investigator assessment according to RECIST 1.1. Prior 
irradiated lesions may be considered measurable and selected as target lesions provided they fulfil the other 
criteria for measurability. 
          An AESI is an AE of scientific and medical interest specific to the understanding of durvalumab. 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.   
           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. 
AE: adverse event; AESI: adverse event of special interest; BP: blood pressure; DoR: duration of response; 
ECG: electrocardiogram; imAE: immune-mediated adverse event; OR: objective response; ORR: objective response rate; OS: 
overall survival; OS12: proportion of patients alive at 12 months from first date of treatment; PFS: progression-free survival; 
PFS6, PFS12: proportion of patients progression-free at 6 months and 12 months, respectively, from first date of treatment; 
RECIST 1.1: Response Evaluation Criteria in Solid Tumors version 1.1; SAE: serious adverse event. 
1.1.3 
Exploratory Objectives 
Exploratory Objectives 
Endpoints / Variables 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
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Note: Analyses of some exploratory objectives may be presented outside of the clinical study report (CSR). 
1.2 
Study Design 
This is a Phase II open-label, single-arm, multicenter, international study to evaluate the clinical 
activity of durvalumab (1500 mg q4w) in patients with Stage III unresectable NSCLC who have 
an ECOG PS of 0 to 2 and who were treated with radiotherapy but are ineligible for 
chemotherapy. 
Patients will be enrolled into 2 cohorts according to radiotherapy pretreatment dose (Cohort A: 
standard radiation therapy [60 gray (Gy) ± 10% or hypofractionated bioequivalent dose (BED)]; 
Cohort B: palliative radiation therapy [40 to < 54 Gy or hypofractionated BED]).  
The general study design is summarised in Figure 1 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan  
Study Code D4194C00009 
Edition Number 2.0  
Date 12 January 2024 
15 
Figure 1 Study Design 
 
 
BED = bioequivalent dose; DoR = Duration of response; ECOG = Eastern Cooperative Oncology Group; Gy = gray; m = 
Month; mOS = median overall survival; mPFS = median progression-free survival; NSCLC = Non-small cell lung cancer; ORR 
= Overall response rate; OS12 = Overall survival at 12 months; PD = Progressive disease; PFS6, PFS12 = Progression-free 
survival at 6, 12 months, respectively; PRAE = Possibly related adverse event; PS = Performance status; q4w = Every 4 weeks; 
RT = radiation therapy 
 
Approximately 102 patients will be treated with durvalumab in Europe and North America. 
Patients will be in complete response (CR), partial response (PR), or have stable disease (SD) 
following radiation therapy, as assessed by the Investigator and further supported by the 
screening imaging radiological assessment. Patients must not have progressed following 
radiation therapy, and radiation therapy must be completed within 6 weeks (42 days) prior to 
first durvalumab administration. The last dose of radiation therapy is defined as the day of the 
last radiation treatment session. 
1.2.1 
Study Treatment 
All patients will receive 1500 mg durvalumab via intravenous (IV) infusion q4w for up to a 
maximum of 12 months (up to 13 doses/cycles). The last administration of durvalumab will be 
on week 48 unless there is clinical progression, RECIST 1.1-defined radiological progression, 
unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. If a 
patient’s weight falls to 30 kg or below, the patient should receive weight-based dosing 
equivalent to 20 mg/kg of durvalumab 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 1500 mg q4w. 


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The standard infusion time is 1 hour; however, if there are interruptions during infusion, the 
total allowed time should not exceed 8 hours at room temperature. 
Figure 2 
Durvalumab monotherapy dosing schedule 
 
max = Maximum; PD = Progression of disease; q4w = Every 4 weeks. 
a 
Or until discontinuation of study drug due to any of the reasons 
 
Patients may delay dosing under certain circumstances. 
• Dosing may be delayed per the Dosing Modification and Toxicity Management Guidelines 
(see Section 8.4.5.1 of CSP), due to either immune-mediated adverse events (imAEs) or 
non-imAEs. 
• If dosing must be delayed for reasons other than treatment-related toxicity, dosing will 
resume as soon as feasible. 
• Dosing intervals of subsequent cycles may be shortened as clinically feasible in order to 
gradually align treatment cycles with the schedule of tumor efficacy (RECIST) and patient-
reported outcomes (PRO) assessments. Subsequent time between 2 consecutive doses 
cannot be less than 22 days, based on the half-life of durvalumab (see the current 
Investigator’s Brochure [IB] for durvalumab). 
One cycle of treatment with durvalumab is equal to 28 calendar days. 
The schedule of assessments including safety, tolerability, efficacy using RECIST version 1.1 
and PROs based on questionnaires are detailed in the study assessment schedule in Appendix 
A. 
If imaging procedures were performed for alternate reasons prior to signing consent, these can 
be used for screening purposes with consent of the patient. However, all screening imaging 
results must have been obtained within 28 days prior to the first dose. 
PRO and tumor efficacy (RECIST) assessment dates are not affected by dose delays and remain 
as originally scheduled, as they are based on the date of the first dose (not the date of therapy). 
All other scheduled assessments must be performed relative to the start of the dosing cycle such 
that all laboratory procedures, etc, required for dosing should be performed within 3 calendar 
days prior to dosing. 
1.2.2 
Tumor Response Assessments 
Tumor assessments using computed tomography (CT)/magnetic resonance imaging (MRI) will 
Durvalumab 1500 mg dose q4w
Cycle
1
2
3
4
5 to 13 or PDa (max. 12 months)
Week
0-3
4-7
8-11
12-15
q4w ± 3 days until 48 weeks


Statistical Analysis Plan  
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be performed at the times specified in the schedule of assessment (Appendix A).  RECIST 1.1 
measurements as assessed by the Investigator will be used to derive the secondary variables of 
PFS, ORR, and DOR. The categorisation of objective tumor response assessment into complete 
response (CR), partial response (PR), stable disease (SD), progressive disease (PD) or not 
evaluable (NE) will be based on RECIST 1.1. 
1.2.3 
Overall Survival Assessments 
All patients in the study should be followed up for survival at months 2, 3, 4, 6, 8, 10, and 12 
following treatment discontinuation or completion, and then every 12 weeks until death, 
withdrawal of consent, or the end of the study. 
1.3 
Number of Patients 
The primary objective of this study is to assess the safety and tolerability of durvalumab 
which is defined as Grade 3 and Grade 4 PRAEs observed within 6 months after the initiation 
of durvalumab treatment. In addition, safety and tolerability of durvalumab will be 
characterized for the cohorts of patients who received Standard Radiotherapy (60 Gy ± 10%) 
or hypofractionated BED and patients who received palliative radiotherapy (40 to < 54 Gy) or 
hypofractionated BED. 
A total of approximately 102 patients are treated with durvalumab in 2 cohorts: approximately 
59 patients in the Standard Radiotherapy Cohort and approximately 43 patients in the 
Palliative Radiotherapy Cohort. It is estimated that a sample size of a minimum 60 patients 
would be required to provide an adequate level of confidence in the estimated incidence of 
Grade 3 and 4 PRAEs occurring within 6 months after initiation of durvalumab treatment, 
which is the primary endpoint. With a sample size of 60 patients, the exact binomial 95% CI 
for an observed incidence rate of 12% would be 5% to 23%. If the underlying/true incidence 
rate was 12% as reported in PACIFIC (D4194C00006), on repeated implementations of this 
study, observing an incidence rate less than 5% or greater than 18.3% would be approximately 
5% for each region/tail.  
Furthermore, if there are 30 patients in each cohort (Standard Radiotherapy and Palliative 
Radiotherapy) and the true incidence of Grade 3 and Grade 4 PRAEs occurring within 6 
months after initiation of durvalumab treatment is 12%, , the precision will be approximately 
± 13.0% (95% CI: 3.1, 29.1) in each cohort. 
An illustration of the precision around the varying incidence rate of Grade 3 and Grade 4 PRAEs 
for the patients overall and for each cohort (Standard Radiotherapy and Palliative Radiotherapy) 
is provided in Table 1. 


Statistical Analysis Plan  
Study Code D4194C00009 
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Table 1    Precision around varying incidence of Grade 3 and Grade 4 Possibly-Related 
Adverse Events  
Sample size 
Grade 3 and Grade 4 PRAE Incidence Rate 
10 % 
12 % 
15 % 
60 
3.8-20.5 
(± 8.4) 
5.0-23.0 
(± 9.0) 
7.1-26.6 
(± 9.7) 
30 
2.1-26.5 
(± 12.2) 
3.1-29.1 
(± 13.0) 
4.7-32.7 
(± 14.0) 
PRAE = possibly related adverse event.  
2. 
ANALYSIS SETS 
2.1 
Definition of Analysis Sets 
With the exception of some summaries of patient disposition and particular individual patient 
data listings, which will be produced for all patients who provided informed consent and who 
were enrolled in the study, the Safety Analysis Set (SAF) will be used for listings, summaries, 
and analyses in the study. 
2.1.1 
Safety Analysis Set 
The Safety Analysis Set: will consist of all patients who received at least one dose (partial or in 
full) of durvalumab. The SAF will be used for analysis of all safety endpoints. In this safety 
study, the standard full analysis set will be same as SAF, therefore, the SAF will be used for 
analysis of efficacy endpoints as well. 
For analysis of time-to-event endpoints, the SAF will be used with defined censored patients.  
 
2.2 
Protocol Deviations 
2.2.1 
Important Protocol Deviations 
According to ICH E3 guidelines version dated 1995 (ICH 1995),  
“Protocol deviations (PDs) consist of any change, divergence or departure from the study 
design or procedures defined in the protocol. Important protocol deviations (IPDs) are a 
subset of protocol deviations that may significantly affect the completeness, accuracy, 
and/or reliability of the study data or that may significantly affect a patient’s rights, safety 
or well-being.”  
For this study, the following 4 general categories will be considered IPDs and will be 
summarized in the Clinical Study Report (CSR): 
• 
Deviation 1: Patients who received treatment and who deviated from the following key 
entry criteria in Clinical Study Protocol (CSP): 


Statistical Analysis Plan  
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• 
Inclusion Criterion 5: Histologically- or cytologically-documented NSCLC with 
locally-advanced, unresectable Stage III disease (according to the International 
Association for the Study of Lung Cancer [IASLC] Staging Manual Version 8 
[IASLC 2016]). 
(a) Imaging to rule out distant metastasis is required. 
(b) Endobronchial ultrasound with biopsy is encouraged in patients with 
suspected lymph node involvement. 
• Inclusion Criterion 6: Deemed ineligible for chemotherapy per Investigator 
assessment (eg, comorbidities, poor PS, etc). 
• Inclusion Criterion 7: Receipt of radiation therapy that was completed within 42 days 
prior to first IP dose administration in the study. 
• Inclusion Criteria 8: Patients must have received a total dose of radiation of 40 to 66 
Gy (standard or hypofractionated BED). Note that patients will be assigned to Cohort 
A (standard radiation therapy [60 Gy ± 10% or hypofractionated BED]) or Cohort B 
(palliative radiation therapy [40 to < 54 Gy or hypofractionated BED]) based upon 
total dose of radiation received. Sites are encouraged to adhere to mean organ radiation 
dosing as follows: 
a) Mean lung dose < 20 Gy and/or V20 < 35%; 
b) Mean esophagus dose < 34 Gy; 
c) Heart V45 < 35% or V30 < 30%. Heart V45 < 35% or V30 < 30%. 
d) Note: Sites should be aware of the recent RTOG 0617 Study data (Bradley et al 
2015) demonstrating that doses higher than 60 Gy may be associated with 
greater toxicity and worse efficacy. Patients with WHO/ECOG PS 2 or chronic 
lung disease (pulmonary emphysema or chronic obstructive pulmonary disease) 
must have received a V20 < 25%. 
• 
Inclusion Criterion 9: Patients must not have progressed following radiation therapy, 
as per Investigator assessed RECIST 1.1 criteria. 
(a) Patients with measurable disease and/or nonmeasurable and/or no evidence of 
disease assessed at baseline by computed tomography (CT)/magnetic resonance 
imaging (MRI) will be eligible for this study. 
(b) Prior irradiated lesions may be considered measurable and selected as target 
lesions (TLs) providing they fulfil the other criteria for measurability. 
• Inclusion Criterion 10: WHO/ECOG PS ≤2. 
• Inclusion Criterion 11: No prior exposure to immune-mediated therapy including, but 
not limited to, anti-CTLA-4, anti-PD-1, anti-PD-L1, and antiprogrammed cell death 
ligand 2 (anti-PD-L2) antibodies, excluding therapeutic anticancer vaccines. 
• Exclusion Criterion 1: Patients with locally-advanced NSCLC whose disease has 
progressed following radiation therapy. 
• Exclusion Criterion 2: Mixed small-cell lung cancer and NSCLC histology. 


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• Exclusion Criterion 5: 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 
interstitial lung disease (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. 
• Exclusion Criterion 9: 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 (known positive hepatitis 
B virus surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency 
virus (human immunodeficiency virus [HIV]; positive HIV 1/2 antibodies). Patients 
with a past or resolved hepatitis B virus infection (defined as the presence of hepatitis 
B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for 
hepatitis C antibody are eligible only if polymerase chain reaction is negative for 
hepatitis C virus ribonucleic acid. 
• Exclusion Criterion 14: Current or prior use of immunosuppressive medication within 
14 days before the first dose of durvalumab. The following are exceptions to this 
criterion: 
- 
Intranasal, inhaled, topical steroids, or local steroid injections (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) 
• 
Deviation 2: The patient met discontinuation criteria but did not discontinue durvalumab 
(eg, patient withdrew consent, patient became pregnant). 
• 
Deviation 3: The patient received a prohibited concomitant medication or procedure as 
detailed in Section 6.4 of the CSP or any other concomitant medication or procedure 
which, upon physician review of all medications and procedures prior to database lock 
(DBL), is considered to have a potential effect on study outcomes.  
• 
Deviation 4: Missed visits, assessments, or treatments that, in the opinion of the principal 
investigator, 
• were due to the 2020 COVID-19 global pandemic and  
• there was a significant effect on either completeness, accuracy, and/or reliability 
of the patient’s data, or the patient’s rights, safety or well-being. 
2.2.2 
Monitoring of Protocol Deviations 
Programmable PDs will be detected from the data recorded in the clinical database and will be 
reviewed at regular PD review meetings. At this meeting, the programmatically-derived PDs 
will be checked to ensure that they have been correctly classified as major or minor PDs.  


Statistical Analysis Plan  
Study Code D4194C00009 
Edition Number 2.0  
Date 12 January 2024 
21 
On an ongoing basis throughout the study, monitoring notes or summaries will also be reviewed 
to determine any important post-entry deviations that are not identifiable via programming.  
If the number of deviations which are considered to have the potential to impact the primary 
analysis is considered important, sensitivity analyses may be performed on subgroups. This will 
be decided during the data review meeting and before the DBL.  
The final classification of IPDs will be made prior to DBL or data cut-off for final analysis. Any 
other deviations from monitoring notes or reports will be reported in an appendix to the CSR. 
3. 
ANALYSIS VARIABLES 
3.1 
Derivation of RECIST Visit Responses 
For all patients, the RECIST tumor 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’s disease has progressed in accordance with RECIST and their best objective response 
to study treatment.   
The baseline radiological tumor assessment is part of the screening procedure and should be 
performed within 28 days after the end of radiotherapy, no more than 28 days before the start 
of durvalumab treatment, and ideally as close as possible to the start of study treatment.  Tumor 
assessments will begin at 8 weeks ± 1 week after durvalumab initiation and continue every 
8 weeks ± 1 week through 48 weeks (relative to the date of first dose of durvalumab), and then 
every 12 weeks ± 1 week thereafter until RECIST 1.1-defined PD, plus an additional regularly 
scheduled follow-up scan. The on-study schedule of q8w ± 1 week (following the first 
assessment at 8 weeks ± 1w after the first dose) for first 48 weeks and then q12w ± 1 w thereafter 
MUST be followed regardless of any delays in dosing. Additional scans can be completed per 
standard practice post disease progression. 
From the investigator’s review of the imaging scans, the RECIST tumor response data will be 
used to determine each patient’s visit response according to RECIST version 1.1. At each visit, 
patients will be programmatically assigned a RECIST 1.1 visit response of CR, PR, SD or PD, 
using the information from target lesions (TLs), non-target lesions (NTLs) and new lesions and 
depending on the status of their disease compared with baseline and previous assessments. If a 
patient has had a tumor assessment which cannot be evaluated, then the patient will be assigned 
a visit response of not evaluable (NE) (unless there is evidence of progression in which case the 
response will be assigned as PD).  
RECIST outcomes (ie, PFS and ORR etc.) will be calculated programmatically from site 
investigator data from overall visit responses. 
 


Statistical Analysis Plan  
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3.1.1 
Site Investigator Assessments Using RECIST 1.1 
3.1.1.1 
Target Lesions 
Measurable disease is defined as having at least one measurable lesion, not previously 
irradiated, which is ≥ 10 mm in the longest diameter (LD), (except lymph nodes which must 
have short axis ≥ 15 mm) with CT or MRI and which is suitable for accurate repeated 
measurements.  
A maximum of five measurable lesions (with a maximum of two lesions per organ), 
representative of all lesions involved and suitable for accurate repeated measurement, should 
be identified as TLs at baseline.  It may be the case that, on occasion, the largest lesion does not 
lend itself to reproducible measurement. In which circumstance the next largest lesion, which 
can be measured reproducibly, should be selected.  If more than one baseline scan is recorded, 
then measurements from the one that is closest and prior to initiation of durvalumab will be 
used to define the baseline sum of TLs.  
All other measurable lesions not recorded as TL, and all non-measurable lesions (or sites of 
disease) should be identified as non-target lesions (NTLs) at baseline.  Measurements are not 
required for these lesions, but their status should be followed at subsequent visits. 
For patients who do not have measurable disease at entry (ie, no TLs) but have non-measurable 
disease, evaluation of overall visit responses will be based on the overall NTL assessment and 
the absence/presence of new lesions (see Section 3.1.1.3 for further details). If a patient does 
not have measurable disease at baseline, then the TL visit response will be not applicable (NA).  


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Edition Number 2.0  
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Table 2  
Target Lesion Visit Responses 
CR: Complete response; NA: Not applicable; NE: Not evaluable; PD: Progressive disease; PR: Partial response; SD: Stable 
Disease; TL: target lesion  
Rounding of Target Lesion Data 
For calculation of PD and PR for TLs percentage changes from baseline and previous minimum 
should be rounded to 1 decimal place (dp) before assigning a target lesion response.  For 
example, 19.95% should be rounded to 20.0% but 19.94% should be rounded to 19.9%   
Missing TL Data  
For a visit to be evaluable then all target lesion measurements should be recorded.  However, a 
visit response of PD should still be assigned if any of the following occurred 
• 
A new lesion is recorded 
• 
A NTL visit response of PD is recorded 
• 
The sum of TLs is sufficiently increased to result in a 20% increase, and an absolute 
increase of ≥ 5mm, from nadir even assuming the non-recorded TLs have disappeared 
Note: the nadir can only be taken from assessments where all the TLs had a LD recorded.  
If there is at least one TL measurement missing and a visit response of PD cannot be assigned, 
the visit response is NE. 
If all TL measurements are missing, then the TL visit response is NE.  Overall visit response 
will also be NE, unless there is a progression of non-TLs or new lesions, in which case the 
Visit Responses 
Description 
Complete response (CR) 
Disappearance of all TLs since baseline. Any pathological lymph 
nodes selected as TLs must have a reduction in short axis to 
<10 mm. 
Partial response (PR) 
At least a 30% decrease in the sum of the diameters of TL, taking 
as reference the baseline sum of diameters as long as criteria for 
PD are not met. 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD 
Progression of disease (PD) 
A ≥20% increase in the sum of diameters of TLs and an absolute 
increase of ≥ 5mm, taking as reference the smallest sum of 
diameters since treatment started including the baseline sum of 
diameters. 
Not evaluable (NE) 
Only relevant in certain situations (ie, if any of the TLs were not 
assessed or not evaluable or had a lesion intervention at this visit; 
and scaling up could not be performed for lesions with 
interventions). Note: If the sum of diameters meets the 
progressive disease criteria, progressive disease overrides not 
evaluable as a TL response. 
Not applicable (NA) 
No TLs are recorded at baseline. 


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response will be PD. 
Lymph Nodes 
For lymph nodes, if the size reduces to < 10mm then these are considered non-pathological. 
However, a size will still be given, and this size should still be used to determine the TL visit 
response as normal.  In the special case where all lymph nodes are < 10mm and all other TLs 
are 0mm then although the sum may be >0mm the calculation of TL response should be 
over-written as a CR.  
Target Lesion Visit Responses Subsequent to Complete Response 
A CR response can only be followed by CR, PD or NE.  If a CR has occurred, then the following 
rules at the subsequent visits must be applied: 
• 
Step 1:  If all lesions meet the CR criteria (ie, 0mm or < 10mm for lymph nodes) then 
response will be set to CR irrespective of whether the criteria for PD of TL is also met ie, 
if a lymph node LD increases by 20% but remains < 10mm.  
• 
Step 2:  If some lesion measurements are missing but all other lesions meet the CR criteria 
(ie, 0mm or < 10mm for lymph nodes) then response will be set to NE irrespective of 
whether when referencing the sum of TL diameters, the criteria for PD is also met.  
• 
Step 3:  If not all lesions meet the CR criteria and the sum of lesions meets the criteria for 
PD then response will be set to PD 
• 
Step 4:  If after steps 1 – 3 a response can still not be determined the response will be set 
to remain as CR 
Target Lesion Too Big to Measure 
If a target lesion becomes too big to measure this should be indicated in the database and a size 
(‘x’) above which it cannot be accurately measured should be recorded.  If using a value of x in 
the calculation of target lesion response would not give an overall visit response of PD, then 
this will be flagged and reviewed by the study team.  It is expected that a visit response of PD 
will remain in the vast majority of cases.   
Target Lesion Too Small to Measure 
If a TL becomes too small to measure, then this will be indicated as such on the case report form 
and a value of 5mm will be entered into the database and used in TL calculations. However, a 
smaller value may be used if the radiologist has not indicated ‘too small to measure’ on the case 
report form and has entered a smaller value that can be reliably measured. If a TL response of 
PD results, then this will be reviewed by the study team.  
Irradiated Lesions/Lesion Intervention 
A previously irradiated lesion may be selected as a TL, provided that it fulfils the criteria for 
reproducible measurability and is the only lesion available.  
Any TL (including lymph nodes), which has had intervention in addition to study treatment 
during the study (eg, irradiation / palliative surgery / embolization), should be handled in the 
following way and once a lesion has had intervention then it should be treated as having 


Statistical Analysis Plan  
Study Code D4194C00009 
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25 
intervention for the remainder of the study noting that an intervention will most likely shrink 
the size of tumors: 
• 
Step 1: the diameters of the TLs (including the lesions that have had intervention) will be 
summed and the calculation will be performed in the usual manner. If the visit response is 
PD this will remain as a valid response category.  
• 
Step 2: If there was no evidence of progression after step 1, treat the lesion diameter (for 
those lesions with intervention) as missing and if  1/3 of the TLs have missing 
measurements then scale up as described in the ‘Scaling’ section below.  If the scaling 
results in a visit response of PD then the patient would be assigned a TL response of PD.   
• 
Step 3: If, after both steps, PD has not been assigned, then, if appropriate (ie, if  1/3 of 
the TLs have missing measurements), the scaled sum of diameters calculated in step 2 
should be used, and PR or SD then assigned as the visit response.  Patients with 
intervention are evaluable for CR as long as all non-intervened lesions are 0 (or <10mm 
for lymph nodes) and the lesions that have been subject to intervention have a value of 0 
(or <10mm for lymph nodes) recorded.  If scaling up is not appropriate due to too few 
non-missing measurements, then the visit response will be set as NE. 
At subsequent visits the above steps will be repeated to determine the TL and overall visit 
response.  When calculating the previous minimum, lesions with intervention should be treated 
as missing and scaled up (as per step 2 above). 
Scaling of the Sum of Target Lesions 
Scaling of the sum of target lesion diameters is used when one or more target lesion diameter is 
missing because of on-study target lesion intervention. 
If >1/3 of target lesion measurements are missing (because of intervention) then target lesion 
response will be NE, unless the sum of diameters of non-missing target lesion would result in 
PD (ie, if using a value of 0 for missing lesions, the sum of diameters has still increased by > 
20% or more compared to nadir and the sum of target lesions has increased by ≥5mm from 
nadir).   
If ≤ 1/3 of the target lesion measurements are missing (because of intervention) then the results 
will be scaled up based on the sizes at the nadir visit to give an estimated sum of diameters and 
this will be used in calculations; this is equivalent to comparing the visit sum of diameters of 
the non-missing lesions to the nadir sum of diameters excluding the lesions with missing 
measurements. 
Example of Scaling 
Lesion 
Longest diameter (mm)  
at nadir visit 
Longest diameter (mm) 
at follow-up visit 
1 
16 
18 
2 
14 
16 
3 
14 
16 
4 
18 
18 
5 
12 
Intervention 
Sum 
74 
68 


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Lesion 5 has had an intervention at the follow-up visit. The sum of the Baseline measures is 
74 mm. The sum of lesions 1-4 at the follow-up is 68 mm.  The sum of the corresponding lesions 
at nadir visit is 62 mm. Scale up as follows to give an estimated follow-up visit TL sum of 
81mm:   
68
62 × 74 = 81𝑚𝑚 
Lesions that Split in Two or more Parts 
If a TL splits in two or more parts, then the LDs of the split lesions should be summed and 
reported as the LD for the lesion that split. 
Lesions that Merge 
If two or more target lesions merge, then the LD of the merged lesion should be recorded for 
one of the TL sizes and the other TL sizes should be recorded as 0mm. 
Change in Method of Assessment of Target Lesions 
CT and MRI are the only methods of assessment that can be used within this trial. If a change 
in method of assessment between CT and MRI occurs this will be considered acceptable and no 
adjustment within the programming is needed. 
Note, if a change in method involves clinical examination (eg, CT changes to clinical 
examination or vice versa), any affected lesions should be treated as missing. 
3.1.1.2 
Non-Target Lesions and New Lesions. 
At each visit an overall assessment of the NTL response should be recorded by the investigator. 
This section provides the definitions of the criteria used to determine and record overall 
response for NTL at the investigational site at each visit. 
Non-target lesion response will be derived based on the Investigator’s overall assessment of 
NTLs as follows:   


Statistical Analysis Plan  
Study Code D4194C00009 
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27 
Table 3  
NTL Visit Responses 
Visit Responses 
Description 
Complete response (CR) 
Disappearance of all NTLs since baseline. All lymph nodes must 
be non-pathological in size (<10 mm short axis). 
Non CR/non PD 
Persistence of one or more NTLs with no evidence of progression. 
Progression (PD) 
Unequivocal progression of existing NTLs. Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions. In all cases the progression MUST be 
clinically significant for the physician to consider changing (or 
stopping) therapy. 
Not evaluable (NE) 
Only relevant when one or some of the NTLs were not assessed 
and, in the Investigator’s opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit. 
Note: for patients without TLs at baseline, this is relevant if any of 
the NTLs were not assessed at this visit and the progression 
criteria have not been met. 
Not applicable (NA) 
Only relevant if there are no NTLs at baseline. 
CR: Complete response; NA: Not applicable; NE: Not evaluable; NTL non-target lesion; PD: Progressive disease; PR: Partial 
response; SD: Stable Disease; TL: target lesion  
To achieve ‘unequivocal progression’ based on NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in the presence of SD or PR in TLs, 
the overall tumor burden has increased sufficiently to merit a discontinuation of therapy. A 
modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify for 
unequivocal progression status. 
Details of any new lesions will also be recorded with the date of assessment. The presence of 
one or more new lesions is assessed as progression. 
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
The finding of a new lesion should be unequivocal: ie, not attributable to differences in scanning 
technique, change in imaging modality or findings thought to represent something other than 
tumor. 
New lesions will be identified via a Yes/No tick box. The absence and presence of new lesions 
at each visit should be listed alongside the TL and NTL visit responses. 
A new lesion indicates progression, so the overall visit response will be PD irrespective of the 
TL and NTL response. 
Symptomatic deterioration is not a descriptor for progression of NTLs: it is a reason for stopping 
study therapy and will not be included in any assessment of NTLs. 
Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumor 


Statistical Analysis Plan  
Study Code D4194C00009 
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28 
assessments where possible until objective disease progression is observed. 
3.1.1.3 
Overall Visit Response 
Table 4 defines how the previously defined TL and NTL visit responses will be combined with 
new lesion information to give an overall visit response. 
Table 4  
Overall Visit Responses 
              Target 
         Non-target 
        New Lesions 
Overall Visit Response 
CR 
CR (or NA) 
No (or NE) 
CR 
CR 
Non-CR/Non-PD or NE 
No (or NE) 
PR 
PR 
 Non-PD or NE or NA 
No (or NE) 
PR 
SD 
 Non-PD or NE or NA 
No (or NE) 
SD 
PD 
Any 
Any 
PD 
Any 
PD 
Any 
PD 
Any 
Any 
Yes 
PD 
NE 
Non-PD or NE or NA 
No (or NE) 
NE 
NA 
CR 
No (or NE) 
CR 
NA 
Non-CR/Non-PD 
No (or NE) 
SD 
NA 
NE 
No (or NE) 
NE 
NA 
NA 
No (or NE) 
NED 
CR complete response; PR partial response; SD stable disease; PD progression of disease; NE not evaluable; NA not applicable 
(only relevant if there were neither target nor non-target lesions at baseline); NED no evidence of disease. 
3.2 
Safety Variables 
Safety and tolerability will be assessed in terms of AEs (including SAEs, AESIs, imAEs), 
deaths, physical examinations, laboratory data, vital signs, ECGs and exposure. These will be 
collected for all patients throughout the study. 
3.2.1 
Primary Safety Endpoint 
The primary endpoint of this study is the incidence of Grade 3 and Grade 4 PRAEs (see Section 
3.2.3.1) which occur within the first six months (ie, up to and including the 183rd day) after the 
initiation of durvalumab. Any Grade 3 or Grade 4 PRAEs which started after the 183rd day of 
the study, or after the 90th day following discontinuation of durvalumab, or after the start of 
subsequent anti-cancer therapy will not be included.  
3.2.2 
Secondary Safety Endpoints 
The secondary safety endpoints of this study include: 
• 
Treatment-emergent adverse events (TEAEs) and SAEs 


Statistical Analysis Plan  
Study Code D4194C00009 
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Date 12 January 2024 
29 
• 
AESI and AEPI (see Section 3.2.3.2) and imAEs (see Section 3.2.3.3) 
• 
ECG 
• 
Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and 
pulse rate 
• 
Laboratory data including clinical chemistry, haematology and urinalysis 
• 
Physical examination 
3.2.3 
Adverse Events 
AEs and SAEs will be collected throughout the study, from time of the patient signing the 
informed consent and 90 days after the last dose of durvalumab. A treatment emergent adverse 
event (TEAE) is an AE with an onset date or a pre-existing AE worsening following the first 
dose of study treatment through to 90 days after the last dose of durvalumab. 
The Medical Dictionary for Regulatory Activities (MedDRA) (using the latest or current 
MedDRA version) will be used to code the AEs. AEs will be graded according to the National 
Cancer Institute Common Terminology Criteria for AEs (CTCAE Version 5.0). The meaning 
of these categories are as follows:   
• Grade 1: Mild AE 
• Grade 2: Moderate AE 
• Grade 3: Severe AE 
• Grade 4: Life-threatening or disabling AE 
• Grade 5: Death related to AE 
Any TEAE will be included in the AE summaries as detailed in Section 4.5.1.  
Missing start and stop dates for AEs will be imputed using the rules described in Section 4.1.3. 
3.2.3.1 
Possibly-Related Adverse Events 
A PRAE is any TEAE with a relatedness to durvalumab of possible, or where the relatedness is 
missing.  When the relatedness of a TEAE is missing on the electronic Case Report Form 
(eCRF), all efforts will be taken to ensure that the Investigator assigns his/her assessment of 
relatedness prior to DBL.  
If relatedness of a TEAE is missing at the DBL, as given in Section 4.1.2, the TEAE will be 
considered as possibly related to durvalumab. 
3.2.3.2 
Adverse Events of Special Interest and AEs of Possible Interest 
Some clinical concepts (including some selected individual preferred terms and higher-level 
terms) have been considered “AEs of special interest” (AESI) and “AEs of possible interest” 
(AEPI) to the durvalumab program.  


Statistical Analysis Plan  
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The AESIs reported in the AstraZeneca-sponsored durvalumab studies are defined as AEs that 
have 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 (for example, therapies for hyperthyroidism 
include beta blockers [e.g., propranolol], calcium channel blockers [e.g., verapamil, diltiazem], 
methimazole, propylthiouracil, and sodium perchlorate, infusion-related reactions and 
hypersensitivity/anaphylactic reactions).  
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 have been identified as Pneumonitis, Hepatic events, Diarrhea/Colitis, 
Intestinal perforations, Adrenal Insufficiency, Type 1 diabetes mellitus, Hyperthyroid events, 
Hypophysitis, Hypothyroid events, Thyroiditis, Renal events, Dermatitis/Rash, Pancreatic 
events, 
Myocarditis, 
Myasthenia 
gravis, 
Guillain-Barre 
syndrome, 
Myositis, 
Infusion/hypersensitivity reactions and Other rare/miscellaneous . Other categories may be 
added or existing terms may be merged as necessary. An AstraZeneca medically qualified 
expert after consultation with the Global Patient Safety Physician has reviewed the AEs of 
interest and identified which MedDRA preferred terms contribute to each AESI/AEPI. A further 
review will take place prior to Database lock (DBL) to ensure any further terms not already 
included are captured within the categories. 
3.2.3.3 
Immune-Mediated Adverse Event (ImAE) 
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. In 
general, imAEs will include AESIs/AEPI that are managed using steroids, immunosuppressants 
and/or hormone replacement therapy.  
This document comprises the specification for the analysis of the imAEs as identified by the 
investigator (as recorded in CRF Adverse Events (AE)).  No adjudication of the imAEs will be 
performed for this analysis.  
3.2.3.4 
Confirmed/Suspected COVID-19 infections 
Confirmed/Suspected Covid-19 infection is defined as an AE occurring during the pandemic 
timeframe (after 11th of March 2020) with preferred term within the AE search criteria 
developed by the latest MedDRA maintenance and support service organization (MSSO) 
guidance. 


Statistical Analysis Plan  
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3.2.4 
Electrocardiograms 
These measurements are recorded as detailed in the study schedule (See Appendix A). If vital 
signs, ECG and blood draws for laboratory tests are scheduled at a visit, they will always be 
performed in the order: ECG, vital signs and then blood draws. 
At Screening, and as clinically indicated throughout the study, 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. From these resting 12-lead ECGs values of the QT and RR intervals and the 
QT interval corrected for heart rate using Fridericia’s correction (QTcF) is derived using the 
following formula: 
• 
QTcF = QT/RR^ (1/3) where RR is in seconds 
In case of clinically significant ECG abnormalities, 2 additional 12-lead ECGs will be 
performed. All three ECGs should include a value of QTcF over a brief period (eg, 30 minutes). 
A QTcF value >470 msec will confirm the ECG abnormality finding. 
The value of QTcF will be re-derived from the values of RR and QT during the creation of the 
reporting database. 
3.2.5 
Vital Signs 
Vital signs measurements will be collected at the start of each treatment cycle as detailed in the 
schedule of assessment (Appendix A). 
Measurements will include respiration rate (breaths/minute), SBP (mmHg), DBP (mmHg), 
pulse rate (beats/min), weight (kg), height (cm) and body temperature (degrees Celsius). 
3.2.6 
Laboratory Data 
Laboratory data (clinical chemistry, haematology and urinalysis) will be collected at the start of 
each treatment cycle as detailed in the schedule of assessment (Appendix A). Coagulation will 
be reported as clinically indicated.  Laboratory data will be from local laboratories and will be 
converted to AZ preferred units, and AZ project reference ranges will be used for the primary 
interpretation of laboratory data. 
The following laboratory parameters will be measured at screening, Day 1 of each cycle, and at 
other times if clinically indicated: 
• Clinical Chemistry: albumin, ALP, ALT, amylase and/or lipase, AST, calcium, glucose, 
LDH, potassium, sodium, total bilirubin, total protein, TSH, urea or BUN (depending on 
local practice) 
• Haematology: haemoglobin, neutrophil count (absolute or percentage), lymphocyte count 
(absolute or percentage), platelets, total white cell count 
• Urinalysis: bilirubin, blood, color and appearance, glucose, ketones, pH, protein, specific 
gravity 
 


Statistical Analysis Plan  
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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) 
In addition, the following laboratory parameters will be collected at baseline, Day 1 of Cycle 1, 
or when clinically indicated: 
• Clinical Chemistry: bicarbonate (when available), chloride, creatinine clearance, gamma 
glutamyltransferase, magnesium, T3 free, T4 free 
• Haematology: activated partial prothrombin time (ratio or absolute), INR 
3.2.7 
Physical Examination 
Physical examinations will be performed as detailed in the schedule of assessment (Appendix 
A). Full physical examinations will include assessments of the head, eyes, ears, nose, and throat 
and the respiratory, cardiovascular, gastrointestinal, urogenital, musculoskeletal, neurological, 
dermatological, hematologic/lymphatic, and endocrine systems. Height will be measured at 
screening only. Targeted physical examinations are to be utilized by the Investigator on the 
basis of clinical observations and symptomatology. Situations in which physical examination 
results should be reported as AEs are described in Section 8.3.7 of the CSP. 
3.2.8 
Exposure to Durvalumab 
The total (or intended) exposure (weeks) of durvalumab is defined as: 
• 
Total treatment duration (weeks) = Total treatment duration (days) / 7 
 
where: 
 
Total treatment duration (days) = [earliest of (last dose date where dose > 0mg + 27 days, 
death date, data cut-off date [DCO])-first dose date] +1 
The actual exposure (weeks) of durvalumab is defined as: 
• 
Actual treatment duration (weeks) = [total treatment duration (days) – total duration of 
dose delays (days)] / 7.  
Dose reductions are not permitted per the CSP for durvalumab and the actual exposure 
calculation makes no adjustment for any dose reductions that may have occurred. 
As patients are scheduled to receive 1500 mg via IV infusion every 4 weeks (28 days), the 
duration of dose delays is the sum of all individual dose delays as follows: 
• 
Total duration of dose delays (days) = sum of maximum[0, (date of dose [x+1] – date of 
dose [x] - 28 days)]. 
If no delays were encountered, the total duration of dose delays would sum up to 0.  


Statistical Analysis Plan  
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According to the protocol, dose delays are defined as doses administered 4 or more days after 
the target dosing date and reason for dose delay is collected in the CRF based on this definition. 
Relative dose intensity (RDI) is the percentage of the actual dose intensity delivered relative to 
the intended dose intensity through to treatment discontinuation.  
RDI is defined as follows: 
RDI = 100% * d/D, where d and D are, respectively, the actual and intended cumulative doses 
delivered up to the date of durvalumab discontinuation or progressive disease or the data cut-
off date, whichever occurs earlier.  D is the total dose that would be delivered if there were no 
modification to dose or schedule. 
Percentage intended dose (PID) is the percentage of the actual dose delivered relative to the 
intended dose through to disease progression. 
PID = 100% * d1/D1, where d1 is the actual cumulative dose delivered up to the earlier of 
progression (or a censoring event) or the data cut-off date and D1 is the intended cumulative 
dose up to the earlier of progression (or a censoring event) or the data cut-off date. D1 is the 
total dose that would be delivered, if there were no modifications to dose or schedule. 
When deriving actual dose administered the volume before and after infusion will also be 
considered. 
To illustrate the calculation of RDI, Table 5 shows an example of durvalumab dosing for 4 
patients. 
Table 5  
Example dose intensity scenarios 
 
 
Study Day 
RDI 
Patient 
1 
29 
57 
85 
113 
141 
169 
197 
225 
230 
100% 
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD 
100% 
2 
X 
X 
X 
X 
X 
X 
X 
X[D] 
 
PD 
56% 
3 
X 
          X                  X        O       X       X 
PD 
67% 
4 
X 
X 
O 
X 
X 
X 
O 
X 
O 
PD 
X: Dose of 1500mg taken; O: Dose missed; [D]: Dose discontinued; PD: Progressive Disease 
In this example, all 4 Patients progressed on Day 230, and so the intended dose through to 
progression was 9 * 1500mg of durvalumab = 13500mg (13.5g). 
Patient 1 received a total of 13.5g of durvalumab, whereas other patients received less 
durvalumab due to:  
• 
Early stopping prior to PD (Patient 2)  
• 
Dosing delays (Patient 3)  
• 
Missed doses (Patient 4)  


Statistical Analysis Plan  
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For RDI the examples of Patients 2 and 4 illustrate that the end of actual dosing period is 
calculated based on the smallest recovery period after the last non-zero dose.  
Patient 1: 
RDI = (9 * 1.5g)/ 13.5g = 100%  
Patient 2:  
RDI = (8 * 1.5g)/ 12g = 100%  
Patient 3:  
RDI = (5 * 1.5g)/ 13.5g = 56%  
Patient 4:  
RDI = (6 * 1.5g)/ 13.5g = 67% 
For the examples the PID differs from RDI for Patient 2 where the calculation is based on the 
intended cumulative dose up to disease progression regardless of treatment discontinuation.  
Patient 1: 
RDI = (9 * 1.5g)/ 13.5g = 100%  
Patient 2:  
PDI = (8 * 1.5g)/ 13.5g = 89%  
Patient 3:  
RDI = (5 * 1.5g)/ 13.5g = 56%  
Patient 4:  
RDI = (6 * 1.5g)/ 13.5g = 67% 
Exposure will also be measured by the number of cycles (doses) of durvalumab received.  If a 
cycle is prolonged due to toxicity this will still be counted as one cycle.  A cycle will be counted 
if treatment is started, even if the full dose is not delivered.   
3.3 
Efficacy Variables 
All RECIST assessments, whether scheduled or unscheduled, and regardless of whether a 
patient discontinues durvalumab treatment or receives another anti-cancer therapy will be 
included in the calculation of efficacy variables. 
3.3.1 
Progression-Free Survival 
Progression-free survival is defined as the time from the date of first dose of durvalumab until 
the date of objective disease progression or death (by any cause in the absence of progression) 
regardless of whether the patient discontinues durvalumab or receives another anticancer 
therapy prior to progression. 
• 
PFS (days) = (date of PFS event or censoring) – (date of first dose of durvalumab) + 1. 
Patients who have not progressed or died at the time of analysis will be censored at the date of 
their last evaluable tumor assessment (ie, this doesn’t include NE or missing value).  
If the patient progresses or dies after 2 or more missed visits, the patient will be censored at the 
date of the latest evaluable assessment prior to the missed visits.   
If the patient has no evaluable visits or does not have baseline data, he/she will be censored at 
Day 1 unless he/she dies within 2 visits of baseline, in which case the date of death is the event 
date.  
Given the scheduled visit assessment scheme (i.e. eight-weekly for the first 48 weeks then 
twelve-weekly thereafter) the definition of 2 missed visits will change.   


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1. If the previous RECIST assessment is baseline then two missing visits will equate to 17 
weeks since the previous RECIST assessment, allowing for a late visit (i.e. 2 x 8 weeks 
+ 1 week for a late assessment = 17 weeks). 
2. If the previous RECIST assessment is post baseline and less than study day 274 (i.e. 
week 39) then two missing visits will equate to 18 weeks since the previous RECIST 
assessment, allowing for early and late visits (i.e. 2 x 8 weeks + 1 week for an early 
assessment + 1 week for a late assessment = 18 weeks).   
3. If the two missed visits occur over the period when the scheduled frequency of RECIST 
assessments changes from eight-weekly to twelve-weekly this will equate to 22 weeks 
(i.e. take the average of 8 and 12 weeks which gives 10 weeks and then apply same 
rationale, hence 2 x 10 weeks + 1 week for an early assessment + 1 week for a late 
assessment = 22 weeks).  The time period for the previous RECIST assessment will be 
from study days 274 to 344 (i.e. week 39 to week 49).   
4. From week 49 onwards (when the scheduling changes to twelve-weekly assessments), 
two missing visits will equate to 26 weeks (i.e. 2 x 12 weeks + 1 week for an early 
assessment + 1 week for a late assessment = 26 weeks). 
If the patient has no evaluable visits or does not have baseline data, he/she will be censored at 
Day 1 unless he/she dies within 2 visits of baseline, in which case the date of death is the event 
date.  
 
3.3.2 
Overall Survival 
The OS is defined as the time from the date of first dose of durvalumab until death due to any 
cause. 
• 
OS (days) = (date of death or censoring) − (date of first dose of durvalumab) + 1 
Any patient not known to have died at the time of analysis will be censored at the last recorded 
date at which the patient was known to have been alive. 
The date that an individual patient was last known to be alive will be identified exclusively 
using the data recorded within the SURVIVE and DEATH modules of the eCRF. 
3.3.3 
Objective Response Rate 
The ORR is defined for the SAF as follows: 
• 
The ORR is the proportion (%) of patients with an overall response of CR or PR 
(confirmed by a follow-up scan at least 4 weeks after showing CR or PR).  
A confirmed response of CR/PR means that a response of CR/PR is recorded at one visit and 
confirmed by repeat imaging, preferably at the next regularly scheduled imaging visit, and not 
less than four weeks after the visit when the response was first observed, with no evidence of 
progression between the initial and CR/PR confirmation visit.  Both visits contributing to the 
confirmed response must be prior to any subsequent anti-cancer therapy for the patient to be 


Statistical Analysis Plan  
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36 
considered as a responder. 
Data obtained up until progression, or the last evaluable assessment in the absence of 
progression, will be included in the assessment of the ORR. Responses that occur after the start 
of subsequent anti-cancer therapy must be excluded from the derivation of ORR (ie, only 
responses that occur prior to receiving subsequent therapy will be included in the numerator). 
 
3.3.4 
Best Objective Response 
Best objective response (BoR) is the best response a patient has had after Day 1 up until 
progression, or the last evaluable assessment in the absence of progression. Responses that 
occur after the start of subsequent anti-cancer therapy must be excluded from the derivation. 
Categorization of BoR will be based on RECIST using the following response categories: CR, 
PR, SD, PD and NE. 
CR or PR must be confirmed. For determination of a best response of SD, the earliest of the 
dates contributing towards a particular overall visit assessment will be used. SD should be 
recorded at least 8 weeks minus 1 week, ie, at least 49 days (to allow for an early assessment 
within the assessment window), after durvalumab initiation. For CR/PR, the initial overall visit 
assessment that showed a response will use the latest of the dates contributing towards a 
particular overall visit assessment. 
For patients whose progression event is death, BoR will be calculated based upon all evaluable 
RECIST assessments prior to death. 
For patients who die with no evaluable RECIST assessments, if the death occurs ≤ 9 weeks (ie, 
8 weeks + 1 week to allow for a late assessment within the assessment window) after 
durvalumab initiation, then BoR will be assigned to the progression (PD) category. For patients 
who die with no evaluable RECIST assessments, if the death occurs > 9 weeks after Day 1 then 
BoR will be assigned to the NE category. 
A patient will be classified as a responder if the RECIST criteria for a CR or PR are satisfied at 
any time following Day 1, prior to RECIST progression and prior to starting any subsequent 
cancer therapy. 
 
3.3.5 
Duration of Response 
For patients who are classified as responders (see Section 3.3.3), the DoR is defined as the time 
from the date of first documented response (which is subsequently confirmed) until the first 
date of documented progression or death in the absence of disease progression 
• 
DoR = (date of PFS event or censoring) – (date of start of response) +1 
The date of the end of response will coincide with the date of disease progression or death from 
any cause used for the PFS endpoint (see Section 3.3.1). If a patient does not progress following 
a response, then their DoR will be censored at the date used in the PFS censoring. The date of 


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the initial response will be defined as the latest of the dates contributing toward the first visit 
response of CR or PR that was subsequently confirmed. DoR will not be defined for those patients 
who do not have documented confirmed response. 
DoR will also be obtained using the algorithm described above for the RECIST 1.1 site 
Investigator tumor data 
3.3.6 
Lung Cancer Mortality 
The lung cancer mortality (NSCLC-related death) is assessed using the deaths which are 
reported as ‘NSCLC-related’ and is defined as the time (days) from the date of first dose of 
durvalumab until date of death due to lung cancer as follows: 
• 
Time to lung cancer mortality = (date of NSCLC-related death or censoring) − (date of 
first dose of durvalumab) + 1 
Any patient not known to have died will be censored at the date at which the patient was last 
known to have been alive. Patients who died due to reasons other than NSCLC will be censored 
at the date of death. 
3.4 
 
 
3.4.1 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan  
Study Code D4194C00009 
Edition Number 2.0  
Date 12 January 2024 
38 
  
• 
 
 
• 
 
 
• 
 
 
 
 
• 
 
 
 
 
• 
 
 
• 
 
 
 
• 
 
  
 
3.4.1.1 
 
 
 
• 
 
 
 
• 
 
 
• 
 
• 
   
• 
 
 
 
 
  
• 
 
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Study Code D4194C00009 
Edition Number 2.0  
Date 12 January 2024 
39 
 
 
• 
 
• 
 
 
• 
 
 
 
 
 
  
 
 
 
 
 
• 
 
 
 
• 
 
• 
:  
 
 
 
• 
:  
 
• 
:  
 
 
 
 
 
 
 
 
  
 
Table 6  
 
 
 
 
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Statistical Analysis Plan  
Study Code D4194C00009 
Edition Number 2.0  
Date 12 January 2024 
40 
 
 
 
• 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
3.4.1.2 
 
 
 
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Statistical Analysis Plan  
Study Code D4194C00009 
Edition Number 2.0  
Date 12 January 2024 
41 
 
 
 
 
 
3.4.2 
 
 
 
 
 
 
 
 
3.4.3 
 
 
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Statistical Analysis Plan  
Study Code D4194C00009 
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Date 12 January 2024 
42 
 
3.5 
Other Variables 
3.5.1 
Baseline Characteristics 
Baseline characteristics that will be collected or derived are: 
• 
Demographics: age (years), sex, race and ethnicity. 
• 
Patient characteristics: weight (Kg), height (cm), body mass index (BMI kg/m^2). 
• 
Medical history: name of past and/or concomitant diseases (verbatim and coded using the 
latest or current version of the MedDRA dictionary), start and stop dates. 
• 
Nicotine use: smoking status (current, former, never) and pack years. 
• 
Characteristics of NSCLC at diagnosis: original diagnosis date, primary tumor location, 
histology type, TNM classification, American Joint Committee on Cancer (AJCC) staging. 
• 
Extent of disease at entry of study: current AJCC staging, evidence of disease (yes/no), sites 
of locally advanced disease, recent progression (yes/no, date). 
• 
Previous disease-related radiotherapy: Total dose, Radiotherapy treated location, Time from 
completion of radiotherapy to study treatment, Dose per fraction, Number of fraction doses, 
frequency of fraction doses per day, concomitant chemoradiotherapy, treatment setting, 
radiotherapy technique. 
• 
Previous disease-related cancer therapy: Number of chemotherapy regimens, number of 
cycles, best response to previous chemoradiotherapy, therapy class, treatment status. 
• 
Relevant surgical history: surgical procedure (verbatim and coded using the latest or current 
version of the MedDRA dictionary) and date of surgery. 
3.5.2 
Prior and Concomitant Medications and Therapies 
All therapies (drug or non-drug), including herbal preparations, whether prescribed or over-the-
counter, that are used during the study will be recorded in the eCRF. Details include generic 
and/or brand names of medications, WHO drug dictionary encoding, reason for use, route, dose, 
dosing frequency, and start and stop dates.  
Prior therapies are defined as those with at least one dose/treatment taken before the date of the 
first dose of study medication. 
Concomitant therapies are defined as those with at least one dose/treatment taken between the 
date of first dose (inclusive) and the date of last dose (inclusive) of durvalumab. 
Missing start and stop dates for medications will be imputed using the rules described in Section 
4.1.3. 
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3.5.3 
 
 
 
 
 
4. 
ANALYSIS METHODS 
4.1 
General Principles 
4.1.1 
General Statistical Considerations 
The following general statistical considerations will be applied for the analyses and presentation 
of the data. In case of any specific deviations, methods will be specifically noted on the relevant 
output. 
• 
All data, demography, baseline characteristics, safety, efficacy and biomarkers, will be 
summarized using descriptive statistics, as appropriate for the type of data, for the SAF. 
In addition, all efficacy and safety data and some selected relevant data (eg, patient 
disposition, demography and baseline characteristics) will be summarised separately for 
each cohort (standard radiotherapy and palliative radiotherapy) and overall. 
• 
Continuous variables will be summarized by the number of observations (n), mean, 
standard deviation, median, minimum, and maximum. 
• 
For the continuous data, the summary statistics will be displayed with the following 
accuracy (number of dps): 
• 
The minimum and maximum with same accuracy as the raw data.  
• 
The mean and median will be rounded to 1 additional dp more than the number of 
dps in the raw data.  
• 
The standard deviation will be rounded to 2 additional dps more than the number of 
dps in the raw data.  
• 
If the number of observations is 1, the SD will not be derived. 
• 
Categorical variables will be summarized by frequency counts and percentages for each 
category and percentages will be rounded to one dp.  
• 
As a default, percentages will be calculated using the number of patients who have non-
missing data as the denominator. Therefore, percentages for missing data will not be 
presented in the results. If the denominator is different from this default, it will be 
explained in a footnote to the output. 
• 
SAS® version 9.4 or higher will be used for all analyses. 
• 
Exact CIs for proportions will be calculated using the Clopper-Pearson method. 
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• 
For percentiles of survival times based on the Kaplan-Meier method (eg, median survival), 
CIs will be calculated using the default method available in the SAS LIFETEST procedure 
(ie, the Klein and Moeschberger extension of the Brookmeyer-Crowley method). 
• 
For point-estimates of survival based on the Kaplan-Meier method (eg, for PFS12), CIs 
will be calculated using the default method available in the SAS LIFETEST procedure 
(ie, using Greenwood’s estimate of standard error and a log-log transformation). 
• 
The data will be included in summaries/analyses using the following criteria: 
• 
All laboratory data, vital signs and ECG data that are recorded at unscheduled visits 
will be included in the summaries using the visit windows defined in Section 4.1.4.1.  
• 
The tumor measurements and PRO data should not be affected by any delays in 
treatment cycles/dates of start of treatment cycles as it is intended that they are only 
recorded at pre-scheduled time points. These data will be included in the summaries 
and analyses of the data using the visit windows defined in Section 4.1.4.2. 
• 
All data collected including scheduled, delayed and unscheduled data will be listed in the 
patient data listings which are produced for all treated patients. They will be ordered by 
treatment/not treated, centre, radiotherapy group, patient and visit and, if relevant, 
timepoint when they were recorded. Patients who are included in the SAF will be flagged. 
Depending on the availability of the data, all data for the patients who are not treated will 
be listed separately. They will be ordered by centre, radiotherapy group, patient and visit 
and timepoint, if relevant.  
• 
All adverse events will be coded using MedDRA and NCI CTCAE Grade and will be 
reported using SOC and PT, and NCI CTCAE Grade, as appropriate. 
• 
All concomitant and previous medications will be coded using WHO drug dictionary and 
will be reported using anatomical therapeutic chemical (ATC) classification and generic 
term.  
• 
Baseline is defined as the last assessment of the variable under consideration prior to the 
first dose of durvalumab regardless of whether the assessment is on Day 1, Screening or 
unscheduled.  
• 
Patients who failed the screening in the first instance but later rescreened and passed the 
screening will be part of summary tables along with other patients who passed the 
screening in the first instance. 
• 
Patients who failed both first screening and rescreening will not be part of summary tables 
but a listing will be generated for these patients. 
• 
Participants affected by the COVID-19 pandemic will be listed including category for 
study disruption due to the pandemic and details of disruption. The study disruptions due 
to the pandemic will also be summarized. Subject disposition will be summarized 
including number (%) of patients who discontinued treatment due to the pandemic and 
who withdrew from study due to pandemic. Important protocol deviations will be 
summarized including number (%) of patients with at least one important protocol 


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deviation related to the pandemic. Number and percentage of patients with 
confirmed/suspected COVID-19 infection along with demographic characteristics, 
medical history and adverse event of patients with confirmed/suspected COVID-19 
infection will be presented. If the study has fewer than 5 and/or less than 2% of the 
patient population with confirmed/suspected COVID-19 infection, then a listing will be 
presented instead of summary.  
  
4.1.2 
General Considerations for Summary of Safety Data 
The following considerations are for the summary of safety data. 
• 
The missing values in ECG, vital signs, laboratory data, coagulation and urinalysis will 
not be imputed.  
• 
If triple ECGs are performed, the mean value of any continuous parameters of the ECG 
will be derived first and it will be used as the value of the ECG at that 
timepoint/assessment. For abnormalities, the worst case will be used for any summary 
tables. 
• 
If a laboratory value is reported as <LLQ (where ‘LLQ’ is the lower limit of 
quantification), then LLQ value will be used to impute ‘<LLQ’ for the summary tables. 
In the data listings, this value will be listed as reported <LLQ.  
• 
Any TEAEs with missing causality data will be considered as related to the durvalumab. 
• 
Any partial dates will be presented as reported in the data listings. The partial dates will 
be imputed for the derivation of time to resolution, time to onset etc. using the criteria 
given in Section 4.1.3.  
4.1.3 
Handling of Missing Data 
Missing safety data will generally not be imputed. However, safety assessment values of the 
form of “<x” (ie, below the lower limit of quantification) or >x (ie, 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. 
If the start date of the concomitant medication or AE is missing, the following rules will be 
applied: 
• 
If the year is missing, the year should be imputed as the year that patient received the first 
dose of durvalumab. 
• 
If the year is available and the month and day are missing, then impute the month as 
January and the day as 01 unless year is the same as first dose date then impute first dose 
date. 
• 
If the year and month are available and the day is missing, impute the day as 01 (the first 
day of the month) unless month is same as month of first dose of study drug then impute 
first dose date. 


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• 
If the start date is completely missing and end date is present, then take day and month as 
01Jan and the year from end date. 
If the stop date of the concomitant medication or AE is missing, the following rules will be 
applied: 
• 
If the year is missing, the year should be imputed as the year that patient received the last 
dose of durvalumab.  
• 
If the year is available and the month and day are missing, then impute the month as 
December and the day as 31 unless year is the same as last dose date then impute last dose 
date. If the last dose date is not available then DCO date will be used. 
• 
If the year and month are available and the day is missing, impute the day as the last day 
of the month (eg, 28, 29, 30 or 31) unless month is same as month of last dose date then 
impute last dose date. If the last dose date is not available, DCO date will be used. 
• 
If the end date is completely missing, then look at whether the AE/medication is still 
ongoing before imputing a date and also when it started in relation to study drug. If the 
ongoing flag is missing then assume that AE is still present / medication is still being taken 
(i.e. do not impute a date). If the AE/medication has stopped and start date is prior to first 
dose date then impute the 1st dose date, if it started on or after first dose date then impute 
a date that is 1 day after the last dose date. 
• 
It is not expected to have missing dates for unscheduled laboratory, ECG, diagnostics data. 
However, if there are missing dates, for any derivations, the dates should be imputed 
following the rules for stop date of concomitant medications and AEs  
4.1.4 
Definitions of Visit Windows 
Time windows are defined for all summaries of vital signs, ECG, laboratory data, PRO around 
visits in Section 4.1.4.1 and for tumor assessments around the scheduled RECIST assessment 
time in Section 4.1.4.2. 
4.1.4.1 
Visit Windows for Safety and PRO Assessments 
The following conventions will apply for safety and PRO data: 
• 
The time windows should be exhaustive so that data recorded at any time point has the 
potential to be summarized. Inclusion within the time window should be based on the 
actual date and not the intended date of the visit. 
• 
All unscheduled visit data will 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 halfway between the two visits (the lower limit of the first 
post-baseline visit will be Day 2).  If an even number of days exists between two 
consecutive visits, then the upper limit will be taken as the midpoint value minus 1 day.   
For example, the visit windows for vital signs data are: 


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• 
Week 1; nominal day 1, visit window Day 1 
• 
Week 4; nominal day 29, visit window 2 – 42 
• 
Week 8; nominal day 57, visit window 43 – 70 
• 
Week 12; nominal day 85, visit window 71 – 98 
• 
Week 16; nominal day 113, visit window 99 – 126 
• 
Visits after treatment discontinuation will be assigned to the last treatment cycle for 
up to 15 days only. Visits after the 15 days will contribute to the following 30 days 
post treatment discontinuation interval, see below. 
• 
Visits up to 90 days after last dose will be assigned similarly to the definition for the visits 
under treatment, but for 30 day intervals after treatment discontinuation, eg,: 
• 
30 days after last dose, visit window 16 – 45  
• 
60 days after last dose, visit window 46 – 75  
• 
90 days after last dose, visit window 76 – 97 
• 
Data recorded after 97 days after last dose will not contribute to the analysis period 
of up to 90 days following the date of last dose, and will not be re-mapped 
• 
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 based summaries: 
• 
If there is more than one value per patient within a time window then the closest value to 
the scheduled visit date should be used, 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 the 
parameter is CTCAE gradable then the record with the highest toxicity grade should be 
used. The listings should highlight the value for that patient that went into the summary 
table, wherever feasible. Note: in summaries of extreme values all on-treatment values 
collected are used including those collected at unscheduled visits.   
• 
For summaries at a patient level, all values should be included, regardless of whether they 
appear in a corresponding visit-based summary, when deriving a patient level statistic such 
as a maximum.  
4.1.4.2 
Visit Windows for Tumor Assessments 
The following conventions will apply for tumor assessment data: 
• 
All tumor assessments available during the study should be used for the efficacy analysis. 
A windowing rule will be applied and will follow the CSP allowed visit window; 
therefore, any RECIST assessment performed within ± 1 week of the CSP scheduled visit 
will be used for that visit. 


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• 
If there are any assessments outside these visit windows, they will also be included in the 
closest visit window following the intent-to-treat principle.  The tumor assessments which 
are outside the visit windows will be flagged in the data listings.  
The above could result in more than one tumor assessments within a window and in that case, 
the one closest to the scheduled assessment will be used.  
4.2 
Study Population 
4.2.1 
Patient Disposition 
The following patient disposition summaries will be produced: 
• 
The number and percentage of patients who were screened, who were screening failures, 
and who received and did not receive durvalumab will be summarised for all patients. 
• 
Discontinuation from durvalumab and/or discontinuation from study, together with reason 
for discontinuation (including the reason due to COVID-19 Pandemic) will be summarised 
using the SAF. 
• 
Disruptions due to COVID-19  
• 
Summary of confirmed/suspected COVID-19 infection. 
The date of the last contact (date of withdrew consent/lost to follow-up/died) will be listed in 
patient disposition listings. COVID-19 study disruptions will also be listed along with issues 
reported in the Clinical Trial Management System. 
 
4.2.2 
Protocol Deviations  
Important protocol deviations are defined in Section 2.2 and will be listed and summarized for 
the SAF. 
The number and percentage of patients with any IPD will be summarized for each IPD category. 
Patients with more than one deviation in the same IPD category will be counted once for that 
IPD category. Any patients who have deviations in more than one IPD category will be counted 
once in the overall summary. The number of patients with at least 1 COVID-19 related 
important protocol deviation and the number of patients with at least 1 important protocol 
deviation, excluding COVID-19 will be presented by IPD category. 
4.2.3 
Demography and Baseline Characteristics 
Demographic and other baseline characteristics (see Section 3.5.1) will be listed for all patients 
and summarised for the SAF, as: 
• 
Demographics (age (years), age group [<50, ≥50-< 65, ≥ 65-<75, and ≥ 75 years], sex, 
race and ethnicity) 
• 
Demographic characteristics in patients with confirmed/suspected COVID-19 infection. 


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• 
Patient characteristics at baseline (height (cm), weight (kg) [prior to start of radiotherapy, 
and after radiotherapy at screening, and the change], weight groups [<40, ≥40-< 75, ≥ 75-
<90, ≥ 90-<120, and  ≥ 120 kg], body mass index (BMI kg/m^2) after radiotherapy, and 
BMI groups [Underweight (<18.5), Normal weight (≥18.5 - <25.0), Overweight (≥25.0 - 
<30.0), Obese (≥30.0) kg/m^2] 
• 
Nicotine use and consumption  
• 
A summary and a list of patients by site and country will be provided. 
• 
Previous disease-related radiotherapy and cancer therapy. 
• 
Disease characteristics (
, AJCC staging at baseline 
and diagnosis, histology type at diagnosis, TNM classification at diagnosis, tumor location 
and time from diagnosis to first dose 
• 
Extent of disease (Radiological assessment, site of locally advanced disease, recurrence 
of earlier cancer, NSCLC progressing at study entry, time from most recent progression 
to study entry, reason tumor not amenable for resection 
• 
Medical history in patients with confirmed/suspected COVID-19 infection. 
Medical history and relevant surgical history are coded using MedDRA and will be summarized 
by SOC and PT.  
4.2.4 
Previous and Concomitant Medications and Procedures 
Prior and concomitant medications and procedures will be listed for all patients in the SAF. 
Concomitant medications and procedures will be summarized by therapeutic subgroup (ATC 
2nd level), chemical subgroup (ATC 4th level), and preferred WHO name for the SAF. Patients 
with the same concomitant medication/procedure multiple times will be counted once per 
medication/procedure. A medication/procedure that can be classified into more than one 
chemical and/or therapeutic subgroups will be presented in each subgroup. 
4.2.5 
Study Drug Administration 
Individual patient data for study drug administration will be listed for all patients in the SAF. 
4.3 
Analysis of Primary Safety Endpoint 
The primary endpoint of this study is the incidence of Grade 3 and Grade 4 PRAEs (see Section 
3.2.3.1) which occur within the first six months (ie, up to and including the 183rd day) after the 
initiation of durvalumab. Any Grade 3 or Grade 4 PRAEs which started after the 183rd day of 
the study, or after the 90th day following discontinuation of durvalumab, or after the start of 
subsequent anti-cancer therapy will not be included. 
The number and percentage (and exact Clopper-Pearson 95% CI) of patients with NCI CTCAE 
Grade 3 or Grade 4 PRAEs, both overall and for those occurring within the first six months after 
initiation, will be summarized for the SAF for all patients and within the standard and palliative 
radiotherapy cohorts. This summary will also be graphically presented as a bar chart. The 
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number and percentages of patients with NCI CTCAE Grade 3 or Grade 4 PRAEs will also be 
summarized by SOC and PT. 
4.4 
Analysis of Secondary Efficacy Endpoints 
4.4.1 
Progression-Free Survival 
Kaplan-Meier plots and descriptive statistics will be provided for PFS. Summary statistics will 
include lower and upper quartile and median PFS, PFS6 (Day 180) and PFS12 (Day 365). 
Summaries of the number (%) of patients experiencing a PFS event (overall and also at Month 
6 and Month 12) and the type of event (disease progression or death) will be provided. 
All summary statistics will be presented with the appropriate 95% CI. 
If necessary, a sensitivity analysis will be conducted to assess the potential impact of COVID-
19 related deaths on PFS. That is, patients who had a PFS event due to death where the primary 
or secondary cause of death was COVID-19 infection or COVID-19 infection was reported as 
a fatal AE, will be censored at the last evaluable RECIST 1.1 assessment prior to COVID-19 
infection related death. 
4.4.2 
Overall Survival 
The following numbers (%) of patients in the SAF will be presented at 12-month (Day 365) 
intervals and overall: those who have died, those still in survival follow-up, those lost to 
follow-up, those who withdrew consent, and those with censored OS.  
Kaplan-Meier plots and descriptive statistics will be presented for OS. Summaries will include 
the lower and upper quartile and median OS and estimates of OS12 (Day 365).  
All summary statistics will be presented with the appropriate 95% CI. 
If necessary, a sensitivity analysis will be conducted to assess the potential impact of COVID-
19 related deaths on OS. That is, patients who had a death event where the primary or 
secondary cause of death was COVID-19 infection or COVID-19 infection was reported as a 
fatal AE, will be censored at the date of their COVID-19 infection related death. 
4.4.3 
Objective Response Rate 
The ORR will be estimated for the SAF and will be presented with the corresponding exact 95% 
CIs.  
The number (%) of patients with a confirmed response and the number (%) of patients with a 
single visit response (ie, an unconfirmed response) will also be presented. 
Best objective response (BoR) will be summarised by n (%) for each category (CR, PR, SD, PD 
and NE).  
4.4.4 
Duration of Response 
A Kaplan-Meier plot and descriptive statistics will be provided for the DoR and the respective 


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Time to onset of first response for patients in the SAF who had responded to treatment (see 
Section 3.3.5). Summary statistics will include: lower and upper quartile and median DoR with 
appropriate 95% CIs. 
4.4.5 
Time to Lung Cancer Mortality (NSCLC-Related Death) 
The following numbers (%) of patients in the SAF will be presented at 12-monthly intervals 
and overall: those with an NSCLC-related death, those still in survival follow-up, those lost to 
follow-up, those who withdrew consent, and those with censored time to lung-cancer mortality 
(separately for those who died from a cause not related to NSCLC and other reasons for 
censoring, as well as overall).  
Kaplan-Meier plots and descriptive statistics will be presented for time to NSCLC-related 
mortality. Summaries will include the lower and upper quartile and median lung cancer 
mortality and estimates at Month12 (Day 365). 
All summary statistics will be presented with the appropriate 95% CI. 
4.5 
Analysis of Secondary Safety Endpoints 
4.5.1 
Adverse Events 
All TEAEs reported up until 90 days following completion or discontinuation of durvalumab 
treatment or until the initiation of the first subsequent therapy (whichever occurs first) will be 
included in the summaries unless explicitly stated otherwise below. 
All TEAEs will be summarised descriptively, in terms of number of patients (n) and percentage 
of patients (%) reporting the event by MedDRA SOC and PT.  
Listings of AEs will include the date of onset, date of resolution (if AE is resolved) and 
investigator’s assessment of severity, relationship to durvalumab, and NCI CTCAE Grade. 
Separate listings will be produced for all AEs, PRAEs, SAEs, AESIs, AEPIs, imAEs, AEs with 
outcome of death, AEs leading to discontinuation of durvalumab, AEs leading to 
discontinuation of study. Listings of AESIs, AEPIs and imAEs will also include the additional 
information (eg, intervention, dose, duration of therapy etc.) recorded for these AEs. All AEs 
that are not treatment-emergent will be flagged in the data listings and the time of onset will be 
flagged as ‘pre-treatment’, ‘post-treatment and no other anti-cancer therapy’ and ‘after initiation 
of other anti-cancer therapy’. 
An overall summary of AE data will be presented including the number and percentage of 
patients reporting the following: 
• 
At least one AE 
• 
At least one PRAE 
• 
At least one AE of CTCAE Grade 3 or Grade 4 
• 
At least one PRAE of CTCAE Grade 3 or Grade 4 
• 
At least one SAE 
• 
At least one Serious PRAE 
• 
At least one AE leading to discontinuation of study treatment 


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• 
At least one PRAE leading to discontinuation of study treatment 
• 
At least one AE leading to treatment interruption 
• 
At least one PRAE leading to treatment interruption 
• 
At least one AE with outcome of death 
• 
At least one PRAE with outcome of death 
• 
At least one AESI 
• 
At least one AEPI 
• 
At least one PRAE of special interest (AESI) 
• 
At least one PRAE of possible interest (AEPI) 
• 
At least one imAE 
• 
At least one immune-mediated PRAE 
 
The following summaries including the number and percent of patients by SOC and PT will be 
presented separately: 
• 
All AEs / PRAEs 
• 
All AEs / PRAEs of CTCAE Grade 3 or Grade 4 
• 
All PRAEs of CTCAE Grade 3 or Grade 4 occurring within the six months of first dosed 
date 
• 
All PRAEs which start within 90 days of last dose of durvalumab (irrespective of start of 
subsequent anti-cancer therapy) 
• 
All AEs 
• 
This summary will include an AE event rate (per 100 patient years) for each PT. The 
number of patients with an AE in each PT is divided by the sum of the actual 
exposure to durvalumab (days) (see Section 0) over all patients. This is multiplied 
by 365.25 x 100 to create an event rate per 100 patient years. 
• 
All AEs by maximum CTCAE Grade 
• 
All AEs / PRAEs with outcome of death 
• 
All SAEs / Serious PRAEs 
• 
All AEs / PRAEs leading to discontinuation from durvalumab (Note: Reason for 
discontinuation recorded on the patient disposition page) 
• 
All AEs / PRAEs leading to dose interruption/discontinuation of durvalumab (Note: 
Reason for discontinuation recorded on the patient disposition page) 
 
A summary of most common AEs and another summary of most common AEs with CTCAE 
Grade 3 or higher, including all events that occur in at least 2.5% of patients overall will be 
presented by PT, by decreasing frequency. This cut-off may be modified after review of the 
data. The raw percentage will be compared to the cut-off, without applying any rounding to the 
percentage value (ie, a TEAE with frequency of 2.4% will not appear in the table if a 
cut-off is 2.5%). 
A summary of deaths will be provided with the following information: 
• 
Number of deaths (NSCLC-related, non-related, and unknown) 
• 
Number of deaths during the on-treatment study period up until 90-day follow-up 


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and prior to initiation of first subsequent therapy 
• 
Number of deaths occurring more than 90 days after the discontinuation of 
durvalumab or after initiation of first subsequent therapy 
Listings of key patient information for Deaths and SAEs will be provided. 
4.5.1.1 
Adverse Events of Special Interest and Possible Interest 
Preferred terms used to identify adverse events of special interest and possible interest (as 
defined in 3.2.3) will be listed before DBL and documented in the Study Master File. Grouped 
summary tables of certain MedDRA preferred terms will be produced and may also show the 
individual preferred terms which constitute each AESI/AEPI grouping. Groupings will be based 
on preferred terms provided by the medical team prior to DBL, and a listing of the preferred 
terms in each grouping will be provided. 
Summaries of the above-mentioned grouped AE categories will include number (%) of patients 
who have: 
• 
Any AESI/AEPI 
• 
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 AESI/AEPI with outcome of death 
• 
Any AESI/AEPI possibly related to study treatment 
• 
Any AESI/AEPI leading to concomitant medication use (steroids) 
• 
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) 
• 
At least one AESI/AEPI leading to discontinuation of study treatment 
• 
Possibly related AESI/AEPI leading to discontinuation of study treatment 
• 
Time to onset of first AESI/AEPI (days) 
• 
Duration (days) of AESI/AEPI 
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. 


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4.5.1.2 
Immune-mediated Adverse events (imAEs) 
The imAEs will be summarized in the similar manner as for the summaries for AESI/AEPI 
described above. 
4.5.1.3 
COVID-19 related Adverse events 
The following summaries of AE data will be presented including the number and percentage of 
patients with: 
• 
Any AE in patients with confirmed/suspected COVID-19 infection 
• 
Any AE in patients without confirmed/suspected COVID-19 infection 
• 
Any AE by SOC, PT and maximum CTCAE grade in patients with 
confirmed/suspected COVID-19 infection. 
• 
Any AE by SOC, PT and maximum CTCAE grade in patients without 
confirmed/suspected COVID-19 infection 
• 
Any AE associated with COVID-19 infection by SOC and PT 
• 
Any AE excluding AEs associated with COVID-19 infection by SOC and PT 
• 
Any AE with confirmed/suspected COVID-19 infection by SOC and PT 
• 
Any AE excluding confirmed COVID-19 infection by SOC and PT 
• 
Any AE associated with COVID-19 infection and with outcome of death by SOC 
and PT 
• 
Any AE excluding associated with COVID-19 infection and with outcome of death 
by SOC and PT 
• 
Any AE associated with COVID-19 infection leading to discontinuation of 
investigational product by SOC and PT 
• 
Any AE excluding associated with COVID-19 infection leading to discontinuation 
of investigational product by SOC and PT 
4.5.2 
Electrocardiograms 
The data for the ECG are used for safety monitoring and to identify AEs. No summaries or 
listings will be created. 


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4.5.3 
Vital Signs 
Box plots of the vital signs results by visit will be presented. 
4.5.4 
Laboratory Data 
Laboratory data obtained up until the 90 days following discontinuation of study treatment or 
until the initiation of the first subsequent anti-cancer therapy following discontinuation of study 
treatment (whichever occurs first) will be used for reporting.  
Absolute values and change from baseline for all continuous haematology and clinical 
chemistry laboratory parameters will be summarised by visit. If a patient does not have the 
baseline value of laboratory data or the value at visit, the change from baseline is considered as 
missing. 
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: 
• 
Haematology: Haemoglobin, Leukocytes, Lymphocytes (absolute count), Neutrophils 
(absolute count), Platelets,  
• 
Clinical chemistry: Alanine transaminase (ALT), Aspartate transaminase (AST), alkaline 
phosphatase (ALP), Total bilirubin, total protein, Sodium (hypo- and hyper-), Potassium 
(hypo- and hyper-), Corrected calcium (hypo- and hyper-), Glucose (hypo- and hyper-), 
and Creatinine  
For categorical urinalysis parameters (Bilirubin, Blood, Glucose, Protein), a shift table will be 
produced comparing baseline value to maximum on-treatment value.  
For the parameters with no CTCAE grading that are listed in the CSP the number and percentage 
of patients with laboratory values outside normal range will be summarized by shift tables from 
baseline to the post-baseline maximum and minimum value on-treatment. 
4.5.4.1 
Liver Enzyme Elevations and Hy's Law 
The following summaries (n, %) of the laboratory data will be used to identify cases of Hy’s 
law: 
• 
Elevated ALT, AST, and total bilirubin during the study 
• 
ALT ≥ 3x – ≤ 5x, > 5x – ≤8x, > 8x, >10x and >20x upper limit of normal (ULN) 
during the study 
• 
AST ≥ 3x – ≤ 5x, > 5x – ≤8x, > 8x. >10x and >20x ULN during the study 
• 
Total bilirubin ≥2x – ≤3x, >3x – ≤5x, >5x ULN during the study 
• 
ALT or AST ≥3x – ≤5x, >5x – ≤8x, >8x, >10x and >20x ULN during the study 
• 
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law): The onset date of ALT or AST elevation should be prior to or on the date of 
total bilirubin elevation 
Narratives will be provided in the CSR for patients who have ALT ≥ 3x ULN plus Total 
bilirubin ≥ 2x ULN or AST ≥ 3x ULN plus Total bilirubin ≥ 2x ULN at any visit. 
Liver biochemistry test results over time for patients with elevated ALT or AST (ie, ≥ 3x ULN), 
and elevated Total bilirubin (ie, ≥ 2x ULN) (at any time) will be plotted.  
Plots of post-baseline ALT and AST vs. post-baseline total bilirubin will also be produced with 
reference lines at 3×ULN for ALT, AST, and 2×ULN for Total bilirubin. In each plot, total 
bilirubin will be in the vertical axis.  
4.5.4.2 
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): 
• 
On-treatment elevated TSH > ULN 
• 
On-treatment elevated TSH > ULN with TSH ≤ ULN at baseline 
• 
On-treatment elevated TSH > ULN  
• With at least one T3 free/ T4 free < LLN 
• With all other T3 free/ T4 free ≥ LLN 
• With T3 free/ T4 free missing 
• 
On-treatment low TSH < LLN 
• 
On-treatment low TSH < LLN with TSH ≥ LLN at baseline 
• 
On-treatment low TSH < LLN  
• With at least one T3 free/ T4 free > ULN 
• With all other T3 free/ T4 free ≤ ULN 
• With T3 free/ T4 free missing 
4.5.4.3 
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 during on-treatment meeting the following categories will be 
presented: 
• 
Shift to worse renal impairment category from baseline 
• 
Patients with subsequent CrCl assessment after worsening from baseline 
• 
Worsened renal impairment reversible and transient 
 
The renal impairment categories are defined as: 
o Normal: CrCl ≥ 90 mL/min 
o Mild Impairment: CrCl ≥ 60 - < 90 mL/min 
o Moderate Impairment: CrCl ≥ 30 - < 60 mL/min 
o Severe Impairment: CrCl ≥ 15 - < 30 mL/min 
o Kidney Failure: CrCl < 15 mL/min 


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57 
 
Creatinine clearance rate will be calculated using serum creatinine and the Cockcroft-Gault 
formula (Cockcroft and Gault 1976). 
4.5.5 
Exposure 
The following summaries will be presented for durvalumab exposure: 
• 
Total (or intended) exposure 
• 
Actual exposure 
• 
Number of cycles received 
• 
Number and Reasons for dose delays of durvalumab. Dose interruptions will be based on 
investigator initiated dosing decisions.  
• 
Relative dose intensity 
4.6 
Analysis of Exploratory Endpoints 
 
 
4.6.1 
 
 
 
 
 
 
. 
 
 
  
 
 
 
 
 
• 
 
 
  
• 
  
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58 
4.6.2 
 
 
 
 
4.6.3 
 
 
 
. 
4.6.4 
 
 
 
 
 
4.6.5 
 
 
 
 
5. 
INTERIM ANALYSES 
No formal interim analysis is planned for this study. 
A data analysis is planned to be performed once all patients had the opportunity to receive 
treatment for 6 months, ie, the DCO for this primary analysis would be expected 6 months after 
the last patient has received first dose of durvalumab. The final analysis will be performed at 
the end of the study when all patients have completed follow-up, or the trial has finished.  
6. 
CHANGES OF ANALYSIS FROM PROTOCOL 
No summary output or listings will be produced for ECG parameters as ECG data is only used 
for safety monitoring and to identify AEs. For vital sign parameters only box plots will be 
produced. 
 
 
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Study Code D4194C00009 
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Date 12 January 2024 
59 
  
7. 
REFERENCES 
 
AstraZeneca 2019  
AstraZeneca, Durvalumab and Tremelimumab Immune-mediated Adverse Events (imAE) 
Characterization Charter, Edition Number 4.2, Date 10 June 2019 
 
Aaronson et al 1993 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst 1993;85(5):365-76.  
 
AJCC  
The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a 
population-based to a more “personalized” approach to cancer staging, CA Cancer J Clin, 
2017;67-93-99 
 
Basch et al 2009 
Basch E, Jia X, Heller G, Barz A, Sit L, Fruscione M, et al. Adverse symptom event reporting 
by patients vs clinicians: relationship with clinical outcomes. J Natl Cancer Inst 2009;101: 1624-
32. 
 
Bergman et al 1994 
Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M. The EORTC QLQ-LC13: a 
modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in 
lung cancer clinical trials. EORTC Study Group on Quality of Life. Eur J Cancer 
1994;30A (5):635-42. 
 
IASLC 2016 
International Association for the Study of Lung Cancer. Staging Manual in Thoracic Oncology. 
Rami-Porta 
R, 
editor; 
2nd 
edition. 
2016. 
Available 
from 
URL: 
https://www.iaslc.org/sites/default/files/wysiwyg-assets/8th_staging_manual_2016_hi-res.pdf. 
Accessed 11 May 2018. 
 
ICH 1995 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH). Structure and Content of Clinical Study Reports E3; 
Version 4; No 1995 
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(6):1988-92. 
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Statistical Analysis Plan  
Study Code D4194C00009 
Edition Number 2.0  
Date 12 January 2024 
60 
Osoba et al 1998 
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998;16(1):139-44.  
SAS 
SAS/STATS® User Guide, Version 9.3, Cary, North Carolina, SAS Institute Inc. 
 
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(7):743-60.


 
 
8. 
APPENDIX 
Schedule of activities are presented in Table 1 and Table 2 of the CSP. 


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