Conditions: Non-small Cell Lung Cancer (NSCLC)
Keywords: Stage III Non-Small Cell Lung Cancer Durvalumab IV infusion immunoglobulin G (IgG) Antibody-dependent cellular cytotoxicity Complement-dependent cytotoxicity Monotherapy
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 117
Healthy volunteers: no

Brief summary:
This is a Phase II, open-label, multi-centre study to determine the safety of a fixed dose of Durvalumab (MEDI4736) (1500 mg) every 4 weeks \[q4w\] in participants with unresectable Stage III Non-Small Cell Lung Cancer (NSCLC), who have not progressed following platinum-based sequential chemoradiation therapy (sCRT). This study will be conducted in Europe and North America.

Detailed description:
This is a Phase II, open-label, multi-centre study to determine safety of a fixed dose of Durvalumab (MEDI4736) (1500 mg) monotherapy in participants with unresectable Stage III NSCLC who have not progressed following definitive, platinum-based sCRT. Approximately, 150 participants will be treated with the study drug in Europe and North America. Participants will be in complete response (CR), partial response (PR), or have stable disease (SD) following definitive, platinum-based sCRT, as assessed by the Investigator and further supported by the screening imaging radiological assessment. Participants must not have progressed following definitive, platinum-based sCRT; radiation therapy must be completed within 42 days prior to first Investigational product (IP) dose administration. Participants must have histologically- or cytologically-documented NSCLC and locally-advanced, unresectable Stage III disease. Participants will be treated with the study drug in 2 cohorts: approximately 100-120 participants in the World Health Organization/Eastern Cooperative Oncology Group Performance Status (WHO/ECOG PS) 0 to 1 Cohort and up to 30 participants in the WHO/ECOG PS 2 Cohort.

Arms:
arm 1: 100-120 participants will receive 1500 mg Durvalumab (MEDI4736) monotherapy via IV infusion q4w for up to a maximum of 24 months (up to 26 doses/cycles) with the last administration at Week 104. The study drug should be discontinued prior to 24 months if there is clinical progression or confirmed radiological progression or if there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. arm 2: up to 30 participants will receive 1500 mg Durvalumab (MEDI4736) monotherapy via IV infusion q4w for up to a maximum of 24 months (up to 26 doses/cycles) with the last administration at Week 104. The study drug should be discontinued prior to 24 months if there is clinical progression or confirmed radiological progression or if there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.

Interventions: intervention 1: Durvalumab
Intervention descriptions: intervention 1: Participants will receive 1500 mg Durvalumab monotherapy via IV infusion q4w for up to a maximum of 24 months with the last administration at Week 104.

Protocol document:
Prot_002.pdf: 


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Clinical Study Protocol 
Drug Substance
Durvalumab (MEDI4736)
Study Code
D4194C00006
Version
4.0
Date
06 July 2021
A Phase II, Open-Label, Multi-Centre, International Safety Study 
of Durvalumab Following Sequential Chemotherapy and Radiation 
Therapy in Patients with Stage III, Unresectable Non-Small Cell
Lung Cancer (PACIFIC 6)
 
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s): 
EudraCT Number: 2018-002220-16




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Section 8.1.2.4 (Administration of patient-reported outcome questionnaires): It was added that an 
appropriate back-up option for the ePRO device used to complete the PRO questionnaires may be considered
if technical or other issues prohibit completion on the device.  A reference to new Section 4.1.1 (Study 
Conduct Mitigation During Study Disruptions Due to Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis) was added to the general rule that site staff should not read or complete the PRO questionnaires on 
behalf of the patient.
Section 8.3.13 (Safety data to be collected following the final data cut-off of the study): It was clarified 
that in this section the DCO is referring to the final DCO.
Section 8.4.1 (Reporting of serious adverse events): The guidance on how to proceed if the WBDC system 
is unavailable was updated to match the safety handling plan.
Section 8.4.5.1 (Specific toxicity management and dose modification information – Durvalumab and 
durvalumab + tremelimumab): The reference to the website containing the current Dosing Modification and 
Toxicity Management Guidelines was removed.
Appendix G (Patient-reported outcomes): It was clarified in a footnote to the 
 
questionnaire that initials and full Date of Birth will not be asked from the patient.
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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY........................................................................................................... 2
TABLE OF CONTENTS...................................................................................................... 6
1
PROTOCOL SUMMARY................................................................................ 11
1.1
Synopsis ........................................................................................................... 11
1.2
Schedule of assessments ................................................................................... 16
1.3
Schema............................................................................................................. 23
2
INTRODUCTION............................................................................................ 24
2.1
Study rationale.................................................................................................. 25
2.2
Background ...................................................................................................... 25
2.2.1
Unmet need and potential role of immunotherapies in NSCLC ......................... 25
2.2.2
Immunotherapies .............................................................................................. 28
2.2.3
Durvalumab (MEDI4736)................................................................................. 30
2.3
Benefit/risk assessment..................................................................................... 30
2.3.1
Potential benefits .............................................................................................. 31
2.3.2
Overall risks ..................................................................................................... 31
2.3.2.1
Durvalumab (MEDI4736) risks......................................................................... 32
2.3.3
Overall benefit/risk ........................................................................................... 33
3
OBJECTIVES AND ENDPOINTS................................................................... 33
4
STUDY DESIGN ............................................................................................. 35
4.1
Overall design................................................................................................... 35
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 38
4.2
Scientific rationale for study design .................................................................. 39
4.2.1
Rationale for study safety endpoints.................................................................. 39
4.2.2
Rationale for study efficacy endpoints .............................................................. 40
4.2.3
Rationale for other study exploratory endpoints ................................................ 40
4.2.4
Rationale for treatment duration........................................................................ 41
4.2.5
Timing of treatment with durvalumab (MEDI4736) relative to sequential 
chemoradiation therapy..................................................................................... 41
4.3
Justification for dose......................................................................................... 42
4.3.1
Durvalumab (MEDI4736) monotherapy dose rationale ..................................... 42
4.3.2
Rationale for fixed dosing................................................................................. 43
4.3.3
Predictive biomarkers and rationale for an unselected population in the 
PACIFIC 6 Study.............................................................................................. 44
4.4
End of study definition...................................................................................... 45
5
STUDY POPULATION ................................................................................... 46
5.1
Inclusion criteria............................................................................................... 46
5.2
Exclusion criteria.............................................................................................. 49




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8.3
Collection of adverse events ............................................................................. 78
8.3.1
Method of detecting adverse events and serious adverse events......................... 78
8.3.2
Time period and frequency for collecting adverse event and serious adverse 
event information.............................................................................................. 79
8.3.3
Follow-up of adverse events and serious adverse events.................................... 79
8.3.4
Adverse event data collection............................................................................ 79
8.3.5
Causality collection........................................................................................... 81
8.3.6
Adverse events based on signs and symptoms................................................... 81
8.3.7
Adverse events based on examinations and tests ............................................... 81
8.3.8
Hy’s law ........................................................................................................... 82
8.3.9
Disease progression .......................................................................................... 82
8.3.10
New cancers ..................................................................................................... 82
8.3.11
Deaths .............................................................................................................. 82
8.3.12
Adverse events of special interest ..................................................................... 83
8.3.13
Safety data to be collected following the final data cut-off of the study............. 84
8.4
Safety reporting and medical management........................................................ 84
8.4.1
Reporting of serious adverse events .................................................................. 84
8.4.2
Pregnancy......................................................................................................... 85
8.4.2.1
Maternal exposure ............................................................................................ 85
8.4.2.2
Paternal exposure.............................................................................................. 86
8.4.3
Overdose .......................................................................................................... 86
8.4.4
Medication error ............................................................................................... 86
8.4.5
Management of investigational product-related toxicities.................................. 87
8.4.5.1
Specific toxicity management and dose modification information –
Durvalumab and durvalumab + tremelimumab.................................................. 87
8.5
Pharmacokinetics.............................................................................................. 88
8.6
Pharmacodynamics........................................................................................... 88
8.7
.... 88
8.7.1
.... 88
8.7.2
.... 89
8.8
.... 89
8.8.1
.... 89
8.8.1.1
.... 90
8.8.1.2
.... 91
8.8.2
.... 91
8.8.3
.... 91
8.8.4
.... 91
8.8.4.1
.... 91
8.8.4.2
.... 92
8.8.4.3
.... 92
8.9
Health economics ............................................................................................. 92
9
STATISTICAL CONSIDERATIONS............................................................... 93
9.1
Statistical hypotheses........................................................................................ 93
9.2
Sample size determination ................................................................................ 93
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LIST OF FIGURES
Figure 1
Study design schema................................................................................ 23
Figure 2
Study flow chart ...................................................................................... 37
Figure 3
Durvalumab (MEDI4736) monotherapy dosing schedule......................... 57
LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations........................... 112
Appendix B
Adverse event definitions and additional safety information .................. 117
Appendix C
Handling of human biological samples .................................................. 122
Appendix D
124
Appendix E
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s law........................................................................... 128
Appendix F
Guidelines for evaluation of objective tumour response using RECIST 
1.1 criteria (Response Evaluation Criteria in Solid Tumours)................. 133
Appendix G
Patient-reported outcomes...................................................................... 144
Appendix H
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis, including 
COVID-19 Outbreak.............................................................................. 151
Appendix I
Abbreviations ........................................................................................ 155
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: 
A Phase II, Open-Label, Multi-Centre, International Safety Study of Durvalumab Following 
Sequential Chemotherapy and Radiation Therapy in Patients with Stage III, Unresectable 
Non-Small Cell Lung Cancer (PACIFIC 6)
Rationale:
This study is being conducted to provide safety, efficacy, and quality of life (QoL) data to 
complement the results of the PACIFIC Study, which assessed treatment with durvalumab
(MEDI4736) in patients with unresectable Stage III non-small cell lung cancer (NSCLC) who 
had not progressed after concurrent chemoradiation therapy (cCRT). Durvalumab 
(MEDI4736) was approved by the United States (US) Food and Drug Administration (FDA) 
for the treatment of unresectable Stage III NSCLC in February 2018. This study will expand 
on the data currently available from the PACIFIC Study by assessing the clinical profile of 
durvalumab (MEDI4736) in patients who have not progressed after sequential chemoradiation 
therapy (sCRT), and in patients of World Health Organisation/Eastern Cooperative Oncology 
Group Performance Status 0 to 1 and 2 (WHO/ECOG PS 0 to 1 and 2). 
OBJECTIVE
ENDPOINT/VARIABLE
PRIMARY OBJECTIVE
To assess the safety and tolerability profile of 
durvalumab (MEDI4736) as defined by Grade 3 and 
Grade 4 TRAEsa within 6 months from the 
initiation of durvalumab (MEDI4736) treatment
Grade 3 or Grade 4 TRAEsa
SECONDARY OBJECTIVES
Efficacy objectives
To assess the efficacy of durvalumab (MEDI4736) 
treatment in terms of PFS and OS 
Median PFS according to RECIST 1.1as assessed by 
the Investigator
Median PFS12 and PFS24 according to RECIST 1.1 as 
assessed by the Investigator
Median OS, OS12, OS24, and OS36
To further assess the efficacy of durvalumab 
(MEDI4736) 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 (MEDI4736) 
treatment in terms of lung cancer mortality
Lung cancer mortality
Secondary safety objective






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Tumour assessments
Tumour assessments will be performed as per RECIST 1.1 criteria, using computed 
tomography (CT)/magnetic resonance imaging (MRI).  The baseline assessment is part of the 
screening procedures and should be performed within 28 days after the end of sCRT and 
before the start of study drug.  Imaging assessment performed according to local standard of 
care (SoC) within 28 days before the first dose of study drug, but prior to signing the informed 
consent form (ICF), can be used for screening purposes if the patient consents to the use of 
those results.  Efficacy for all patients will be assessed by objective tumour assessments every 
8 weeks (q8w) for the first 12 months and every 12 weeks (q12w) thereafter, until confirmed 
objective disease progression as defined by RECIST 1.1 (irrespective of the reason for 
stopping study drug and/or initiation of subsequent therapy).  If an unscheduled assessment is 
performed and the patient has not progressed, every attempt should be made to perform the 
subsequent assessments at their scheduled visits.  The schedule of imaging radiological 
assessments must be followed regardless of any dose delays with durvalumab (MEDI4736).
Progression during treatment
During the treatment period, patients who are clinically stable at an initial 
RECIST 1.1‑defined radiological PD may continue to receive study drug at the discretion of 
the Investigator and patient, after re-consenting for treatment through progression.  A 
follow-up scan is to be performed after the initial RECIST 1.1-defined radiological PD, no 
less than 4 weeks after the prior assessment of PD and no later than the next regularly 
scheduled imaging visit, and this scan is evaluated using the Confirmation of Radiological 
Progression Criteria.  If the subsequent scan does not confirm the immediate prior radiological 
PD, then the patient may continue on study drug at the discretion of the Investigator and after
the patient has consented to do so; imaging assessments should continue until the next 
RECIST 1.1-defined PD, which in turn will require a subsequent scan evaluated using the 
Confirmation of Radiological Progression Criteria.    
Follow-up of patients post discontinuation of study drug
Patients who have discontinued treatment due to toxicity or symptomatic deterioration, 
clinical progression, withdrawal from treatment, or patients who have started a subsequent 
anticancer therapy, will be followed up for adverse events (AEs) and with patient-reported 
outcomes (PRO) questionnaires for 90 days after the last dose of IP, and thereafter followed
up with tumour assessments until RECIST 1.1‑defined radiological PD plus an additional 
follow-up scan or until death (whichever comes first).
Overall survival
All patients in the study should be followed up for survival every 12 weeks until death, 
withdrawal of consent, or the end of the study.


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Steering Committee
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.
Interim analysis
No formal interim analysis is planned for this study.  However, the SC will conduct an early 
safety evaluation when 10 patients in the WHO/ECOG PS 2 cohort have been treated for a 
minimum of 6 months or discontinued due to an AE or disease progression, whichever occurs 
first.  At the time of the early safety evaluation, safety data for patients in the WHO/ECOG 
PS 0 to 1 cohort will also be provided to the SC for completeness in the overall risk/benefit 
assessment.  If needed for publication purposes, an additional early assessment of study data 
may be conducted when minimum 50 patients in the WHO/ECOG PS 0 to 1 cohort or 
WHO/ECOG PS 2 cohort have had the opportunity to receive durvalumab (MEDI4736) for a 
minimum of 6 months.
Statistical methods
The primary objective of this study is to assess the safety and tolerability of durvalumab
(MEDI4736), defined as Grade 3 and Grade 4 treatment-related adverse events (TRAEs)
observed during the initial 6 months of durvalumab (MEDI4736) treatment.  In addition, 
safety and tolerability of durvalumab (MEDI4736) will be characterized for the cohorts of 
WHO/ECOG PS 0 to 1 and 2 patients.
Safety data will be summarized descriptively overall, by seriousness, by causality and by 
maximum National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event 
(CTCAE) Grade based on the safety analysis set (ie, all patients who received at least 1 dose 
of study drug).  The exact 95% confidence intervals (CIs) around the incidence of Grade 3 and 
Grade 4 TRAEs will be reported for patients overall and separately for the cohorts of 
WHO/ECOG PS 0 to 1 and 2 patients.
The median progression-free survival (PFS) and median overall survival (OS), as well as the 
median time to NSCLC-related death, together with their corresponding 95% CIs will be 
calculated using Kaplan-Meier product limit methods and will be reported for patients overall 
and separately for the cohorts of WHO/ECOG PS 0 to 1 and 2 patients.  In addition, the 
objective response rate (ORR) (based on Investigator assessment by RECIST 1.1 criteria), 
together with the corresponding 95% CI, will be reported for patients overall and separately 
for the cohorts of WHO/ECOG PS 0 to 1 and 2 patients.
This is a safety study and no formal sample size calculation will be done.  Between 100 and 
120 patients will be enrolled in the WHO/ECOG PS 0 to 1 Cohort and up to 30 patients in the 


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WHO/ECOG PS 2 Cohort depending on recruitment.  
 
 
1.2
Schedule of assessments
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 (Schedule of assessments 
[SoA]).
Whenever vital sign assessments and blood draws are scheduled for the same nominal time, 
the assessments should occur in the following order: vital signs and then blood draws.  
Whenever electrocardiograms (ECGs), vital signs assessments, and blood draws are scheduled 
for the same nominal time, the assessments should occur in the following order: ECG, vital 
sign assessments, and then blood draws. 
Patients may delay dosing due to immune-mediated adverse events (imAEs) or non-imAEs or 
for reasons other than TRAE.

In case of imAEs or non-imAEs, dosing may be delayed per the Dosing Modification and 
Toxicity Management Guidelines (Section 8.4.5).

If dosing must be delayed for reasons other than TRAEs, dosing will resume as soon as 
feasible.
One cycle of treatment with the IP is equal to 28 calendar days.
Dosing intervals of subsequent cycles may be shortened as clinically feasible in order to 
gradually align treatment cycles with the schedule of tumour efficacy (RECIST) and PRO 
assessments. Subsequent time between 2 consecutive doses cannot be less than 22 days, 
based on the half-life of durvalumab (MEDI4736) (see current Investigator Brochure [IB]).
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 of first IP dose administration.
PROs and tumour efficacy (RECIST) assessment dates are not affected by dose delays and 
remain as originally scheduled, as they are based on the date of first IP administration (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 assessments for screening and treatment period
Screening
C1a
C2a
C3a
C4a
C5 to PD (max. 24 months)a,b
Final 
visit
For 
details 
see 
Section
Week
-4 to -1
1
q4w ±3 days unless dosing needs to be held for 
toxicity reasons
Day
-28 to -1
1
q28d ±3 days unless dosing needs to be held for 
toxicity reasons
Informed consent
Informed consent: Study procedures
X
5.1
X
5.1
Study procedures
Physical examination (full)
X
8.2.2
Targeted physical examinations (symptomatic patients 
only)
X
X
X
X
X
X
8.2.2
Assessment of early toxicities (phone call)d
X
X
X
8.2.5
Vital signs (temperature, respiratory rate, blood pressure, 
and pulse), body weight, and heighte
X
X
X
X
X
X
X
8.2.3
ECGf
X
As clinically indicated
8.2.4
Concomitant medications
6.4
Medical history
X
Demography, including baseline characteristics and 
tobacco use
X
Eligibility criteria
X
X
5.1, 5.2
Laboratory assessments
Clinical chemistry
X
Xg
Xh
Xh
Xh
Xh
X
8.2.1
Haematology
X
Xg
Xh
Xh
Xh
Xh
X
8.2.1
Coagulation
Xi
As clinically indicated
8.2.1
TSH (reflex free T3 or free T4)g,j,k
X
Xk
X
X
X
X
X
8.2.1
Urinalysis 
X
As clinically indicated
8.2.1
Hepatitis B and C, HIV, and tuberculosis
X
8.2.1
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Screening
C1a
C2a
C3a
C4a
C5 to PD (max. 24 months)a,b
Final 
visit
For 
details 
see 
Section
Week
-4 to -1
1
q4w ±3 days unless dosing needs to be held for 
toxicity reasons
Day
-28 to -1
1
q28d ±3 days unless dosing needs to be held for 
toxicity reasons
Pregnancy testl
X
X
X
X
X
X
X
8.2.1
Monitoring
X
X
X
X
X
X
X
8.2.6
AE/SAE assessmentm
8.3
Drug accountability
X
All visits
6.3
IP administration
Durvalumab (MEDI4736)n
X
X
X
X
X
X
6.1
QoL assessments
 
X
X
X
X
X
X
X
8.1.2.1, 
8.1.2.2
X
X
X
X
X
X
X
8.1.2.3
Biomarker assessments
X
8.8.1.1
 
X
8.8.1.1
X
X
X
X
8.8.1.2
X
8.7.1
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2
INTRODUCTION
Lung cancer has been the most common cancer in the world for several decades (WHO 2012).  
In 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 worldwide, with 
1.59 million deaths (19.4% of the total).  NSCLC represents approximately 80% to 85% of all 
lung cancers (American Cancer Society 2016) and approximately 30% of patients present with 
Stage III disease (Cancer Treatment Centers of America 2017).  
Standard treatment for patients with a good performance status (PS) and unresectable Stage III 
NSCLC has been platinum-based doublet chemotherapy concurrent with radiotherapy
(chemoradiation therapy [CRT]) administered with curative intent (Yoon et al 2017).  
However, the median PFS among patients who have received CRT is poor (approximately 
8 months) (Ahn et al 2015).  A meta-analysis of cCRT versus sCRT showed better outcomes 
with cCRT, but even with cCRT, the 5-year OS is only approximately 15% (Aupérin et al 
2010).
More recently, the PACIFIC Study (D4191C00001) demonstrated that the addition of 
durvalumab (MEDI4736) following platinum-based cCRT significantly improves PFS 
(Antonia et al 2017).  The median PFS with durvalumab (MEDI4736) was 16.8 months (95% 
CI 13.0, 18.1) versus 5.6 months with placebo (95% CI: 4.6, 7.8), and with a stratified hazard 
ratio (HR) for disease progression or death of 0.52 (95% CI: 0.42, 0.65; p<0.001).  The 
response rate was higher with durvalumab (MEDI4736) versus placebo (28.4% versus 16.0%; 
p<0.001) and the median time to death or distant metastasis was longer with durvalumab 
(MEDI4736) than with placebo (23.2 versus 14.6 months; p<0.001).  Grade 3 or 4 AEs were 
similar in both groups, occurring in 29.9% of the patients who received durvalumab 
(MEDI4736) and 26.1% of those who received placebo.
The PACIFIC Study data led to the approval of durvalumab (MEDI4736) by the US FDA in 
February 2018, Health Canada in May 2018, and EMA in September 2018 for the treatment of 
unresectable Stage III NSCLC following CRT.  Additional regulatory applications are 
currently under review globally.  The standard of care for patients with unresectable Stage III 
NSCLC is now anticipated to be cCRT followed by durvalumab (MEDI4736).
A significant proportion of patients are unable to receive cCRT for a number of reasons, 
including lack of immediate access to radiation therapy facilities or poor PS.  As such, many 
patients receive sCRT and this study aims to assess the clinical profile of durvalumab 
(MEDI4736) therapy following sCRT in patients with WHO/ECOG PS 0 to 1 and 
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2.1
Study rationale
Prior to the PACIFIC Study, minimal advances had been made for the treatment of patients 
with unresectable Stage III NSCLC.  The treatment of choice in patients with unresectable 
stage IIIA and IIIB NSCLC has been cCRT (Postmus et al 2017, NCCN 2018).  If cCRT is 
not feasible, including in frail patients who are unable to tolerate cCRT, sequential 
chemotherapy followed by definitive radiation therapy (sCRT) represents an alternative 
(NCCN 2018).  Overall, around 15% of the patients with unresectable Stage IIIA or Stage IIIB 
disease receive sCRT in the US and these numbers might be higher in Europe.  Compared to 
sCRT, cCRT leads to better survival by optimising local control, but cCRT does not reduce 
the risk of distant relapse (Aupérin et al 2010).  A pooled analysis of 41 Phase II/III studies 
confirmed that consolidation chemotherapy after cCRT does not improve survival for patients 
with Stage III locally-advanced NSCLC (Tsujino et al 2013).
CRT induces initial tumour shrinkage as a result of tumour cell death and may enhance 
antigen release and presentation, which in turn may aid in the priming of immune cells to 
recognise and eliminate tumour cells.  
Chemotherapy and radiotherapy can also up-regulate the expression of programmed cell death 
ligand 1 (PD-L1) (Zhang et al 2008, Deng et al 2014, Dovedi et al 2014) due to the release of 
cytokines and other inflammatory molecules.  These factors may confer greater sensitivity to 
PD-1/L1 pathway blockade.  The results of the PACIFIC Study demonstrate that durvalumab 
added after definitive CRT provides clinical benefit by potentiating the pro-inflammatory 
effects of the definitive therapy.  
The PACIFIC Study only evaluated patients who had not progressed after completing cCRT.  
A significant unmet medical need still exists in patients who are not eligible for cCRT.  
Collection of safety, efficacy, and QoL data for durvalumab (MEDI4736) as consolidation 
therapy after sCRT is warranted.
2.2
Background
2.2.1
Unmet need and potential role of immunotherapies in NSCLC
The addition of systemic therapy to radiation therapy has been reported to improve survival of 
patients with NSCLC in studies that have used cisplatin-based systemic therapy regimens 
(Aupérin et al 2006, Non-small Cell Lung Cancer Collaborative Group 1995).  cCRT has been 
found to be more beneficial than sCRT (Fournel et al 2005, Curran et al 2011, Aupérin et al 
2010).  In the Stage III unresectable setting, a combination of systemic therapy and 
radiotherapy is usually administered.  CALGB 8433 showed an improvement of survival of 
CRT over radiotherapy alone for these patients (Dillman et al 1996).  Additionally, the West 
Japan Lung Cancer Group has shown that concurrent cisplatin-based chemotherapy was 
superior to sCRT in Stage III patients (Furuse et al 1999).  In the Radiation Therapy Oncology 


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Group (RTOG) 9410 study, 2 cCRT regimens and 1 sCRT regimen were compared in Stage II 
and III NSCLC patients (Curran et al 2011), showing that concurrent delivery of 
cisplatin-based chemotherapy with thoracic radiotherapy confers a long-term survival benefit 
compared with the sequential delivery of these therapies.  Two important meta-analyses have 
demonstrated that adding sequential or concomitant chemotherapy to radical radiotherapy 
improved survival in locally-advanced NSCLC.  The HR for survival with the addition of 
sequential chemotherapy to radiotherapy was 0.88 (95% CI: 0.81, 0.96) (Non-small Cell Lung 
Cancer Collaborative Group 1995) and the HR with the addition of platinum-based 
concomitant chemotherapy to radiotherapy was 0.89 (95% CI: 0.81, 0.98) (Aupérin et al 
2006); however, these data should be interpreted with caution since there was some 
heterogeneity between the studies as well as in different sensitivity analyses.  The NSCLC 
Collaborative Group performed a meta-analysis of 6 randomised studies, which further 
confirmed the benefit in OS of cCRT compared to sequential therapy (Aupérin et al 2010) 
(HR: 0.84, 95% CI: 0.74, 0.95; p=0.004), mainly due to a better locoregional control, but at 
the cost of an increased acute oesophageal toxicity.  No differences were observed between 
cCRT and sCRT for PFS (HR: 0.90, 95% CI: 0.79, 1.01; p=0.07).  Despite the benefit to OS 
with cCRT, OS remains low with a 5-year OS of only approximately 15% (Aupérin et al 
2010).  These studies indicate that cisplatin-based systemic therapy with concurrent 
radiotherapy is an effective means of treatment, although relapses are still frequent. 
While advances have been made in improving survival from Stage III NSCLC by optimising 
local control, evidence suggests that cCRT or sCRT do not reduce the risk of distant relapse
(Aupérin et al 2010).  With fewer cycles and, in some cases, lower doses of chemotherapy 
delivered in the concurrent setting, several studies have assessed whether delivering induction 
or consolidation treatment will improve survival, with discordant results.  A Phase II study by 
the Southwest Oncology Group suggests a possible median survival benefit in patients treated 
with cCRT followed by consolidation docetaxel (median survival was 26 months) (Gandara et 
al 2006).  Similarly, a retrospective study found that consolidation therapy after cCRT resulted
in approximately 11 months longer median OS than cCRT alone (Liu et al 2015).  These 
findings were not corroborated by a Phase III study conducted by the Hoosier Oncology 
Group and US Oncology that evaluated the role of consolidation docetaxel in patients with 
inoperable Stage III NSCLC (Hanna et al 2008). The study terminated earlier than planned 
after an interim analysis showed no significant differences in survival between the 2 arms; 
median survival time for patients in the docetaxel arm versus the observation arm was 21.2 
versus 23.2 months.  There was a significant increase in severe toxicities in the docetaxel arm.  
More recently, a pooled analysis of 41 Phase II/III studies confirmed that there remains no 
evidence to suggest that consolidation chemotherapy after cCRT improves survival for 
patients with Stage III NSCLC and current guidelines continue to recommend cCRT alone for 
the treatment of inoperable Stage III NSCLC (Bayman et al 2014; Tsujino et al 2013).  


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The sequential/consolidation setting post cCRT or sCRT seems to be ideal to evaluate the 
efficacy of immunotherapy, which is aimed at boosting the ability of the patient’s immune 
system to eliminate cancer cells.  CRT often induces initial tumour shrinkage followed by 
eventual PD as the tumours find mechanisms to bypass the CRT-induced growth inhibition.  
The initial tumour shrinkage observed in some patients following CRT is the result of cell 
death and tumour damage.  CRT-induced cell death can enhance the ability of the immune 
system to recognise and respond to the tumour through enhanced antigen release and 
presentation which, in turn, aids in the priming of immune cells to recognise and eliminate 
tumour cells (Zhang et al 2008; Deng et al 2014; Dovedi et al 2014).  Therefore, triggering or 
augmenting an antigenic anti-tumour response with CRT and combining or following this 
treatment with anti-PD-L1 therapy, which acts to preserve ongoing immune responses by 
blocking an immunosuppressive signal theoretically may result in enhanced anti-tumour 
activity by improving local control and decreasing systemic spread. 
Tumours that are poorly immunogenic or that have become immunosuppressive can 
potentially be made immunogenic through administration of pro-immunogenic therapies 
designed to increase antigen release from the cancer cell.  Potential priming agents for 
immunotherapy agents include chemotherapy and radiotherapy.  Some cytotoxic therapies, 
such as anthracyclines or ionising radiation, promote ‘immunogenic cell death’, which 
includes the release of ‘danger’ molecules from tumour cells such as calreticulin, high 
mobility group protein B1 and adenosine triphosphate.  These danger molecules polarize 
dendritic cells toward a pro-inflammatory phenotype and increase priming toward T helper 1 
anti-tumour T cells and away from regulatory T cells (Vanneman and Dranoff 2012).  
Additionally, a recent Phase II study in patients with Stage IIIB/IV NSCLC or 
extensive-disease small-cell lung cancer investigated whether the anti-cytotoxic T-lymphocyte 
antigen 4 (CTLA-4) agent ipilimumab could be given safely in combination with standard 
chemotherapy (carboplatin–paclitaxel) as well as whether it would be optimal to initiate 
ipilimumab at the same time as chemotherapy, or after 2 cycles of treatment.  The results from 
this Phase II study showed that the combination was reasonably well-tolerated, and that a 
‘phased regimen’ in which immunotherapy began after chemotherapy resulted in substantially 
improved PFS compared with carboplatin–paclitaxel alone.  While this study did not actively 
investigate dosing effects, the data show that the clinical effects of administering 
immunotherapy in combination with chemotherapy are strongly dependent on the sequencing 
of treatment (Dunn et al 2004).
Recently, the results of a landmark Phase III PACIFIC Study (Antonia et al 2017) were 
reported.  The PACIFIC Study evaluated the role of immune checkpoint blockade in 
unresectable Stage III NSCLC.  Eligible patients had disease that had not yet progressed after 
at least 2 cycles of platinum-based cCRT at a dose of 54 to 66 Gy.  A total of 713 patients 
(PS 0 to 1) were randomly assigned to receive an anti-PD-L1 antibody, durvalumab
(MEDI4736), at a dose of 10 mg/kg of body weight or placebo Q2W for up to 12 months.  


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Pre-planned interim analysis showed that the co-primary endpoint of median PFS was 
16.8 months (95% CI: 13.0, 18.1) with durvalumab (MEDI4736) versus 5.6 months (95% CI: 
4.6, 7.8) with placebo (stratified HR for disease progression or death: 0.52; 95% CI: 0.42,
0.65; p<0.001).  The response rate was higher with durvalumab (MEDI4736) 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).  The 
median time to death or distant metastasis was longer with durvalumab (MEDI4736) than with 
placebo (23.2 months versus 14.6 months; p <0.001).  Grade 3 or 4 AEs occurred in 29.9% of 
the patients who received durvalumab (MEDI4736) and 26.1% of those who received placebo.  
Treatment-related (as assessed by the reporting Investigator) CTCAE AEs of Grade 3 or 4 
were reported in 57 (12.0%) patients receiving durvalumab and 11 (4.7%) patients receiving 
placebo (PACIFIC Study, data on file). 
The PACIFIC Study only evaluated patients who had not progressed after completing cCRT, 
and therefore a significant unmet medical need still exists in patients who are not eligible for 
cCRT.  Collection of safety, efficacy, and QoL data for durvalumab as consolidation therapy 
after sCRT is warranted.
2.2.2
Immunotherapies
It is increasingly understood that cancers are recognised by the immune system, and under 
some circumstances, the immune system may control or even eliminate tumours (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 (cluster of differentiation [CD] 279) is expressed on the 
surface of activated T cells (Keir et al 2008).  It has 2 known ligands: PD-L1 (B7 homolog 1 
[B7-H1]; CD274) and programmed cell death 1 ligand 2 (PD-L2) (B7-DC; CD273) (Okazaki 
and Honjo 2007).  PD-1 and PD-L1/PD-L2 belong to a family of immune checkpoint proteins 
that act as co-inhibitory factors, which can halt or limit the development of T cell response.  
When PD-L1 binds to PD-1, an inhibitory signal is transmitted into the T cell, which reduces 
cytokine production and suppresses T cell proliferation.  Tumour 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 tumour cells or on 
non-transformed cells in the tumour microenvironment (Pardoll 2012).  PD-L1 expressed on 
the tumour 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 tumour microenvironment.  
The PD-1/PD-L1 pathway represents an adaptive immune resistance mechanism that is 
exerted by tumour cells in response to endogenous anti-tumour activity.


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The inhibitory mechanism described above is co-opted by tumours that express PD-L1 as a 
way of evading immune detection and elimination (Qin et al 2016).  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 (Stewart et al 2015).  This activity overcomes 
PD-L1-mediated inhibition of anti-tumour immunity.  While functional blockade of PD-L1 
results in T cell reactivation, this mechanism of action (MOA) is different from direct agonism 
of a stimulatory receptor such as CD28.
PD-L1 is expressed in a broad range of cancers.  Based on these findings, an anti-PD-L1 
antibody could be used therapeutically to enhance anti-tumour immune responses in patients 
with cancer.  Results of pre-clinical and clinical studies of monoclonal antibodies (mAbs) 
targeting the PD-L1/PD-1 pathway have shown evidence of clinical activity and a manageable 
safety profile, supporting the hypothesis that an anti-PD-L1 antibody could be used to 
therapeutically enhance anti-tumour immune response in cancer patients (Brahmer et al 2012, 
Hirano et al 2005, Iwai et al 2002, Okudaira et al 2009, Topalian et al 2012,Zhang et al 2008) 
with responses that tend to be more pronounced in patients with tumours that express PD-L1 
(Powles et al 2014, Rizvi et al 2015, Segal et al 2015).  This hypothesis has been proven 
correct in a number of Phase II and III clinical studies of NSCLC, including PACIFIC
(Antonia et al 2017), KN024 (Reck et al 2016), KN042 (Mok et al 2016), KN189 (Gandhi et 
al 2018), IMPower150 (Socinski et al 2018), IMPower130 (Papadimitrakopoulou et al 2016), 
CM227(Hellmann et al 2018) and others.
In contrast, CTLA-4 is constitutively expressed by regulatory T cells and upregulated on 
activated T cells.  CTLA-4 delivers a negative regulatory signal to T cells upon binding of 
CD80 (B7.1) or CD86 (B7.2) ligands on antigen-presenting cells (Fife and Bluestone 2008).  
Blockade of CTLA-4 binding to CD80/86 by anti-CTLA-4 antibodies results in markedly 
enhanced T cell activation and anti-tumour activity in animal models, including killing of 
established murine solid tumours and induction of protective anti-tumour immunity.  
Therefore, it is expected that treatment with an anti-CTLA-4 antibody will lead to increased 
activation of the human immune system, increasing anti-tumour activity in patients with solid 
tumours.
Interestingly, high mutation burden (Hellmann et al 2018) may contribute to the responses 
seen with immune therapy and is becoming a biomarker of increasing interest for potential 
prediction of efficacy with immunotherapies.
A wealth of clinical data exists to demonstrate that blockade of negative regulatory signals to 
T cells such as CTLA-4 and PD-L1 results in promising clinical activity.  Ipilimumab was 
first granted US FDA approval for the treatment of metastatic melanoma and is currently 
under investigation for several other malignancies.  Nivolumab and pembrolizumab, 2 anti-
PD-1 agents, and durvalumab and atezolizumab, 2 anti-PD-L1 agents, have been granted 


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approvals by agencies for the treatment of a number of malignancies including metastatic 
melanoma, squamous and non-squamous cell NSCLC, squamous cell carcinoma of the head 
and neck, and urothelial carcinoma.  In addition, there are data from agents in the anti-PD-
1/PD-L1 class showing clinical activity in a wide range of tumour types.
2.2.3
Durvalumab (MEDI4736)
Durvalumab (MEDI4736) is a human mAb of the immunoglobulin G (IgG) 1 kappa subclass 
that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with PD-1 on 
T cells and CD80 (B7.1) on immune cells.  It is being developed by AstraZeneca/MedImmune 
for use in the treatment of cancer (MedImmune is a wholly owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune is referred to as AstraZeneca throughout this document).  The 
proposed MOA for durvalumab (MEDI4736) 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 tumour elimination.  In 
vitro studies demonstrate that durvalumab (MEDI4736) antagonizes the inhibitory effect of 
PD-L1 on primary human T cells resulting in the restored proliferation of interferon gamma 
(IFN-γ) (Stewart et al 2015).  In vivo studies have shown that durvalumab (MEDI4736) 
inhibits tumour growth in xenograft models via a T cell-dependent mechanism (Stewart et al 
2015).  Based on these data, durvalumab (MEDI4736) is expected to stimulate the patient’s 
anti-tumour immune response by binding to PD-L1 and shifting the balance toward an 
anti-tumour response.  Durvalumab (MEDI4736) has been engineered to reduce 
antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. 
To date, durvalumab (MEDI4736) has been given to more than 6000 patients as part of 
ongoing studies either as monotherapy or in combination with other anticancer agents.  Details 
on the safety profile of durvalumab (MEDI4736) monotherapy are summarized in 
Section 4.3.1 and Section 8.3.12.  Refer to the current durvalumab (MEDI4736) IB for a 
complete summary of pre-clinical 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 (MEDI4736) 
are based on the first-in-human, single-agent study (Study 1108) in patients with advanced 
solid tumours, the study of durvalumab (MEDI4736) monotherapy in NSCLC (Study 
D4191C00003 [ATLANTIC]), and the study of durvalumab (MEDI4736) monotherapy in 
NSCLC following completion of platinum-based chemotherapy concurrent with radiation 
therapy (PACIFIC Study).  Data from these studies have demonstrated clinical activity of 
durvalumab (MEDI4736) therapy in patients with NSCLC.  Details pertaining to Study 1108 
and ATLANTIC are provided in the current durvalumab (MEDI4736) IB.


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More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of durvalumab (MEDI4736) may be found in the durvalumab (MEDI4736) IB.
2.3.1
Potential benefits
The efficacy of durvalumab (MEDI4736) was evaluated in the PACIFIC Study, a 
multi-centre, randomised, 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 
WHO PS 0 or 1 (Antonia et al 2017). A total of 713 patients were randomised 2:1 to receive 
durvalumab (MEDI4736) 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 
pre-specified 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 (MEDI4736) 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 favour 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 (MEDI4736) than with placebo (28.4% versus 16.0%; p<0.001), and 
the median DoR was longer (72.8% versus 46.8% of the patients had an ongoing response at 
18 months).  The median time to death or distant metastasis was longer with durvalumab 
(MEDI4736) than with placebo (23.2 months versus 14.6 months; HR: 0.52; 95% CI, 0.39, 
0.69; p <0.001). The OS data were immature at the time of the interim analysis of the PFS, as 
the number of events required for the planned first OS interim analysis had not been reached 
at the time of this PFS analysis.
2.3.2
Overall risks
Monoclonal antibodies directed against immune checkpoint proteins, such as PD-L1, aim to 
boost endogenous immune responses directed against tumour 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 (GI) AEs such as colitis and 
diarrhoea, 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. 


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2.3.2.1
Durvalumab (MEDI4736) risks
Risks with durvalumab (MEDI4736) include, but are not limited to, diarrhoea/colitis, 
pneumonitis/ILD, endocrinopathies (i.e., events of hypophysitis/hypopituitarism, adrenal 
insufficiency, hyper- and hypo-thyroidism, type I diabetes mellitus [DM] and diabetes 
insipidus), hepatitis/increases in transaminases, nephritis/increases in creatinine, 
rash/dermatitis (including pemphigoid), myocarditis, myositis/polymyositis, immune 
thrombocytopenia, infusion related reactions, hypersensitivity reactions, pancreatitis, serious 
infections, and other rare or less frequent inflammatory events including neuromuscular 
toxicities (eg, Guillain-Barre syndrome, myasthenia gravis).
For information on all identified and potential risks with durvalumab (MEDI4736), please 
always refer to the current version of the durvalumab (MEDI4736) IB.
In the PACIFIC Study (Antonia et al 2017), treatment-emergent adverse events (TEAEs)
occurred in 67.8% of patients in the durvalumab (MEDI4736) group compared to 53.4% in 
the placebo group.  Grade 3 or 4 AEs occurred in 29.9% of patients who received durvalumab 
(MEDI4736) and 26.1% of those who received placebo.  The most common Grade 3 or 4 AE 
was pneumonia, which occurred in 4.4% of patients who received durvalumab (MEDI4736) 
and in 3.8% of patients in the placebo group.  Pneumonitis or radiation pneumonitis of any 
grade occurred in 33.9% and 24.8% of patients who received durvalumab (MEDI4736) and 
placebo, respectively; pneumonitis or radiation pneumonitis of Grade 3 or 4 occurred in 3.4% 
and 2.6% of patients, respectively.  The most frequent AEs leading to discontinuation of 
durvalumab (MEDI4736) and placebo were pneumonitis or radiation pneumonitis (in 6.3% 
and 4.3% of patients, respectively) and pneumonia (in 1.1% and 1.3% of patients, 
respectively).  Adverse events of special interest (AESIs) of any grade were reported in 66.1% 
of patients in the durvalumab (MEDI4736) group and in 48.7% of patients in the placebo 
group; events of Grade 3 or higher were less than 10% in both groups.  The most frequent 
AESIs of any grade with durvalumab (MEDI4736) versus placebo were diarrhoea (18.3% and 
18.8%), pneumonitis (12.6% and 7.7%), rash (12.2% and 7.3%), and pruritus (12.2% and 
4.7%).  Finally, the rate of imAEs was 24.2% with durvalumab (MEDI4736) and 8.1% with 
placebo.  The rates of severe imAEs, and of pneumonitis in particular, were not significantly 
different (any Grade 3 or 4 immune-mediated event 3.4% and 2.6%, and Grade 3 or 4 
pneumonitis 1.7% and 2.6%, for durvalumab and placebo, respectively).  Overall, the safety 
profile of durvalumab (MEDI4736) in this population was consistent with that of other 
immunotherapies and with its known safety profile as monotherapy with NSCLC.
In monotherapy clinical studies, AEs at an incidence of >20% include events such as fatigue
and decreased appetite.  Approximately 10% of patients discontinued the drug due to an AE.  
Please see the current version of the IB for a detailed summary of the monotherapy data 
including AEs, serious adverse events (SAEs), and Common Toxicity Criteria (CTC)
Grades 3 to 5 events reported across the durvalumab (MEDI4736) program.


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The majority of TRAEs 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 (MEDI4736) monotherapy AE data can be found in the 
current version of the durvalumab (MEDI4736) IB.
2.3.3
Overall benefit/risk
In summary, the potential for clinical benefit associated with inhibition of the PD-1/PD-L1 
pathway, supported by the clinical benefit in terms of PFS and ORR observed in earlier 
studies in patients with NSCLC, including the pivotal Phase III PACIFIC Study, outweighs 
the known and potential risks based on the AEs reported in patients treated with durvalumab 
(MEDI4736) and other PD-1/PD-L1 inhibitors.  Thus, the benefit/risk assessment, favours the 
conduct of this proposed study.  
3
OBJECTIVES AND ENDPOINTS
The study objectives and corresponding endpoints/variables are listed in Table 3.
Table 3
Study objectives 
OBJECTIVE
ENDPOINT/VARIABLE
PRIMARY OBJECTIVE
To assess the safety and tolerability profile of 
durvalumab (MEDI4736) as defined by Grade 3 and 
Grade 4 TRAEsa within 6 months from the 
initiation of durvalumab (MEDI4736) treatment
Grade 3 or Grade 4 TRAEsa
SECONDARY OBJECTIVES
Efficacy objectives
To assess the efficacy of durvalumab (MEDI4736) 
treatment in terms of PFS and OS 
Median PFS according to RECIST 1.1as assessed by 
the Investigator
Median PFS12 and PFS24 according to RECIST 1.1 as 
assessed by the Investigator
Median OS, OS12, OS24, and OS36
To further assess the efficacy of durvalumab 
(MEDI4736) 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 (MEDI4736) 
treatment in terms of lung cancer mortality
Lung cancer mortality






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Investigational product, dosage and mode of administration
Durvalumab (MEDI4736) 1500 mg via IV infusion q4w, starting on Week 1 after 
confirmation of eligibility, for a maximum of 24 months from Cycle 1 Day 1, or until PD 
(unless the Investigator considers the patient continues to receive benefit from the IP), 
initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or 
another discontinuation criterion is met.
Treatment initiation within the first 14 days after sCRT therapy is, however, highly
encouraged.  For patients who are recovering from toxicities associated with prior treatment, 
administration of the first IP dose may be delayed by up to 42 days from the end of the sCRT.  
For details on treatments given during the study, see Section 6.1.
Tumour response assessments
Tumour assessments using CT/MRI will be performed at the times specified in Table 1 and 
Table 2.  RECIST 1.1 measurements as assessed by the Investigator will be used to derive the 
secondary variables of PFS, ORR, and DoR.  Categorisation of objective tumour response 
assessment will be based on the RECIST 1.1 criteria of response: CR, PR, SD and PD.  
Overall survival assessments
Once a patient has had objective progression recorded and has discontinued study drug, the 
patient will be followed up for survival status q12w until death, withdrawal of consent or the 
end of the study.
Schedule of assessments
The SoA at screening and during the treatment period is presented in Table 1.  The SoA
during follow-up for patients who have discontinued the study drug due to confirmed PD, 
toxicity, or any other reason, is presented in Table 2. 
Guidelines for the management of toxicities are described in Section 8.4.5.
Details of the PGx component of the study (relating to deoxyribonucleic acid [DNA]) are 
provided in Appendix D.
Interim analysis
No formal interim analysis is planned for this study.  However, the SC will conduct an early 
safety evaluation when 10 patients in the WHO/ECOG PS 2 cohort have been treated for a 
minimum of 6 months or discontinued due to an AE or disease progression, whichever occurs 
first.  At the time of the early safety evaluation, safety data for patients in the WHO/ECOG 
PS 0 to 1 cohort will also be provided to the SC for completeness in the overall risk/benefit 
assessment.  If needed for publication purposes, an additional early assessment of study data 


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may be conducted when minimum 50 patients in the WHO/ECOG PS 0 to 1 cohort or 
WHO/ECOG PS 2 cohort have had the opportunity to receive durvalumab (MEDI4736) for a 
minimum of 6 months.
End of analysis portion of study
Once the planned statistical analyses have been performed, the analysis portion of the clinical 
study will have been completed.  Patients in OS follow-up (progressed and have completed 
treatment) will be considered to have completed the study.
For patients who continue to receive IP after the time of the data cut-off (DCO), Investigators 
will report all SAEs to AstraZeneca Patient Safety until 90 days after last IP dose.  Following 
the DCO for the study, SAE reporting applies only to patients who are receiving IP or who are 
within the 90-day follow-up period post the last dose of IP (for more details see Section 4.4).  
Figure 2
Study flow chart
Screening assessments
Day 28 to 1a
WHO/ECOG PS 0 to 1 Cohort: 100-120 
patients 
WHO/ECOG PS 2 Cohort: up to 30 patients
C1, Day 1
Patients start durvalumab (MEDI4736) 
treatment
Treatment period for up to 24 months
(assessments per Table 1):
Tumour assessments using RECIST 1.1 
performed at screening and then q8w until 
52 weeks and q12w thereafterb
Discontinuation of treatment
Due to toxicity or other 
reasons
Due to confirmed PDc
Continue tumour 
assessments using 
RECIST 1.1.
Follow-up assessments until 
confirmed PD per Table 2
Confirmed PDc
Follow-up assessments and 
survival contact per Table 2


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a
Screening assessments can be performed in a step-wise process.  The baseline tumour assessment is part of the 
screening procedures and should be performed within 42 days after the end of sCRT and 28 days before the start of 
study drug.  For patients who are recovering from toxicities associated with prior treatment, IP treatment initiation may 
be delayed by up to 42 days from the end of the sCRT.
b
During the treatment period, patients who are clinically stable at an initial RECIST 1.1-defined radiological PD may 
continue to receive study drug at the discretion of the Investigator and patient.  A follow-up scan is to be performed 
after the initial RECIST 1.1-defined radiological PD, no less than 4 weeks after the prior assessment of PD and no later 
than the next regularly scheduled imaging visit, and this scan is evaluated using the Confirmation of Radiological 
Progression Criteria outlined in Appendix F.  If the subsequent scan does not confirm the immediate prior radiological 
PD, then the patient may continue on study drug at the discretion of the Investigator and if the patient has consented to 
do so; imaging assessments should continue until the next RECIST 1.1-defined radiological PD, which in turn will 
require a subsequent scan evaluated using the Confirmation of Radiological Progression Criteria outlined in
Appendix F.  For all patients who are treated through progression, the Investigator should ensure patients do not have 
any significant, unacceptable, or irreversible toxicities that indicate continuing treatment will not further benefit the 
patient.  The patient must continue to meet those inclusion and exclusion criteria that are relevant to treatment through 
disease progression as specified in Section 6.1.3.  Patients with rapid tumour progression or with symptomatic 
progression that requires urgent medical intervention (eg, central nervous system metastasis, respiratory failure due to 
tumour compression, spinal cord compression) will not be eligible to continue to receive study drug.
c
Patients with confirmed PD who continue to receive the study drug at the discretion of the Investigator (following 
consultation with AstraZeneca) can receive the study drug for a maximum of 24 months from Cycle 1 Day 1.  For all 
patients who are treated through progression, the Investigator should ensure patients do not have any significant, 
unacceptable, or irreversible toxicities that indicate continuing treatment will not further benefit the patient.  The patient 
must continue to meet those inclusion and exclusion criteria that are relevant to treatment through disease progression 
as specified in Section 6.1.3.  The same exceptions as noted in footnote b apply.  Patients will follow the assessments in 
Table 1 including tumour assessments q8w (relative to the date of IP treatment initiation) until the study drug is 
stopped.  Patients who continue to receive treatment after the DCO should receive tumour assessment scans and other 
assessments as per local clinical practice.  It is recommended that the patients continue the scheduled site visits and 
Investigators monitor the patient’s safety laboratory assessments prior to and periodically during the treatment with 
durvalumab (MEDI4736) in order to manage AEs in accordance with the durvalumab (MEDI4736) toxicity 
management guidelines (Section 8.4.5).  The study drug should be discontinued if there is confirmed PD in TLs 
following a previous response (PR or CR) to the study drug in those lesions.
Note: At DCO for the study, patients who are receiving IP can either choose to discontinue from the study or, where the 
Investigator judges that patients are gaining clinical benefit, patients may continue to receive IP.  For patients who do 
continue to receive IP beyond the time of the DCO, Investigators must continue to report all SAEs to AstraZeneca Patient 
Safety until 90 days after last IP dose.  Any SAE or non-serious 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 ( Section 8.4.5), unless the event is considered by the Investigator to be unlikely to resolve or the 
patient is lost to follow-up.
AE: Adverse event; C: Cycle; CR: Complete response; DCO: Data cut-off; IP: Investigational product; PD: Progression of 
disease; PR: Partial response; SAE: Serious adverse event; q8w, q12w: Every 8, 12 weeks, respectively; 
RECIST 1.1: Response Evaluation Criteria in Solid Tumours version 1.1; sCRT: Sequential chemoradiation therapy; 
WHO/ECOG PS: World Health Organisation/Eastern Cooperative Oncology Group Performance Status; TL: Target lesion.
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster or public health crisis 
(eg, during quarantines and resulting site closures, regional travel restrictions and
considerations if site personnel or study patients become infected with severe acute respiratory 
syndrome coronavirus 2 [SARS-CoV-2] or similar pandemic infection), which would prevent 
the conduct of study-related activities at study sites, thereby compromising the study site staff 
or the patient’s ability to conduct the study.  The investigator or designee should contact the 
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To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study patients, maintain 
compliance with Good Clinical Practice (GCP), and minimize risks to study integrity.  Where 
allowable by local health authorities, ethics committees, health care provider guidelines (eg, 
hospital policies) or local government, these changes may include the following options:

Obtaining consent/reconsent (note, in the case of verbal consent/reconsent, the ICF should 
be signed at the patient’s next contact with the study site).

Home or Remote visit: Performed by a site qualified health care professional (HCP) or 
HCP provided by a third-party vendor (TPV).

Telemedicine visit: Remote contact with the patients using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices. 
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix H.
4.2
Scientific rationale for study design 
4.2.1
Rationale for study safety endpoints
This study is designed to further evaluate the safety of durvalumab (MEDI4736) 
monotherapy, using a fixed-dosing regimen, in unresectable Stage III NSCLC patients who 
have not progressed following definitive, platinum-based sCRT.  This study is designed to 
complement and expand the safety database from the ongoing Phase III PACIFIC Study.  As 
the PACIFIC Study evaluated a weight-based dosing regimen (mg/kg) for durvalumab 
(MEDI4736), expanding data on the safety profile of the fixed-dose combination is warranted, 
particularly for more severe AEs, and in the context of the very recent concept of immune 
checkpoint blockade as consolidation therapy in unresectable Stage III NSCLC patients who 
have undergone sCRT.  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 
(MEDI4736) under this context exists, including in the sub-populations of WHO/ECOG PS 
0 to 1 and 2 patients, who have not been representatively included in pivotal studies.  
In the PACIFIC Study, the majority of imAEs with durvalumab (MEDI4736) occurred during 
the first 6 months of treatment (see the current version of the durvalumab [MEDI4736] 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 2014, Weber et al 2017). The PACIFIC 6 Study will assess the 
safety of durvalumab (MEDI4736) within the first 6 months of treatment as defined by Grade 
3 and Grade 4 TRAEs, including the evaluation of the nature of toxicities (SAEs, AEs, AESIs, 
imAEs), interventions and treatment, and outcome of treatment.  


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4.2.2
Rationale for study efficacy endpoints
The secondary aim of this study is to determine the efficacy of durvalumab (MEDI4736) 
1500 mg q4w in terms of 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 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 mechanisms or additional 
clinical studies while the PACIFIC 6 Study is ongoing.  This poses challenges in being able to 
fully characterize effects on OS if patients subsequently receive these immunotherapeutic 
agents.  
Anti-tumour activity will be assessed according to RECIST 1.1 guidelines, with the 
understanding that in the context of post-radiation changes, tumour 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 tumour-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’ tumour data from all scans based upon 
RECIST 1.1.
4.2.3
Rationale for other study exploratory endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
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4.2.4
Rationale for treatment duration
Treatment in this study will continue up to 24 months or until RECIST 1.1-defined PD and 
Investigator determination that the patient is no longer benefitting from treatment with IP, or 
until another discontinuation criterion is met (see Section 7.1).  This guidance is supported by 
data from the CheckMate-153 Study that indicated that patients treated with nivolumab (an 
anti-PD-1 agent) until PD showed superior PFS when compared to treatment with nivolumab 
with a 1-year fixed duration (HR: 0.43; 95% CI: 0.25, 0.76), a trend toward improved OS, and 
no new safety signals after 1 year of treatment (Spigel et al 2017).  In the PACIFIC Study,
although patients were treated for up to 12 months with durvalumab (MEDI4736), no new 
safety signals were observed after 6 months of treatment.  Numerous Phase 3 studies are 
currently evaluating durvalumab (MEDI4736) treatment until PD for patients with a variety of 
malignancies; while the results of these studies are not yet available, no new safety signals 
have been identified as a result of the longer duration.  The 12-month and 18-month PFS rates
following durvalumab (MEDI4736) treatment in Stage III NSCLC patients in the PACIFIC 
Study were 55.9% (95% CI: 51.0, 60.4) and 44.2% (95% CI: 37.7, 50.5), respectively, 
suggesting that a significant number of patients had to discontinue therapy prior to disease 
progression based on the 12-month treatment regimen. Based on these observations, no new 
safety signals are expected beyond 1 year of treatment with durvalumab, but there exists the 
potential for additional clinical and survival benefit beyond 1 year of treatment.  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 
(MEDI4736) will be administered for a maximum of 24 months in this study.
4.2.5
Timing of treatment with durvalumab (MEDI4736) relative to 
sequential chemoradiation therapy
Non-clinical data show that both chemotherapy and ionising radiation up-regulate PD-L1 
expression (Deng et al 2014, Zhang et al 2008).  In addition, chemotherapy and radiotherapy 
both release new antigens leaving the cancer to act as an in situ vaccine that can elicit 
tumour-specific T cells.  Thus, starting durvalumab (MEDI4736) as close as possible to the 
completion of the sCRT, 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 
(MEDI4736) treatment initiation will be consistent with the PACIFIC Study, i.e., 42 days after 
the end of CRT.
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4.3
Justification for dose
This study will utilise a fixed dose for durvalumab (MEDI4736) treatment (1500 mg q4w IV).  
Based on an average body weight of 75 kg, a fixed dose of 1500 mg of durvalumab 
(MEDI4736) q4w is equivalent to a weight-based dose of 20 mg/kg q4w. 
4.3.1
Durvalumab (MEDI4736) monotherapy dose rationale
A durvalumab (MEDI4736) dose of 20 mg/kg q4w is supported by in-vitro data, non-clinical 
activity, clinical PK/pharmacodynamics (PDx), biomarkers, and activity data from Study 1108 
in patients with advanced solid tumours and from a Phase I study performed in Japanese 
patients with advanced solid tumour (D4190C00002).
Pharmacokinetics/pharmacodynamics data
Based on available PK/PDx data from the ongoing Study 1108 with doses ranging from 0.1 to 
10 mg/kg q2w or 15 mg/kg q3w, durvalumab (MEDI4736) exhibited non-linear 
(dose-dependent) PK consistent with target-mediated drug disposition.  The PK approached 
linearity at ≥3 mg/kg q2w, suggesting near complete target saturation (membrane-bound and 
sPD-L1), and further shows that the durvalumab (MEDI4736) 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 (MEDI4736) with PD-L1.  A low level of immunogenicity has 
been observed.  No patients have experienced immune-complex disease following exposure to 
durvalumab (MEDI4736).  (For further information on immunogenicity, please see the current 
durvalumab [MEDI4736] IB.)
Data from Study D4190C00006 (hereafter referred to as Study 006), a Phase I study in 
NSCLC patients using the combination of durvalumab (MEDI4736) and tremelimumab also 
show an approximately dose-proportional increase in PK exposure for durvalumab 
(MEDI4736) over the dose range of 3 to 20 mg/kg durvalumab (MEDI4736) q4w or q2w.  
(For further information on PK observations in Study 006, please see the current durvalumab 
[MEDI4736] IB.) The observed durvalumab (MEDI4736) PK data from the combination 
Study 006 were well in line with the predicted monotherapy PK data (5th median and 95th
percentiles) for a q4w regimen. 
A population PK model was developed using the data from Study 1108 (doses=0.1 to 
10 mg/kg q2w or 15 mg/kg q3w) (Fairman et al 2014).  Multiple simulations indicate that a 
similar overall exposure is expected following both 10 mg/kg q2w and 20 mg/kg q4w 
regimens, as represented by the area under the plasma concentration-time curve at steady state 
(AUCss; 4 weeks).  Median maximum drug concentration at steady state (Cmax,ss) is expected 
to be higher with 20 mg/kg q4w (~1.5 fold) and median trough plasma concentration 


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(Ctrough,ss) is expected to be higher with 10 mg/kg q2w (~1.25 fold).  Clinical activity with the 
20 mg/kg q4w dosing regimen is anticipated to be 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, PDx, and clinical activity in 
diverse cancer populations; (c) maintain sufficient PK exposure in case of anti-drug antibody 
impact; and (d) achieve PK exposure that yielded maximal anti-tumour activity in animal 
models.
Given the similar area under the plasma concentration versus 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 based on 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 (MEDI4736) 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 (MEDI4736) using monotherapy data 
from Study 1108 and the PACIFIC Study (n=1310, doses including 10 mg/kg q2w or 
15 mg/kg q3w or 20 mg/kg q4w; solid tumours).  Population PK analysis indicated only minor 
impact of body weight on the PK of durvalumab (MEDI4736) (coefficient of ≤0.5).  The 
impact of body weight-based (10 mg/kg q2w or 20 mg/kg q4w) and fixed dosing (750 mg 
q2w or 1500 mg q4w) of durvalumab (MEDI4736) was evaluated by comparing predicted 
steady state PK exposure (AUCss,0-28days, Cmax,ss, and Cmin,ss) using the population PK model.  
A fixed dose of 750 mg was selected to approximate 10 mg/kg and a fixed dose of 1500 mg 
q4w was selected to approximate 20 mg/kg q4w (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 (10 mg/kg q2w) and fixed dosing 
(750 mg q2w) regimens yield similar median steady state PK exposures and associated 
variability, supporting the potential switch of durvalumab (MEDI4736) from weight-based to 
fixed dose.  Similar considerations hold for the q4w dosing regimens (20 mg/kg q4w versus 
1500 mg q4w).
Similar findings have been reported by others (Narwal et al 2013, Ng et al 2006, Wang 
et al 2009, Zhang et al 2012).  Wang and colleagues investigated 12 mAbs and found that 
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/PDx parameters (Zhang et al 2012). 


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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, it was 
considered feasible to switch to fixed-dosing regimens.  Based on average body weight of 
75 kg, a fixed dose of 1500 mg q4w durvalumab (MEDI4736) (equivalent to 20 mg/kg q4w) 
is included in the PACIFIC 6 Study.
4.3.3
Predictive biomarkers and rationale for an unselected population in the 
PACIFIC 6 Study
For this study, enrolment is not restricted to any biomarker-defined sub-population, but where 
possible, these patient characteristics are assessed in an exploratory manner and in the context 
of this study and other studies.
In the PACIFIC Study, benefit was also observed irrespective of PD-L1 status.  Indeed, no 
significant between-group differences were noted in PD-L1 expression.  Importantly, half the 
patients enrolled in this study had squamous cell lung cancer, in which the correlation between 
the PD-L1 biomarker and benefit in advanced-stage NSCLC is weak.
Tumour biopsies and viable tissue may be difficult to obtain post sCRT.  Tumours evolve with 
time and in response to treatment and PD-L1 expression is likely to be different post cCRT.  
In addition, non-clinical data shows that both chemotherapy and ionising radiation up-regulate 
PD-L1 expression (Deng et al 2014, Zhang et al 2008).  Therefore, PD-L1 expression from a 
biopsy sample prior to sCRT may not accurately reflect the state of disease at the time the 
patient enrols in this study.  In addition, tumours that are poorly immunogenic or that have 
become immunosuppressive can likely be made immunogenic through administration of 
pro-immunogenic therapies designed to increase antigen release from the cancer cell.  
Therefore, as stated, inclusion in this study is not restricted based on PD-L1 expression from 
any available tissue samples.  If it is feasible, biopsies will be taken post CRT.  If possible 
based on the number and viability of the samples collected, it will be retrospectively assessed
whether there is any correlation between PD-L1 expression and response to treatment.  
Current experience with single-agent immunotherapy studies suggests that clinical responses 
may be restricted to a subset of any given patient population and that it might be beneficial to 
enrich the patient population by selecting patients likely to respond to therapy.  At the time of 
the initial writing of this protocol, no assay has been established/validated and no single 
approach has proven accurate for Stage III NSCLC patient enrichment for immune-mediated 
therapies.  However, independent data from multiple sources using different assays and 
scoring methods suggests that PD-L1 expression on tumour cells and or tumour-infiltrating 
cells may be associated with greater clinical benefit.  For example, data presented by Roche 
for MPDL3280A suggest that PD-L1 expression on infiltrating lymphocytes in NSCLC, 
melanoma, and renal cell carcinoma patient cohorts is associated with greater clinical benefit 
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immunohistochemistry, the authors found a 36% ORR in PD-L1-positive patients with 50% of 
patients who were PD-L1-positive having SD and 33% having a PR.  In contrast, in PD-L1 
negative patients, they found only a 13% ORR with 28% of patients having SD and 13% 
having a PR.  Importantly, a significant portion of patients (17%) that were negative for 
PD-L1 were able to respond to MPDL3280A treatment.
Similarly, in data presented by Bristol-Myers Squibb, PD-L1 staining assessed using a 
different method and scoring algorithm appeared to be associated with greater clinical benefit 
in patients treated with nivolumab (anti-PD-1) (Grosso et al 2013).  The authors found a 44% 
ORR in PD-L1-positive patients versus a 17% ORR in PD-L1-negative patients.  
Additionally, in their studies, PD-L1-positive patients had a higher PFS (9.1 months versus 
2.0 months) and OS (21 months versus 12 months) than PD-L1-negative patients.
Therefore, while it appears that PD-L1 expression may improve the probability and/or quality 
of response to PD-1 pathway targeting agents and, therefore, may have merit as an enrichment 
tool, it is important to note that the published findings are from single-arm studies and may 
not permit to distinguish between prognostic factors or predictive markers for response to 
PD-L1 and PD-L1 therapies.  
In summary, the Phase III PACIFIC Study demonstrated clinical benefit in patients 
irrespective of PD-L1 status; furthermore, it will be difficult to obtain post-sCRT biopsies 
immediately prior to enrolment in the PACIFIC 6 Study.  Therefore, in the PACIFIC 6 Study, 
enrolment will not be restricted to any biomarker-defined sub-population.
4.4
End of study definition
The end of the study is defined as the last visit of the last patient undergoing the study.  A 
patient is considered to have completed the study when he/she has completed his/her last 
study visit per protocol.
The final DCO is planned to occur when the last patient had the opportunity to receive 
durvalumab (MEDI4736) for a maximum of 24 months, followed by a 90-day safety 
follow‑up period post the last dose of IP.
At the final DCO, the clinical study database will close to new data.  However, patients will 
be permitted to continue to receive IP beyond the closure of the database if a rollover or safety 
extension study is available at the time of the final DCO and, in the opinion of the 
Investigator, they are continuing to receive benefit from IP.  For patients who do continue to 
receive IP beyond the time of the final DCO, Investigators will continue to report all SAEs to 
AstraZeneca Patient Safety until 90 days after last IP dose, in accordance with Section 8.4.1.  
If an Investigator learns of any SAEs, including death, at any time after a patient has 
completed the study, and he/she considers there is a reasonable possibility that the event is 
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Any SAE or non-serious AE ongoing at the time of this final 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 (Section 8.4.5), unless the event is 
considered by the Investigator to be unlikely to resolve or the patient is lost to follow-up.
See Appendix A, A 6 for guidelines for the dissemination of study results.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to receive IP treatment.  Under no circumstances can there be exceptions to this 
rule.  Patients who do not meet the entry requirements are considered to be screen failures
(refer to Section 5.6).
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
For inclusion in the study, patients should fulfil the following criteria:
Informed consent
1
Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the 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 informed consent prior to collection of 
sample for genetic analysis (optional).
The ICF process is described in Appendix A, A 3.
Age
4
18 years or older at the time of signing the ICF.
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]).  
Positron emission tomography (PET)/CT, MRI of the brain, and endobronchial ultrasound 
with biopsy are highly encouraged at diagnosis.


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6
Receipt of sCRT which must have been completed within 42 days prior to first IP dose 
administration in the study.
(a) The platinum-based chemotherapy regimen must contain cisplatin or carboplatin and 
1 of the following agents: etoposide, vinblastine, vinorelbine, a taxane (paclitaxel or 
docetaxel), or pemetrexed, according to the local SoC regimens.  Platinum-based 
chemotherapy containing cisplatin or carboplatin and gemcitabine is permitted under 
certain conditions – refer to bullet point 6(b).
(b) Patients must have received at least 2 cycles of platinum-based chemotherapy before 
radiation therapy.  The interval between administration of the last dose of 
chemotherapy regimen and start of radiation therapy must be no more than 6 weeks.  
Consolidation chemotherapy after radiation is not permitted.
(i)
If the patient’s platinum-based chemotherapy contained gemcitabine, no overlap 
between chemotherapy and radiation therapy is permitted.
(ii) If the patient’s platinum-based chemotherapy contained any of the agents listed 
in 6(a) other than gemcitabine, an overlap of 1 cycle of chemotherapy and 
radiation therapy is acceptable.
(c) Patients must have received a total dose of radiation of 60 Gy ±10% (54 Gy to 
66 Gy).  Sites are encouraged to adhere to mean organ radiation dosing as follows:
(i)
Mean lung dose <20 Gy and/or V20 <35%;
(ii) Mean oesophagus <34 Gy;
(iii) Heart V45 <35% or V30 <30%.
Note: Sites should be aware of the recent RTOG 0617 Study data 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%.
7
Patients must not have progressed following platinum-based sCRT, as per 
Investigator-assessed RECIST 1.1 criteria. In order to assess disease progression, the 
baseline imaging (CT/MRI) used for Screening purposes should be compared against the 
most recently performed scan that allows physician assessment as per RECIST 1.1 criteria 
(i.e. fulfils the RECIST 1.1 defined imaging acquisition parameters). If an intermediate 
scan taken between chemotherapy and radiotherapy is available and that scan is suitable 
for physician assessment as per RECIST 1.1 criteria, then this scan should be used.
(a) Patients with measurable disease and/or non-measurable and/or no evidence of 
disease (NED) assessed at baseline by CT/MRI will be entered in this study.
(b) Prior irradiated lesions may be considered measurable and selected as TLs provided
they fulfil the other criteria for measurability.
8
Must have a life expectancy of at least 12 weeks at enrolment.
9
WHO/ECOG PS ≤2.
10 Adequate organ and marrow function at enrolment as defined below. These parameters 
should be achieved without augmentation by growth factors, transfusions, or infusions 
within 14 days of screening unless required for SoC:
(a) Haemoglobin ≥9.0 g/dL;
(b) Absolute neutrophil count >1.0 × 109/L;


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(c) Platelet count >75 × 109/L;
(d) Serum bilirubin ≤1.5 × upper limit of normal (ULN).  This will not apply to patients 
with confirmed Gilbert’s syndrome, who will be allowed in consultation with their 
physician.
(e) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN.
(f) Measured creatinine clearance >40 mL/min or calculated creatinine clearance 
>40 mL/min as determined by Cockcroft-Gault (using actual body weight)
(Cockcroft and Gault 1976).
Males:
Creatinine clearance (mL/min) = Weight (kg) × (140Age)
72 × serum creatinine (mg/dL)
Females:
Creatinine clearance (mL/min) = Weight (kg) × (140Age) 
× 0.85
72 × serum creatinine (mg/dL)
Weight
11 Body weight >30 kg at enrolment and first IP dose administration.
Sex
12 Male or female.
Reproduction
13 Evidence of post-menopausal status, or negative urinary or serum pregnancy test for 
female pre-menopausal patients.  Women will be considered post-menopausal if they 
have been amenorrheic for 12 months without an alternative medical cause.  The 
following age-specific requirements apply:
(a) Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy).
(b) Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent 
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy).


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5.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
Medical conditions
1
Patients with locally-advanced NSCLC whose disease has progressed following 
platinum-based sCRT.
2
Patients who have disease considered for surgical treatment as part of their care plan, such 
as Pancoast or superior sulcus tumours.
3
Mixed small-cell lung cancer and NSCLC histology.
4
History of allogeneic organ transplantation.
5
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:
(a) Patients with vitiligo or alopecia.
(b) Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement. 
(c) Any chronic skin condition that does not require systemic therapy.
(d) Patients without active disease in the last 5 years at enrolment may be included but 
only after consultation with the Study Physician.
(e) Patients with celiac disease controlled by diet alone.
6
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina 
pectoris, cardiac arrhythmia, ILD, serious chronic GI conditions associated with 
diarrhoea, 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.
7
History of another primary malignancy except for:
(a) Malignancy treated with curative intent and with no known active disease ≥5 years 
before the first dose of IP and of low potential risk for recurrence.
(b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease.
(c) Adequately treated carcinoma in situ without evidence of disease.
8
History of leptomeningeal carcinomatosis.
9
History of active primary immunodeficiency.
10 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 surface antigen [HbsAg] result), 
hepatitis C virus (HCV), or human immunodeficiency virus (HIV) (positive HIV 1/2 
antibodies).  Patients with a past or resolved hepatitis B virus (HBV) infection (defined as 
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Patients positive for hepatitis C antibody are eligible only if polymerase chain reaction is 
negative for HCV ribonucleic acid (RNA).
11 Any unresolved toxicity of NCI CTCAE Grade ≥2 from previous anticancer therapy with 
the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion 
criteria.
(a) Patients with Grade ≥2 neuropathy or Grade ≥2 lymphopenia will be evaluated on a 
case-by-case basis after consultation with the Study Physician.
(b) Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab (MEDI4736) may be included only after consultation 
with the Study Physician.
12 Known allergy or hypersensitivity to durvalumab (MEDI4736) or any of the IP 
excipients.
Prior/concomitant therapy
13 Patients who have received cCRT for locally-advanced NSCLC, or who received sCRT 
with at least 2 concomitant CRT cycles. Prior surgical resection (ie, Stage I or II) is 
permitted.
Note: Patients whose platinum-based chemotherapy contained gemcitabine and who 
received sCRT with at least 1 concomitant CRT cycle are excluded from this study.
14 Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up to 
30 days after the last dose of IP.
15 Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of IP.  
Note: Local surgery of isolated lesions for palliative intent is acceptable.
16 Prior exposure to immune-mediated therapy, including but not limited to, other 
anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic 
anticancer vaccines.
17 Current or prior use of immunosuppressive medication within 14 days before the first 
dose of IP.  The following are exceptions to this criterion:
(a) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular 
injection);
(b) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or its equivalent;
(c) Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
Prior/concurrent clinical study experience
18 Previous IP assignment in the present study. 
19 Concurrent enrolment in another clinical study, unless it is an observational 
(noninterventional) clinical study or the follow-up period of an interventional study. 


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20 Participation in another clinical study with an IP during the 4 weeks prior to the first IP
dose administration.
21 Prior randomisation or treatment in a previous durvalumab (MEDI4736) ± tremelimumab 
clinical study regardless of treatment arm assignment.
Other exclusions
22 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 IP.
23 Judgment by the Investigator that the patient is unsuitable to participate in the study and 
the patient is unlikely to comply with study procedures, restrictions, and requirements.
24 Genetic research study (optional):
Exclusion criteria for participation in the optional (DNA) genetic research component of 
the study include:
(a) Previous allogeneic bone marrow transplant.
(b) Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample 
collection.
Procedures for withdrawal of incorrectly enrolled patients are provided in Section 7.3.
5.3
Lifestyle restrictions 
The following restrictions apply while the patient is receiving IP and for the specified times 
before and after:
1
Female patients of childbearing potential
(a) Female patients of childbearing potential who are not abstinent and intend to be 
sexually active with a non-sterilized male partner must use at least 1 highly effective 
method of contraception (Table 4) from the time of screening throughout the total 
duration of the drug treatment and the drug washout period (90 days after the last 
dose of durvalumab [MEDI4736] 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
(a) 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 
[MEDI4736] 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.


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(b) 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 post-menopausal range for the institution.

Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago.

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 where inhibition of ovulation is not the primary MOA [excluding 
Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills).


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Table 4
Highly effective methods of contraception (<1% failure rate)
Barrier/intrauterine methods
Hormonal methods
•
Copper T intrauterine device
•
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®)a
•
Implants: 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 IP or until alternate 
anticancer therapy is started. 
4
Restrictions relating to concomitant medications are described in Section 6.4.
5.4
Patient enrolment
All patients will be centrally assigned to study drug using an Interactive Voice Response 
System (IVRS)/Interactive Web Response System (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.
At screening/baseline (Days -28 to -1), the Investigators or suitably trained delegate will:
1
Obtain signed informed consent from the potential patient before any study specific
procedures are performed that are not part of routine medical care.
2
Obtain a unique 7-digit enrolment number (E-code), through the IVRS/IWRS. This 
number is the patient’s unique identifier and will be maintained throughout the study.
3
Determine patient eligibility (see Section 5.1 and 5.2).
4
Obtain signed informed consent for genetic research study (optional and where 
applicable).
Patients will begin treatment on Day 1. If a patient does not meet eligibility criteria or 
withdraws from participation in the study after enrolment, then his/her E- number cannot be 


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reused.  Investigator(s) should keep a record/screening log of patients who entered pre-study 
screening.
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 the study drug.  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 study 
drug, 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 the study drug.  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 fulfil 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”.  This reason for study withdrawal is only valid for screen failures (ie, not for 
patients who are assigned IP treatment).  Patients may be re-screened a single time, but they 
may not be re-assigned IP treatment. If a patient who has failed screening is re-screened, 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.
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure patients to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities.  Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE.
6
STUDY TREATMENTS
Study treatment is defined as any IPs (including marketed product comparator and placebo) 
intended to be administered to a study participant according to the study protocol.  Study 
treatment in this study refers to durvalumab (MEDI4736).
6.1
Treatments administered
6.1.1
Investigational product
AstraZeneca will supply durvalumab (MEDI4736) (described in Table 5). 


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Table 5
Study treatment
Study treatment name
Durvalumab (MEDI4736)
Dosage formulation
500-mg vial solution for infusion after dilution, 50 mg/mL
Route of administration
IV
Dosing instructionsa
1500 mg IV q4wb
Packaging and labelling
Provided in 500-mg vials, labelled in accordance with GMP Annex 13 and per 
country regulatory requirementc
Provider
AstraZeneca
a
Refer to Section 6.1.3 for details on duration of treatment and criteria for treatment through progression.
b
If a patient’s weight decreases to ≤30 kg, the patient should receive weight-based dosing equivalent to 
20 mg/kg of durvalumab (MEDI4736) q4w until the weight improves to >30 kg, at which point the patient 
should start receiving the fixed dosing of durvalumab (MEDI4736) 1500 mg q4w.
c
Label text will show the product name as “MEDI4736” or “durvalumab (MEDI4736)” depending upon the 
agreed product name used in the approved study master label document.  All naming conventions are 
correct during this transitional period.
Note: Cycles of durvalumab (MEDI4736) administration are 28 days.
GMP: Good Manufacturing Practice; IP: Investigational product; IV: Intravenous; q4w: Every 4 weeks.
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for 
infusion after dilution.  The solution contains 50 mg/mL durvalumab (MEDI4736), 
 
 
  The label claim fill volume 
is 10.0 mL.
Durvalumab is a sterile, clear to opalescent, colorless to slightly yellow solution, free 
from visible particles.
IP vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen.  Investigational 
product should be kept in original packaging until use to prevent prolonged light exposure.
Preparation of durvalumab (MEDI4736) doses for administration with an IV bag
The dose of durvalumab (MEDI4736) for administration must be prepared by the pharmacist 
using aseptic technique.  Total time from needle puncture of the durvalumab (MEDI4736) vial 
to the start of administration should not exceed: 

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
If the final product is stored at both refrigerated and ambient temperatures, the total time 
should not exceed 24 hours.
A dose of 1500 mg (for patients >30 kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
CCI
CCI


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concentration ranging from 1 to 20 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 (MEDI4736) to the 
IV bag.  The IV bag size should be selected such that the final concentration is within 
1 to 20 mg/mL.  The bag should be mixed by gently inverting to ensure homogeneity of the 
dose in the bag. 
If participant weight falls to ≤30 kg, weight-based dosing at 20 mg/kg will be administered 
using an IV bag size selected such that the final concentration is within 1 to 20 mg/mL.
Standard infusion time is 1 hour ± 10 minutes, however if there are interruptions, the total 
allowed time should not exceed 8 hours at room temperature.
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed according to local practices to ensure the full dose was
administered.  Infusion time does not include the final flush time.
If either preparation time or infusion time exceeds the time limits, a new dose must be 
prepared from new vials.  Durvalumab (MEDI4736) does not contain preservatives, and any 
unused portion must be discarded.
6.1.2
Dose and treatment regimens
Patients will receive 1500 mg durvalumab (MEDI4736) monotherapy via IV infusion q4w for 
up to a maximum of 24 months from Cycle 1 Day 1 (up to 26 doses/cycles) with the last 
administration at Week 104 (Figure 3). The study drug should be discontinued prior to 
24 months if there is clinical progression or confirmed radiological progression or if there is 
unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.  
Please note, if a patient’s weight decreases to ≤30 kg, the patient should receive weight-based 
dosing equivalent to 20 mg/kg of durvalumab (MEDI4736) q4w after consultation between 
the Investigator and Study Physician, until the weight improves to >30 kg, at which point the 
patient should start receiving the fixed dosing of durvalumab (MEDI4736) 1500 mg q4w.


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Figure 3
Durvalumab (MEDI4736) monotherapy dosing schedule
a
Or until discontinuation of study drug due to any of the reasons listed in Section 7.1.
Max.: Maximum; PD: Progression of disease; q4w: Every 4 weeks.
6.1.3
Duration of treatment and criteria for treatment through progression 
and discontinuation
Patients with CR, PR, or SD (based on Investigator assessment) following completion of 
sCRT will receive durvalumab (MEDI4736) treatment for a maximum of 24 months or until 
RECIST 1.1‑defined PD (unless the Investigator considers the patient continues to receive 
benefit from the IP), initiation of alternative cancer therapy, 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 the study drug at the discretion of the 
Investigator and patient, as long as they are deemed to be receiving clinical benefit, after re-
consenting for treatment through progression.  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.

There is absence of clinical symptoms or signs indicating clinically significant disease 
progression accompanied by a decline in WHO/ECOG PS to >1 for the Cohort of PS 0 to 
1 patients, and to >2 for the Cohort of PS 2 patients.

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 tumour 
compression, or spinal cord compression) requiring urgent alternative medical 
intervention.  (Concurrent radiation treatment is not permitted.  If patients require 
palliative radiation or prophylactic radiation [eg, of brain], consult AstraZeneca for 
exception to this rule; protocol therapy will need to be held prior to and during the 
radiation.)

The patient still fulfils the eligibility criteria for this study (see Sections 5.1 and 5.2) with 
the exception of inclusion criterion 11 and exclusion criteria 13, 16, 17, 18, and 21.

The patient agrees to re-consenting to be treated through progression.


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An individual patient will not receive any further IP if any of the discontinuation criteria listed 
in Section 7.1 apply.
Treatment after final overall survival data cut-off
At the time of the final DCO, the analysis portion of the clinical study will have been 
completed and all patients remaining in the study will be considered to have completed the 
analysis portion of the study.  At the time of final 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 final DCO may continue receiving IP if the 
Investigator judges that they are gaining clinical benefit.
All patients will receive scans and follow-up care in accordance with standard local clinical 
practice.  All data will be recorded on patient charts but will not otherwise be reported for the 
purposes of this study.
For patients who do continue to receive IP beyond the time of the final DCO, 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 
non-serious 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 (Section 8.4.5), 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.
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.
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 end of 24 months of
study treatment, or at the time of the final DCO / database closure, patients currently receiving 


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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.
6.1.4
Storage 
The Investigator, or an approved representative (eg, pharmacist), will ensure that all IP is 
stored in a secured area, at 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 minimise bias: randomisation and blinding
Not applicable.
6.3
Treatment compliance
All administrations of the IP should be recorded in the appropriate sections of the electronic 
case report form (eCRF).
Any change from the dosing schedule, dose interruptions, dose reductions, and dose 
discontinuations should be recorded in the eCRF.
Treatment compliance will be ensured by reconciliation of site drug accountability logs.
The pharmacist is responsible for managing the IP from receipt by the study site until the 
destruction or return of all unused IP.  
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 (ie, until 90 days 
after last dose of IP), including the follow-up period following the last dose of IP.
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 enrolment 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


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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 in 
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 drug
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 drug
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 drug.  (Concurrent use of hormones for non-cancer-
related conditions [eg, insulin for diabetes and hormone 
replacement therapy] is acceptable.  Local treatment of 
isolated lesions, excluding 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 
IP
Immunosuppressive medications, including but not 
limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and tumour necrosis 
factor-α blockers
Should not be given concomitantly, or used for 
premedication prior to the immuno-oncology infusions.  
The following are allowed exceptions:
•
Use of immunosuppressive medications for the 
management of IP-related AEs;
•
Use in patients with contrast allergies; 
•
In addition, use of inhaled, topical, and intranasal 
corticosteroids is permitted.
A temporary period of steroids will be allowed if clinically 
indicated and considered to be essential for the 
management of non-immunotherapy related events 
experienced by the patient (eg, chronic obstructive 
pulmonary disease, radiation, nausea, etc)
EGFR TKIs
Should not be given concomitantly 
Should be used with caution in the 90 days post last dose 
of durvalumab (MEDI4736).
Increased incidences of pneumonitis (with third generation 
EGFR TKIs) and increased incidence of transaminase 
increases (with 1st generation EGFR TKIs) has been 
reported when durvalumab (MEDI4736) has been given 
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Prohibited medication/class of drug
Usage
Herbal and natural remedies which may have 
immune-modulating effects
Should not be given concomitantly unless agreed by the 
Sponsor
AE: Adverse event; CRT: Chemoradiation therapy; CTLA-4: Cytotoxic T-lymphocyte antigen 4; 
EGFR: Epidermal growth factor receptor; IP: Investigational product; mAb: Monoclonal antibody; PD-1: 
Programmed cell death 1; PD-L1: Programmed cell death ligand 1; SoC: Standard of care; TKI: Tyrosine kinase 
inhibitor; TL: Target lesion; TNF-α: tumour necrosis factor alpha.
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 in Table 6
To be administered as prescribed by the Investigator
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management)
Should be used, when necessary, for all patients
Inactivated viruses, such as those in the influenza 
vaccine
Permitted
6.4.1
Other concomitant treatment
Medication, other than the supportive medication listed in Table 7, that is considered 
necessary for the patient’s safety and well-being, may be given at the discretion of the 
Investigator and recorded in the appropriate sections of the eCRF.
6.4.2
Durvalumab (MEDI4736) drug-drug interactions
There is no information to date on drug-drug interactions with durvalumab (MEDI4736) either 
pre-clinically or in patients.  As durvalumab (MEDI4736) is an mAb and therefore a protein, it 
will be degraded to small peptides and amino acids and will be eliminated by renal and 
reticuloendothelial clearance.  It is therefore not expected that durvalumab (MEDI4736) will 
induce or inhibit the major drug metabolizing cytochrome P450 pathways.  As a result, there 
are no expected PK drug-drug interactions.  The MOA of durvalumab (MEDI4736) involves 
binding to PD-L1, and therefore significant PDx 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.


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6.4.3
Rescue medication
As a result of imAEs that could potentially be experienced by patients on durvalumab
(MEDI4736), steroids and other immunosuppressant rescue medication have 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 supplying these 2 rescue medications to the 
sites if local regulations prevent the use of infliximab and mycophenolate in this indication, as 
they are considered off-label for management of immunotherapy related toxicities.  These 
rescue medications must be receipted, controlled, and administered by the pharmacist and 
stored according to the labelled storage conditions, with temperature excursions reported 
accordingly by the pharmacist.  
6.5
Dose modification
Dose delays are permitted for the management of certain IP-related toxicities as described in 
the Dosing Modification and Toxicity Management Guidelines (see Section 8.4.5.1 and
Dosing Modification and Toxicity Management Guidelines in the Annex document to this 
CSP).  Dose reductions are not permitted.
6.6
Treatment after the end of the study
After the final analysis, AstraZeneca will continue to supply the IP to patients up to the time 
that they discontinue the treatment for whatever reason (see Section 6.1.3).
7
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL 
7.1
Discontinuation of study drug
An individual patient will not receive any further IP 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.  Patient who discontinue
treatment are normally expected to continue to participate in the study unless they 
specifically withdraw their consent to further participation in any study procedures and 
assessments (see Section 7.3). 

An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates further 
dosing.

Any AE that meets criteria for discontinuation as defined in the Dosing Modification and 
Toxicity Management Guidelines (Section 8.4.5).

Pregnancy or intent to become pregnant.


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
Non-compliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from treatment with IP (eg, refusal to adhere to 
scheduled visits).

Initiation of alternative anticancer therapy including another IP.

Clinical progression or confirmed radiological progression (refer to Appendix F) and 
Investigator determination that the patient is no longer benefitting from treatment with the 
IP.
7.1.1
Procedures for discontinuation of study drug
Discontinuation of study drug, 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 who 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 assessments with schedule relative to the date 
of administration of the last dose of IP (see Table 2). 
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 52 weeks and q12w ±1 week 
thereafter until clinical progression/deterioration or RECIST 1.1-defined radiological 
progression plus 1 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).  Additional scans are to be completed per standard practice 
post progression (not mandatory to be recorded in eCRF).
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.


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Patients who decline to return to the site for evaluations should be contacted by telephone as 
indicated in 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 survival 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 potentially lost to 
follow-up, and evaluations should resume according to the protocol.
In order to support the analysis of the secondary endpoints of PFS and OS, the survival status 
of all enrolled patients should be re-checked; this includes those patients who withdrew 
consent or are classified as “potentially lost to follow-up.”

Potentially lost to follow-up: Site personnel should check hospital records, the patients’ 
current physician, and a publicly available death registry (if available) to obtain a current 
survival status.  (The applicable eCRF modules will be updated.)

In the event that the patient has actively withdrawn consent to the processing of their 
personal data, the survival status of the patient can be obtained by site personnel from 
publicly available death registries (if available) where it is possible to do so under 
applicable local laws to obtain a current survival status.  (The applicable eCRF modules 
will be updated.)
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit:

The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule.

Before a patient is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the patient or next of kin by, for example, repeat 
telephone calls, certified letter to the patient’s last known mailing address, or local 
equivalent methods.  These contact attempts should be documented in the patient’s 
medical record.  

Efforts to reach the patient should continue until the end of the study.  Should the patient 
be unreachable at the end of the study, the patient should be considered to be lost to 


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follow-up with unknown vital status at the end of study and censored at latest follow-up 
contact.
7.3
Withdrawal from the study
Patients are free to withdraw from the study at any time (IP and assessments) without 
prejudice to further treatment.
Patients who withdraw consent for further participation in the study will not receive any 
further IP or further study observation, with the exception of follow-up for survival, which 
will continue until the end of the study unless the patient has expressly withdrawn their 
consent to survival 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)

The use of any samples (see Appendix C).
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in Table 1 and Table 2. 
A Web-Based Data Capture (WBDC) system will be used for data collection and query 
handling.  The Investigator will ensure that data are recorded on the eCRF as specified in the 
study protocol and in accordance with the instructions provided. 
The Investigator ensures the accuracy, completeness, legibility, and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement.  The Investigator will sign the completed eCRFs.  A copy of the completed 
eCRFs will be archived at the study site.
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study drug.
Adherence to the study design requirements, including those specified in Table 1 and Table 2, 
is essential and required for study conduct.


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All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria.  The Investigator will maintain a screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable.
Procedures conducted as part of the patient’s routine clinical management (eg, blood count)
and obtained before signing of the ICF may be utilised for screening or baseline purposes, 
provided that the procedures met the protocol-specified criteria and were performed within the 
time frame defined in Table 1 and Table 2 and the patient consents to the use of these results.
8.1
Efficacy assessments
The key efficacy endpoints are: median PFS; proportion of patients progression-free at 
12 months (PFS12) and 24 months (PFS24); median OS; proportion of patients alive at 
12 months (OS12), 24 months (OS24), and 36 months (OS36), respectively; 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.  
Tumour assessments utilise 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 tumour 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 a maximum of 
24 months or until disease progression (clinical progression/deterioration ± radiological 
progression by RECIST 1.1), and scanning/tumour assessments continue throughout 
treatment.  An additional follow-up scan is requested following progression if clinically 
feasible.
The RECIST 1.1 guidelines (see Appendix F) provide a method of assessment of change in 
tumour burden in response to treatment.  Screening/baseline imaging should be performed no 
more than 28 days before the date of the first IP dose administration, and ideally as close as 
possible to the date of first IP dose administration.  The RECIST 1.1 assessments of baseline
images identify target lesions (TLs) (defined measurable) and non-target lesions (NTLs).  On-
study images are evaluated for TLs and NTLs chosen at baseline and for new lesions (NLs) 
when they appear.  This allows determination of follow-up TL response, NTL lesion response, 
the presence of unequivocal NLs, and overall timepoint responses (CR, PR, SD, PD, or not 
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8.1.1
Survival assessments
Assessments for survival must be made q12w (±2 weeks) following treatment discontinuation.  
Survival information may be obtained via telephone contact with the patient or the patient’s 
family or by contact with the patient’s current physician.  The details of first and subsequent 
therapies for cancer, after discontinuation of treatment, will be collected.
In addition, patients on treatment or in survival follow-up will be contacted following the 
DCO for the primary analysis and all subsequent survival analyses to provide complete 
survival data.  Survival calls will be made following the date of DCO for the analysis (these 
contacts should generally occur within 7 days of the DCO). If participants are confirmed to be 
alive or if the death date is after the DCO date, then these participants will be censored at the 
date of DCO.
8.1.2
Patient-reported outcome assessments
‘Patient-reported outcomes’ is an umbrella term referring to any report of the status of a 
patient’s health condition that comes directly from the patient, without interpretation of 
anyone else.  PROs have become a significant endpoint when evaluating effectiveness of 
treatments in clinical studies.  The following PRO questionnaires will be administered in this 
study: 
 
 
 
 
 
8.1.2.1
 
 
 
 
 
 
 
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8.1.2.2
 
 
 
 
 
 
 
 
 
 
8.1.2.3
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.1.2.4
Administration of patient-reported outcome questionnaires
Patients will perform the PRO assessments using an electronic tablet (ePRO) during clinic 
visits and will take approximately 15 minutes to complete.
Each centre must allocate the responsibility for the administration of the PRO instruments to a 
specific individual (eg, a research nurse or study coordinator) and, if possible, assign a 
back-up person to cover if that individual is absent.  The PRO questionnaires must be 
administered and completed at the clinic as per Table 1 and Table 2. 
It is important that the site staff explains the value and relevance of PRO data, which is to hear 
directly from patients how they feel.  The following best practice guidelines should be 
followed:

PRO questionnaires must be completed prior to treatment administration.  As feasible, 
site staff should ensure PRO questionnaires are completed prior to discussion of disease 
progression and other study procedures, such as laboratory samples to further avoid 
biasing the patient’s response to the questions.

The research nurse or appointed site staff should stress that the information is 
confidential.  Therefore, if the patient has any medical problems, he or she should discuss 
them with the doctor or research nurse separately from the PRO assessment.  The 
PRO questionnaires must be completed in private by the patient.

The research nurse or appointed site staff must remind patients that there are no right or 
wrong answers and avoid introducing bias by not clarifying items.  The patient should not 
receive help from relatives, friends, or clinic staff to answer the PRO questionnaires. The 
patients should be given sufficient time to complete the PRO questionnaires at their own 
speed.

The research nurse or appointed site staff must train the patient on how to use the ePRO 
device using the materials and training provided in the ePRO device.

All PRO questionnaires are to be completed using an ePRO device. If technical or other 
issues prohibit completion on the device, an appropriate back-up option may be 
considered for the study with prior approval and instruction from the Sponsor.
A key aspect of study success is to have high PRO compliance.  Therefore, it is essential to 
follow the SoA and that sites make sure the device is charged and fully functional at all times 
in order to minimise missing data.
As a general rule, site staff should not read or complete the PRO questionnaires on behalf of 
the patient (see Section 4.1.1 for study conduct mitigation during study disruptions).  If the 
patient is unable to read the questionnaire (eg, is blind or illiterate), that patient should be 
exempted from completing PRO questionnaires but may still participate in the study.
Patients exempted in this regard should be flagged appropriately by the site staff in the source 
documents.


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8.1.2.5
Calculation or derivation of patient-reported outcome variables
 
 
 
 
Table 8
 
 
 
 
 
 
 
 
 
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8.2
Safety assessments 
Planned timepoints for all safety assessments are provided in Table 1 and Table 2. 
8.2.1
Clinical safety laboratory assessments
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the times indicated in the assessment schedules and as clinically indicated (see 
Table 1 and Table 2).  
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a 
licensed clinical laboratory according to local standard procedures.  Sample tubes and sample
sizes may vary depending on the laboratory method used and routine practice at the site.  
Urine pregnancy tests may be performed at the site using a licensed test (urine or serum 
pregnancy test).  Abnormal clinically significant laboratory results should be repeated as soon 
as possible (preferably within 24 to 48 hours).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  The date, time of collection, and results (values and units) will be recorded on 
the appropriate eCRF page.
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The laboratory variables to be measured are presented in Table 10 (clinical chemistry), Table 
11 (haematology), and Table 12 (urinalysis).
Other safety assessments to be performed at screening include HbsAg, hepatitis C antibodies, 
and HIV antibodies.
The following laboratory variables will be measured.
Table 10
Clinical chemistry
Albumin
Lactate dehydrogenase
Alkaline phosphatasea
Lipaseb
ALTa
Magnesiumc
Amylaseb
Potassium
ASTa
Sodium
Bicarbonatec
Total bilirubina
Calcium 
Total protein
Chloridec
TSHd
Creatinine
T3 freee (reflex)
Creatinine clearance
T4 freee (reflex)
Gamma glutamyltransferasec
Urea or blood urea nitrogen, depending on local practice
Glucose
a
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently.  
If total bilirubin is ≥2 × ULN (and no evidence of Gilbert’s syndrome) then fractionate into direct and 
indirect bilirubin.
b
It is preferable that both amylase and lipase parameters are assessed.  For sites where only 1 of these 
parameters is routinely measured, then either lipase or amylase is acceptable.
c
Bicarbonate (where available), chloride, 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 IP dose administration), it does not need to be 
repeated at Day 1.
e
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE 
related to the endocrine system.
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; IP: Investigational product; T3: 
Triiodothyronine; T4: Thyroxine; TSH: Thyroid-stimulating hormone; ULN: Upper limit of normal.
Table 11
Haematology
Absolute neutrophil counta
Absolute lymphocyte counta
Haemoglobin
Platelet count
Total white cell count
Coagulationb
a
Can be recorded as absolute counts or as percentages.  Absolute counts will be calculated by Data 
Management if entered as percentage.  Total white cell count, therefore, has to be provided.


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b
For coagulation parameters, activated partial thromboplastin time (either as ratio or as an absolute value in 
seconds) and international normalised ratio are to be assessed at baseline on Day 1 and as clinically 
indicated.
Table 12
Urinalysis
Bilirubin
Ketones
Blood
pH
Colour and appearance
Protein
Glucose
Specific gravity
Note: Microscopy is preferred to investigate white blood cells and use the high-power field for red blood cells, 
dipstick can be used as well.
Note: Urinalysis should be done at baseline (screening) and then as clinically indicated.
If a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, refer to 
Appendix E for further instructions for cases of increases in liver biochemistry and evaluation 
of Hy’s law (HL).  These cases should be reported as SAEs if, after evaluation, they meet the 
criteria for a HL case or if any of the individual liver test parameters fulfil 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 last dose of IP (see Table 2).
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 Table 1
and Table 2).  Full physical examinations will include assessments of the head, eyes, ears, 
nose, and throat and the respiratory, cardiovascular, GI, urogenital, musculoskeletal, 
neurological, dermatological, haematologic/lymphatic, and endocrine systems.  Height will be 
measured at screening only.  Targeted physical examinations are to be utilised by the 
Investigator on the basis of clinical observations and symptomatology.  Targeted physical 
examinations during the treatment cycles (C1 onwards) are not required for asymptomatic 
patients.  Situations in which physical examination results should be reported as AEs are 
described in Section 8.3.7. 


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8.2.3
Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiratory rate) will be evaluated 
according to the assessment schedules (see Table 1 and Table 2).  Body weight is also 
recorded at each visit along with vital signs.  The following timepoints for vital signs 
assessments apply to infusions of durvalumab (MEDI4736).
First IP dose administration
On the day of first IP dose administration, patients will be monitored and vital signs will be 
collected/recorded in the eCRF prior to, during, and after infusion of IP as presented in the 
bulleted list below. 
BP and pulse, and other vital signs (including temperature and respiratory rate) will be 
collected before, during, and after IP infusion at the following times (based on a 60-minute 
± 10 minutes infusion):

Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minute [ie, the beginning of the infusion])

Approximately 30 minutes during the infusion (halfway through infusion) 

At the end of the infusion (approximately 60 minutes ±10 minutes)

A 1-hour observation period is recommended after the first infusion of IP.  If no clinically 
significant infusion reactions are observed during or after the first cycle, subsequent 
infusion observation periods can be at the Investigator’s discretion (suggested 30 minutes 
after each IP infusion). 
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow 
the principles as described above or be taken more frequently if clinically indicated.  
Additional monitoring with assessment of vital signs will be at the discretion of the 
Investigator per standard clinical practice or as clinically indicated.
Subsequent IP dose administrations
BP, pulse, and other vital signs (including temperature and respiratory rate) should be 
measured and collected/recorded in the eCRF prior to the start of the infusion.  Patients should 
be carefully monitored and BP and other vital signs should be measured during and post 
infusion as per institution standard and as clinically indicated.  Any clinically significant 
changes in vital signs should be entered in an unscheduled vital signs eCRF page. 
Situations in which vital signs results should be reported as AEs are described in 
Section 8.3.7.  For any AEs of infusion reactions, please enter the vital signs values into the 
eCRF.




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exclude alternative causes such as lymphangitic carcinomatosis, infection, allergy, cardiogenic 
oedema, or pulmonary haemorrhage.  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 
(Section 8.4.5) 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 (including images) will be collected.

Physical examination

Signs and symptoms (cough, shortness of breath and pyrexia, etc) including 
auscultation for lung field will be assessed.

Peripheral oxygen saturation (SpO2)

Other items

When pneumonitis (ILD) is suspected during study treatment, the following markers 
should be measured where possible:
o
ILD Markers (KL-6, SP-D) and β-D-glucan
o
Tumour markers: Particular tumour markers that are related to disease 
progression
o
Additional Clinical chemistry: C-reactive protein (CRP), lactate dehydrogenase 
(LDH)
8.3
Collection of adverse events
The Investigator is responsible for ensuring that all staff involved in the study are familiar 
with the content of this Section.
The definitions of an AE and SAE can be found in Appendix B.
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legally authorised 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 adverse events and serious adverse events
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 
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8.3.2
Time period and frequency for collecting adverse event and serious 
adverse event information 
AEs and SAEs will be collected from time of signature of informed consent throughout the 
treatment period and including the follow-up period (90 days after the last dose of IP). If an 
event that starts post the defined safety follow-up period noted above is considered to be due 
to a late-onset toxicity to study drug then it should be reported as an AE or SAE, as 
applicable.
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 the data being available.
Investigators are not obligated to actively seek AE or SAE in former study patients.  However, 
if the Investigator learns of any SAE, including a death, at any time after a patient’s last visit 
and he/she considers the event to be reasonably related to the study drug or study 
participation, the Investigator may notify the Sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are described in Appendix B.
8.3.3
Follow-up of adverse events and serious adverse events
During the course of the study, all AEs and SAEs should be proactively followed up for each 
patient.  Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation or study completion.
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated (this may be beyond the 90 days after the last 
dose of IP), but without further recording in the eCRF. Any SAE or non-serious 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
(Section 8.4.5), unless the event is considered by the Investigator to be unlikely to resolve or 
the patient is lost to follow-up.  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 


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
Changes in CTCAE Grade (report only the maximum CTCAE Grade for the 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

Date the Investigator became aware of the SAE

Seriousness criteria fulfilled

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Whether an autopsy was performed

Causality assessment in relation to study procedure(s)

Causality assessment in relation to other medication, as explained in Section 8.3.5

Description of the SAE
The grading scales found in the revised NCI CTCAE version 4.03 will be utilised for all 
events with an assigned CTCAE grading.  For those events without assigned CTCAE grades, 
the recommendation in the CTCAE criteria that converts mild, moderate, and severe events 
into CTCAE grades should be used.  A copy of the CTCAE version 4.03 can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity, whereas seriousness is defined by the criteria in Appendix B, B 2.  An AE of severe 
intensity need not necessarily considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Appendix B, B 2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke, but it would be an SAE if it satisfies the criteria 
shown in Appendix B, B 2.


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8.3.5
Causality collection
The Investigator will assess causal relationship between IP and each AE, and answer “yes” or 
“no” to the question “Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?”
For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure, the causal relationship 
is implied as “yes”.
A guide to the interpretation of the causality question is found in Appendix B, B 7.
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff, “Have you had any health problems since the previous visit/you were 
last asked?”, or revealed by observation will be collected and recorded in the eCRF.  When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.7
Adverse events based on examinations and tests
The results from the protocol-mandated laboratory tests and vital signs will be summarized in 
the CSR.  Deterioration as compared to baseline in protocol-mandated laboratory values and 
vital signs should therefore only be reported as AEs if they fulfil any of the SAE criteria or are 
the reason for discontinuation of treatment with an IP. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE, and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible, the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value).  
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AEs.
Deterioration of a laboratory value that is unequivocally due to disease progression should not 
be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study, see Sections 8.3.9 and 8.3.10.


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8.3.8
Hy’s law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need 
to be reported as SAEs.  Please refer to Appendix E for further instruction on cases of 
increases in liver biochemistry and evaluation of HL.
8.3.9
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP is being studied.  It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease.  The development of new 
or progression of existing metastasis to the primary cancer under study should be considered 
as disease progression and not an AE.  Events that are unequivocally due to disease 
progression should not be reported as an AE during the study.
8.3.10
New cancers
The development of a new cancer should be regarded as an SAE.  New primary cancers are 
those that are not the primary reason for the administration of the IP and have been identified 
after the patient’s inclusion in this study. 
8.3.11
Deaths
All deaths that occur during the study treatment period or within the protocol-defined 
follow-up period after the administration of the last dose of IP must be reported as follows:

Death clearly the result of disease progression should be reported to the Study 
Monitor/Physician at the next monitoring visit and should be documented in the eCRF in 
the Statement of Death page.  It should not be reported as an SAE. 

Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported to the Study Monitor/Physician as an SAE within 
24 hours.  It should also be documented in the Statement of Death page in the eCRF.  The 
report should contain a comment regarding the co-involvement of PD, if appropriate, and 
should assign main and contributory causes of death. 

Deaths with an unknown cause should always be reported as an SAE.  It should also be 
documented in the Statement of Death page in the eCRF.  A post mortem may be helpful 
in the assessment of the cause of death, and if performed, a copy of the post-mortem 
results should be forwarded to AstraZeneca Patient Safety or its representative within the 
usual timeframes. 
Deaths occurring after the protocol-defined safety follow-up period after the administration of 
the last dose of IP should be documented in the Statement of Death page.  If the death 
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event is considered to be due to a late-onset toxicity to the IP then it should also be reported as 
an SAE.
8.3.12
Adverse events of special interest
An AESI is one of scientific and medical interest specific to understanding of the IP and may 
require close monitoring and rapid communication by the Investigator to the Sponsor.  An 
AESI may be serious or non-serious.  The rapid reporting of AESIs allows ongoing 
surveillance of these events in order to characterize and understand them in association with 
the use of this IP.
AESIs for durvalumab (MEDI4736) 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 (MEDI4736) 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 aetiology.  Serologic, immunologic, and histologic 
(biopsy) data, as appropriate, should be used to support an imAE diagnosis.  Appropriate 
efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic 
causes of the imAE. 
If the Investigator has any questions with regard to an event being an imAE, the Investigator 
should promptly contact the Study Physician.  AESIs may have additional clinical information 
collected in the eCRF.
AESI/imAEs observed with anti PD-L/PD-1 agents such as durvalumab include pneumonitis, 
hepatitis, diarrhea/colitis, intestinal perforation, endocrinopathies (hypo- and 
hyper-thyroidism, adrenal insufficiency, hypophysitis/hypopituitarism and Type 1 diabetes 
mellitus), nephritis, rash/dermatitis, myocarditis,myositis/polymyositis, pancreatitis and 
rare/less frequent imAEs including neuromuscular toxicities such as myasthenia gravis and 
Guillain-Barre syndrome.
Other inflammatory responses that are rare/less frequent with a potential immune-mediated 
etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and other events 
involving the eye, skin, hematological, rheumatological events, vasculitis, non-infectious 
meningitis and non-infectious encephalitis. It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all organs
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological aetiology are also considered AESIs. 


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Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the durvalumab (MEDI4736) IB.  More specific guidelines for their evaluation and 
treatment are described in detail in the Dosing Modification and Toxicity Management 
Guidelines (Section 8.4.5).  These guidelines have been prepared by the Sponsor to assist the 
Investigator in the exercise of his/her clinical judgment in treating these types of toxicities.  
These guidelines apply to AEs considered causally related to the IP/study regimen by the 
reporting Investigator.
8.3.13
Safety data to be collected following the final data cut-off of the study
For patients continuing to receive IP 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 IP in order to 
manage AEs in accordance with the durvalumab (MEDI4736) Dosing Modification and 
Toxicity Management Guidelines (see Section 8.4.5). All data post the final DCO and 
database closure will be recorded in the patient notes but, with the exception of SAEs, will not 
otherwise be reported for the purposes of this study.
All SAEs that occur in patients still receiving IP treatment (or within the 90 days following 
the last dose of IP treatment) post the final DCO and database closure must be reported as 
detailed in Section 8.4.1.
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP or to the 
study procedure(s).  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 
24 hours of when he/she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day, ie, immediately but no later than 24 hours of when he or she becomes 
aware of it.


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Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is unavailable, the Investigator will contact the Study Representative 
immediately. The Study Representative will give guidance on how to send the SAE report,
eg, using a paper back-up SAE report, recognizing that the same reporting time frames still 
apply.
As soon as the WBDC system is available again, the Investigator must enter all SAE 
information in the WBDC system as well.
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study.  A medical emergency usually 
constitutes an SAE and is to be reported as such.
For further guidance on the definition of an SAE, see Appendix B.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for 
pregnancy discovered before the study patient has received any IP.
8.4.2.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day (ie, immediately but no 
later than 24 hours) of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 
1 to 5 calendar days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.


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The PREGREP module in the eCRF 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 following the last dose of IP.  
Pregnancy of the patient’s partners is not considered to be an AE.  However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) occurring from the date of the first dose until 90 days after 
the last dose of IP should, if possible, be followed up and documented.  
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the patient’s partner. Therefore, the local study 
team should adopt the generic ICF template in line with local procedures and submit it to the 
relevant Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) prior to 
use.
8.4.3
Overdose
Use of durvalumab (MEDI4736) 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 (MEDI4736), 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 eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he/she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see 
Section 8.3.2.  For other overdoses, reporting must occur within 30 days.
8.4.4
Medication error
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day (ie, immediately 
but no later than 24 hours) of when he or she becomes aware of it.


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The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.2) and within 30 days for all other 
medication errors.
The definition of a medication error can be found in Appendix B, B 8.
8.4.5
Management of investigational product-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 4.03. 
8.4.5.1
Specific toxicity management and dose modification information –
Durvalumab and durvalumab + tremelimumab
Comprehensive toxicity management guidelines (TMGs) have been developed to assist 
investigators with the recognition and management of toxicities associated with use of the 
immune-checkpoint inhibitors, durvalumab [MED4736] (PD-L1 inhibitor) and tremelimumab 
(CTLA-4 inhibitor). Given the similar underlying mechanism of toxicities observed with 
these two compounds, these TMGs are applicable to the management of patients receiving 
either drug as monotherapy or both drugs in combination. Additionally, these guidelines are 
applicable when either drug is used alone or both drugs are used in combination and, also 
other anti-cancer drugs (i.e., antineoplastic chemotherapy, targeted agents) are administered 
concurrently or sequentially as part of a protocol-specific treatment regimen. The TMGs 
provide information for the management of immune mediated reactions, infusion-related
reactions, and non-immune-mediated reactions that may be observed with checkpoint inhibitor 
monotherapy or combination checkpoint inhibitor regimens, with specific instructions for 
checkpoint inhibitor-specific dose modifications (including discontinuation) and treatment 
interventions. Investigators are advised however to use local practice guidelines and consult 
local references for the management of toxicities observed with other anti-cancer treatment.
The most current version of the TMGs is provided to the investigative site as an Annex to 
Protocol document entitled, “Dosing Modification and Toxicity Management Guidelines for 
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Monotherapy or Combination Therapy with Tremelimumab or Tremelimumab 
Monotherapy),” and is maintained within the Site Master File.
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative aetiology, events should be considered 
potentially immune-related. In addition, there are certain circumstances in which durvalumab 
and tremelimumab should be permanently discontinued (see Section 7.1 of this protocol and 
the TMGs). Following the first dose of IP, subsequent administration of durvalumab and 
tremelimumab can be modified based on toxicities observed as described in the Dosing 
Modification and Toxicity Management Guidelines (see the Annex document to this CSP). 
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 and the durvalumab + 
tremelimumab regimen by the reporting Investigator.
Dose reductions are not permitted.  In case of doubt, the Investigator should consult with 
the Study Physician.
8.5
Pharmacokinetics
PK parameters are not evaluated in this study.
8.6
Pharmacodynamics
PDx parameters are not evaluated in this study.
8.7
8.7.1
 
 
 
 
 
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8.8.1.2
 
 
 
 
 
8.8.2
 
 
 
 
 
8.8.3
 
 
 
 
  
 
 
 
8.8.4
8.8.4.1
 
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8.8.4.2
 
 
 
 
 
 
 
 
8.8.4.3
 
8.9
Health economics
Health economic parameters are not evaluated in this study.
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9
STATISTICAL CONSIDERATIONS 
9.1
Statistical hypotheses
No formal statistical hypothesis will be tested in this study.
9.2
Sample size determination
The primary objective of this study is to assess the safety and tolerability of durvalumab 
(MEDI4736) which is defined as Grade 3 and Grade 4 TRAEs observed within 6 months after 
the initiation of durvalumab (MEDI4736) treatment.  In addition, safety and tolerability of 
durvalumab (MEDI4736) will be characterized for the cohorts of WHO/ECOG PS 0 to 1 and 
2 patients.
This is a safety study and no formal sample size calculation will be done.  Between 100 and 
120 patients will be enrolled in the WHO/ECOG PS 0 to 1 Cohort and up to 30 patients in the 
WHO/ECOG PS 2 Cohort depending on recruitment.  
 
 
 
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9.3
Populations for analyses
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 1 dose of IP.  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
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 (MEDI4736) 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:
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(a) Number and proportion of patients with AESIs, by pre-defined type (or newly 
defined by this study) in total and by seriousness, severity and causality, including 
immune-relatedness;
(b) Number and proportion of patients who received steroids, immunosuppressants 
and/or hormone replacement therapy to manage AESIs;
(c) Time from start of durvalumab (MEDI4736) to the onset of an AESI pre-defined 
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.
PFS (days) = Date of event or Censor date – treatment start date +1
Patients who have not progressed or died at the time of analysis will be censored at the 
time of the latest date of assessment from their last evaluable 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.
8
OS: Defined as the time from the first date of treatment until death due to any cause.
OS (days) = Death date or Censor date treatment start date +1
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.
9
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.
10 ORR: Based on Investigator−assessed response to treatment of CR and PR, per 
RECIST1.1.
11 DoR: Defined as the time from the date of first documented response per RECIST1.1 
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9.5.2
Analysis of the secondary variables
9.5.2.1
Safety variables
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 last dose 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 the last dose 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)
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 pre-dose and at least 1 post-dose value recorded.

If a CTCAE criterion does not consider changes from baseline, to be evaluable, the 
patient need only have 1 post-dose value recorded.


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The denominator in vital signs data should include only those patients with recorded data.
9.5.2.2
Efficacy variables
Efficacy data will be reported for patients overall and separately for the cohorts of 
WHO/ECOG PS 0 to 1 and 2 patients 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 12 and 24 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, 24, and 36 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.
9.5.2.3
Patient-reported outcomes
 
 
 
 
 
CCI
CCI
CCI


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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.  However, the SC will conduct an early 
safety evaluation when 10 patients in the WHO/ECOG PS 2 cohort have been treated for a 
minimum of 6 months or discontinued due to an AE or disease progression, whichever occurs 
first.  At the time of the early safety evaluation, safety data for patients in the WHO/ECOG 
PS 0 to 1 cohort will also be provided to the SC for completeness in the overall risk/benefit 
assessment.  If needed for publication purposes, an additional early assessment of study data 
may be conducted when minimum 50 patients in the WHO/ECOG PS 0 to 1 cohort or 
WHO/ECOG PS 2 cohort have had the opportunity to receive durvalumab (MEDI4736) for a 
minimum of 6 months.
Details of the early safety evaluations will be documented in the SAP and SC Charter.  In 
addition to the early safety evaluations, during the study, data may be summarized and 
presented at congresses or conferences.
9.6.1
Steering committee
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.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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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 Organisation 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 
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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11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


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


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


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


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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 authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the Sponsor.  No records may be 
transferred to another location or party without written notification to the Sponsor. 
A 8
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected.  Source documents are filed at the Investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained.  The Investigator may need to 
request previous medical records or transfer records, depending on the study.  Also, current 
medical records must be available.
All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the reconstruction and 
evaluation of the study.  Source data are contained in source documents (original records or 
certified copies).


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A 9
Study and site closure
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed.
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the Investigator

Discontinuation of further study drug development
A 10
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 multi-centre 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 AE is the development of any untoward medical occurrence in a patient or clinical study 
patient administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavourable and unintended 
sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence.  An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
B 2
Definitions of serious adverse event
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils 1 or more of the following criteria:

Results in death.

Is immediately life-threatening.

Requires in-patient hospitalisation or prolongation of existing hospitalisation. 

Results in persistent or significant disability or incapacity. 

Is a congenital abnormality or birth defect.

Is an important medical event that may jeopardise the patient or may require medical 
treatment to prevent one of the outcomes listed above.

Adverse Events for malignant tumours 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 judgement on an 
individual event basis should be applied to clarify that the malignant tumour event should 
be assessed and reported as a Non-Serious AE.  For example, if the tumour is included as 
medical history and progression occurs during the study, but the progression does not 
change treatment and/or prognosis of the malignant tumour, the AE may not fulfill the 
attributes for being assessed as serious, although reporting of the progression of the 
malignant tumour as an AE is valid and should occur.  Also, some types of malignant 
tumours, which do not spread remotely after a routine treatment that does not require 
hospitalization, may be assessed as Non-Serious; examples include Stage 1 basal cell 
carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.

In Oncology studies, the above instruction applies only when the malignant tumour event 
in question is a new malignant tumour (i.e., it is not the tumour 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 tumour under study).
Malignant tumours that – as part of normal, if rare, progression – undergo transformation 


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(eg, Richter's transformation of B cell chronic lymphocytic leukemia into diffuse large 
B cell lymphoma) should not be considered a new malignant tumour.
B 3
Life threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (eg, hepatitis that resolved without hepatic failure).
B 4
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
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, hospitalisation, disability or incapacity but may jeopardise the patient or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious.  These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.

Angioedema not severe enough to require intubation but requiring IV hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse
B 6
CTCAE Grade
The grading scales found in the revised NCI CTCAE latest version will be utilised for all 
events with an assigned CTCAE grading.  For those events without assigned CTCAE grades, 
the recommendation in the CTCAE criteria that converts mild, moderate and severe events 
into CTCAE grades should be used.  A copy of the CTCAE can be downloaded from the 


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


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The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 8
Medication error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant 
or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error. 

Occurred

Was identified and intercepted before the participant received the drug

Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed

Wrong participant received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/IWRS – including those which lead to one of the 
above listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s) eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging


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
Errors related to background and rescue medication, or standard of care medication in 
open-label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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


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


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Appendix D
CCI
CCI


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CCI


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CCI


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CCI


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Appendix E
Actions required in cases of increases in liver biochemistry 
and evaluation of Hy’s law
E 1
Introduction
This appendix describes the process to be followed in order to identify and appropriately 
report cases of HL.  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 (Section 8.4.5).
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a patient meets 
potential Hy’s law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether 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 AE and SAE according to the outcome of the review and assessment in line with 
standard safety reporting processes.
E 2
Definitions
Potential Hy’s law (PHL)
AST or ALT ≥3 × ULN together with total bilirubin (TBL) ≥2 × ULN at any point during the 
study following the start of IP irrespective of an increase in alkaline phosphatase (ALP).  
Hy’s law (HL)
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other reason, other than the 
IP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified time frame within which the 
elevations in transaminases and TBL must occur.
E 3
Identification of potential Hy’s law cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:


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
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

Request a repeat of the test (new blood draw) by the central laboratory

Complete the appropriate unscheduled laboratory CRF module(s) with the original local 
laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:

Determine whether the patient meets PHL criteria (see Appendix E, E 2 for definition) by 
reviewing laboratory reports from all previous visits (including both central and local 
laboratory results)
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Notify the AstraZeneca representative

Determine whether the patient meets PHL criteria (see Appendix E, 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:

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP.
E 4.2
Potential Hy’s law criteria met
If the patient does meet PHL criteria the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team 


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The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will:

Monitor the patient until liver biochemistry parameters and appropriate clinical symptoms 
and signs return to normal or baseline levels, or as long as medically indicated. 

Investigate the aetiology of the event and perform diagnostic investigations as discussed 
with the Study Physician.

Complete the 3 Liver CRF Modules as information becomes available. 

If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures.
E 5
Review and assessment of potential Hy’s law cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the IP.  
The AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF

If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the AstraZeneca standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IP:

Report an SAE (report term ‘Hy’s law’) according to AstraZeneca Standard processes. 

The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.


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If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:

Report an SAE (report term ‘Potential Hy’s law’) applying serious criteria and causality 
assessment as per above

Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review 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 drug
This Section is applicable to patients with liver metastases who meet PHL criteria on study 
drug having previously met PHL criteria at a study visit prior to starting Study treatment.
At the first on-study drug occurrence of PHL criteria being met, the Investigator will 
determine if there has been a significant change in the patients’ condition# compared with the 
last visit where PHL criteria were met.#

If there is no significant change, no action is required.

If there is a significant change, notify the AstraZeneca representative, who will inform the 
central Study Team, then follow the subsequent process described in Appendix E, E 5.

# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or 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 drug, and has already 
met PHL criteria at a previous on-study treatment visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:


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Was the alternative cause for the previous occurrence of PHL criteria being met found to be 
the disease under study (eg, chronic or progressing malignant disease, severe infection or liver 
disease), or did the patient meet PHL criteria prior to starting study drug and at first on-study 
treatment visit, as described in Appendix E, E 6.
If No: Follow the process described in Appendix E, E 4.1.
If Yes: Determine if there has been a significant# change in the patient’s condition compared 
with when PHL criteria were previously met.
If there is no significant change, no action is required.
If there is a significant change, follow the process described in Appendix E, E 4.
# 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 tumour response using 
RECIST 1.1 criteria (Response Evaluation Criteria in Solid 
Tumours)
Introduction 
This appendix details the implementation of RECIST 1.1 guidelines (Eisenhauer et al 2009) 
for this study with regard to Investigator assessment of tumour burden including 
protocol-specific requirements for this study.  Additional special guidance is provided for 
determination of confirmation of radiologic progression.
Patients with measurable disease and/or non-measurable and/or NED assessed at baseline by 
CT/MRI will be entered in this study.
Definitions of measurable, non-measurable, target and non-target lesions
Measurable:
A lesion that can be accurately measured at baseline as ≥10 mm in the longest diameter 
(except lymph nodes which must have short axis1 diameter of ≥15 mm) with CT or MRI and 
which is suitable for accurate repeated measurements.
Non-measurable:

All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis diameter at baseline2).

Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, 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 non-measurable.

Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present in the 
same patient, these should be selected over cystic lesions as TLs.
                                               
1 The short axis is defined as the longest axis perpendicular to long axis.
2 Lymph nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded or 
followed as NTLs.


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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 that it fulfils the criteria for 
reproducible measurability and is the only lesion available.  
Non-target lesions:
Additional measurable lesions not recorded as TLs and non-measurable 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 
NLs is provided in Table 14.
Table 14
Summary of imaging modalities for tumour assessment
Target lesions 
Non-target lesions
New lesions
CT (preferred)
MRI
CT (preferred)
MRI
Plain X-ray
Chest X-ray
CT (preferred)
MRI
Plain X-ray
Chest X-ray
Bone scan
FDG-PET/CT
CT: Computed tomography; FDG-PET/CT: 18F-Fluoro-deoxyglucose positron emission tomography/computed 
tomography; MRI: Magnetic resonance imaging.
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 NLs. 
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 tumour 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 IV CT contrast, a non-contrast CT examination of the chest and 
an MRI with IV MRI contrast of the abdomen is appropriate.  In patients with severely 


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compromised renal function a non-contrast CT examination of the chest and abdomen is 
appropriate.  For brain lesion assessment, MRI with IV contrast is the preferred method over 
IV contrast-enhanced CT.  It is strongly recommended to maintain use of the same imaging 
modality (CT or MRI), acquisition protocol, facility and scanner across all imaging timepoints 
per patient.
Clinical examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for RECIST 1.1 assessments.  Tumours 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 NLs.
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 1.1 assessment of tumours as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation and may 
not provide an accurate assessment of true tumour size.  Tumours 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 tumour assessments as they are not validated 
in the context of tumour assessment.
Tumour markers 
Tumour markers on cytological or histological (biopsy) samples will not be used for tumour
response assessments as per RECIST 1.1.
Histology and cytology
Histology on tumour biopsy samples will not be used as part of the tumour 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 tumour response assessment in this study.  An effusion that appears or 


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significantly worsens (from trace to large) radiologically by CT/MRI anatomical scans will be 
considered to be disease progression due to NLs 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.  NLs may be recorded in case positive hot-spots appear on a 
bone scan that were not present on a previous bone scan; however, a newly observed 
equivocal hot-spot on a bone scan 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 scan
18F-Fluoro-deoxyglucose positron emission tomography/computed tomography 
(FDG-PET/CT) scans may be used as a method for identifying NLs, according to the 
following algorithm: NLs will be recorded where there is positive 18F-Fluoro-deoxyglucose 
uptake3 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 NLs on CT/MRI scans then follow-up CT/MRI 
assessments should be continued, scheduled as per protocol or clinical indicated, in order to 
verify NLs.
At present, low dose or attenuation correction CT portions of a combined FDG-PET/CT scan 
are of limited use in anatomically-based efficacy assessments, and it is therefore suggested 
that they should not substitute for dedicated diagnostic contrast-enhanced CT scans for tumour 
measurements by RECIST 1.1.  In exceptional situations, if a study site can document that the 
CT performed, as part of a PET/CT examination, is of identical diagnostic quality (with IV 
contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT can be used 
for RECIST 1.1 tumour 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.
                                               
3 A positive FDG-PET scan lesion should be reported only when an uptake (eg, SUV) greater than twice that of 
the surrounding tissue or liver is observed.


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Tumour response evaluation 
Schedule of evaluation
The methods of assessment of tumour 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, NLs at follow-up.
Baseline assessments should be performed no more than 28 days before the date of first IP 
administration, and ideally should be performed as close as possible to the date of first IP 
administration.  Efficacy by RECIST 1.1 for all patients will be assessed according to the 
schedules of assessment.  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 target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved 
should be identified as TL at baseline.  TLs should be selected on the basis of their size 
(longest diameter for non-nodal lesions or short axis 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, which can be measured 
reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes).  All measurements should be recorded in 
millimetres.  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.

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 NL.

If a TL splits into 2 or more parts, then record the sum of the diameters of those parts.


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
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 1.1 CRF.  If a TL has been completely removed 
(surgery), the longest diameter should be recorded as 0 mm.
Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumour 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 NE 
(eg, missing anatomy) or had a lesion intervention at this visit.  Note: if 
the sum of diameters meets the PD criteria, PD overrides NE as a TL 
response.
TL: Target lesion.
Non-target lesions
Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.  Measurements are not required for these lesions, but their status should be followed 
at subsequent visits.  At each visit an overall assessment of the NTL response should be 
recorded by the Investigator.  This section provides the definitions of the criteria used to 


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determine and record overall response for NTL at the investigational study site at each visit 
(see Table 16).
Table 16
Evaluation of non-target lesions
Complete response (CR)
Disappearance of all NTLs since baseline.  All lymph nodes must be 
non-pathological in size (<10 mm short axis).
Non-CR/non-PD
Persistence of 1 or more NTL.
Progression of disease (PD)
Unequivocal progression of existing NTLs.  Unequivocal progression 
may be due to an important progression in 1 lesion only or in several 
lesions.  In all cases the progression MUST be clinically significant for 
the physician to consider changing (or stopping) therapy.
Not evaluable (NE)
Only relevant when 1 or some of the NTLs were not assessed and, in the 
Investigator’s opinion, they are not able to provide an evaluable overall 
NTL assessment at this visit.
Note: for patients without TLs at baseline, this is relevant if any of the 
NTLs were not assessed at this visit and the progression criteria have not 
been met.
NTL: Non-target lesion; TL: Target lesion.
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, 
the overall tumour burden has increased sufficiently to merit discontinuation of therapy.  A 
modest ‘increase’ in the size of 1 or more NTLs is usually not sufficient to qualify for 
unequivocal progression status.
New lesions
Details of any NLs will also be recorded with the date of assessment.  The presence of 1 or 
more NLs is assessed as progression.  The finding of a NL should be unequivocal, ie, not 
attributable to differences in scanning technique, change in imaging modality or findings 
thought to represent something other than tumour.  If a NL is equivocal, for example because 
of its small size, the treatment and tumour assessments should be continued until the 
previously NL has been assessed as unequivocal and then the progression date should be 
declared using the date of the initial scan when the NL first appeared.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate disease progression.
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 
tumour assessments where clinically feasible.
Evaluation of overall visit response
The overall visit response will be derived using the algorithm shown in Table 17.
Table 17
Overall visit response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
CR
Non-CR/Non-PD 
No
PR
CR
NE
No 
PR
PR
Non-PD or NE
No
PR
SD 
Non-PD or NE
No
SD
NE
Non-PD or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR: Complete response; NA: Not applicable (only relevant if there were no target and/or NTLs at baseline); NE: 
Not evaluable; NTL: Non-target lesion; PD: Progression of disease; PR: Partial response; SD: Stable disease.
Confirmation of radiological progression
A follow-up scan is performed 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 tumour assessments of this follow-up scan.  Patients with confirmed 
radiological PD who continue to receive study drug 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 tumour 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 NLs 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 tumour evaluation using 
RECIST 1.1 are anatomic coverage, contrast administration, slice thickness, and 
reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumours is the chest, 
abdomen and pelvis.  Coverage should encompass all areas of known predilection for 


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metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual patients.  Because a lesion later 
identified in a body part not scanned at baseline would be considered as a new lesion 
representing disease progression, careful consideration should be given to the extent of 
imaging coverage at baseline and at subsequent follow-up timepoints.  This will enable better 
consistency not only of tumour measurements but also identification of new disease.
b. IV contrast administration: Optimal visualization and measurement of metastases in solid 
tumours 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 non-contrast CT or MRI (enhanced or 
non-enhanced) should be performed should also be based on the tumour type, anatomic 
location of the disease and should be optimised to allow for comparison to the prior studies if 
possible.  Each case should be discussed with the radiologist to determine if substitution of 
these other approaches is possible and, if not, the patient should be considered NE from that 
point forward.  Care must be taken in measurement of TLs on a different modality and 
interpretation of non-target disease or NLs, 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 


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images from each examination should be included in the assessment and not “selected” 
images of the apparent lesion.
MRI scan
MRI has excellent contrast, spatial and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity 
and measurement.  Furthermore, the availability of MRI is variable globally.  The modality 
used at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  Generally, axial imaging of the abdomen and 
pelvis (and other anatomies [eg, neck]) with T1 and T2 weighted imaging along with 
gadolinium-enhanced imaging can be performed.  The field of view, matrix, number of 
excitations, phase encoding steps, use of fat suppression and fast sequences should be 
optimised for the specific body part being imaged as well as the scanner utilised.  CT of the 
chest is typically recommended over MRI due to significant motion artefacts (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 tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47.










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CCI






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Appendix H
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis, including COVID-19 Outbreak
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
agreement from the sponsor.
H 1
Reconsent of Study Participants During Study Interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Sections H 2 to H 5. Local and regional regulations and/or guidelines regarding 
reconsent of study participants should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should 
be signed at the participant’s next contact with the study site). Visiting the study sites for the 
sole purpose of obtaining reconsent should be avoided. 
H 2
Rescreening of Participants to Reconfirm Study Eligibility 
Not applicable.
H 3
Home or Remote Visit to Replace On-site Visit (Where 
Applicable)
A qualified HCP from the study site or TPV service may visit the participants home/or other 
remote location as per local Standard Operating Procedures (SOPs), as applicable. Supplies 
will be provided for a safe and efficient visit. The qualified HCP will be expected to collect 
information per the CSP.
H 4
Telemedicine Visit to Replace On-site Visit (Where Applicable)
In this appendix the term telemedicine visit refers to remote contact with the participants using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices.


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During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow AEs and concomitant medication to be reported and 
documented.
H 5
Data Capture During Telemedicine or Home/Remote Visits
Data collected during telemedicine or home/remote visits will be captured by the qualified 
HCP from the study site or TPV service in the source documents, or by the participant 
themselves.
H 6
COVID-19 Risk Assessment 
The safety of participants is of primary importance. Any potential risks of participating in the 
study, particularly with the added challenges due to COVID-19 outbreak, should be weighed 
against the anticipated benefit (see also principle 2.2 of ICH GCP). Investigators are advised 
to use clinical judgment in determining infection prevention precautions for study participants.
The emergence of SARS-CoV-2 presents a potential safety risk for cancer patients. 
Participants enrolling in this study may require more frequent visits to the site for study 
treatment administration and for study assessments compared to participants receiving 
standard of care. Therefore, several risk mitigation factors have been implemented related to 
study conduct during the COVID-19 outbreak, for patient management in an event of 
COVID-19, and actions to be taken on study treatment (see Section H 8). With these measures 
in place, it is considered that the anticipated potential benefits for the participants enrolled in 
this study outweigh the potential risks. All implemented measures prioritise trial participant 
safety and data validity; in case these two conflict with each other, trial participant safety 
should always prevail (see also European Medicines Agency Guidance on the management of 
clinical trials during the COVID-19 [coronavirus] pandemic [EMA 2020]). 
Notably, participants with active COVID-19 infection confirmed by local laboratory testing
will not be eligible for study enrolment (see CSP Section 5.2, Exclusion Criterion 6). 
H 7
Potential Risks during COVID-19
Every effort should be made to follow the CSP. Section H 9 provides a dose modification and 
management plan for participants with confirmed or suspected COVID-19 who are being 
treated with study intervention durvalumab. The risk-benefit assessment should be carefully 
considered for each participant enrolling in the study based on the known safety risks related 
to COVID-19, individual needs, and local guidelines and restrictions. Investigators must 
continue to use their best clinical judgment in determining the most optimal care for 
participants and utmost diligence in determining their eligibility for study participation, 


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continued study treatment, and overall assessment of benefit/risk of study treatment or 
participation.
The sponsor must be promptly notified of a site’s inability to perform study activities due to 
COVID-19 outbreak in order to minimise any potential risks.
H 8
Study Treatment Administration
If an AE or SAE is associated with COVID-19, the investigator should determine whether the 
participants’ treatment with investigational product should continue, be interrupted, or be 
discontinued in accordance with the CSP.
AEs, SAEs, cycle delays and/or treatment suspensions associated with COVID-19 along with 
logistical issues should be reported according to the eCRF Completion Guidelines. 
For dosing discontinuations, where applicable, the dosing discontinuation guidelines should 
be followed, and the Discontinuation of IP Form completed.
H 9
Ongoing Participants
Participants receiving study intervention should continue to undergo safety assessments prior 
to dosing in accordance with the CSP. In case it is not feasible to perform safety assessments, 
study intervention should be interrupted until such assessments can be completed.
H 9.1
If a Participant has an Event Suspected to be COVID-19
Delay or omit study intervention as appropriate and test for COVID-19 per local health 
authority or institutional guidance. 

Signs and symptoms of COVID-19 include but are not limited to new onset of fever, 
new or worsening cough, shortness of breath, difficulty breathing and sometimes 
abnormal chest imaging and may be similar to those of an imAE. 

In accordance with the CSP and the TMGs for imAEs, thorough evaluation should be 
performed to accurately identify the underlying pathology in case an AE is 
encountered for a participant. 

If COVID-19 is ruled out, study intervention may be resumed per the CSP.

If COVID-19 is confirmed or diagnosis still suspected after evaluation, manage 
COVID-19 per local guidance until full recovery.
H 9.2
Participants with Confirmed COVID-19
Participants with confirmed COVID-19 (by local laboratory testing and/or combination of 
key symptoms) should have study intervention withheld and COVID-19 managed per local 
guidance.


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In case of confirmed COVID-19 and a simultaneous imAE requiring treatment, investigators 
are advised to apply clinical judgement regarding the use of corticosteroids as per the 
durvalumab/tremelimumab TMGs. This includes also the consideration of alternate 
immunosuppressive agents other than corticosteroids for imAE management, depending on 
the individual participant’s presentation (Curigliano et al 2020).
H 9.3
Restarting Study Intervention
Study intervention must not be resumed until recovery from COVID-19 (eg, confirmed by 
imaging, lab testing and/or absence of symptoms) and COVID-19-specific treatment has been 
completed per local guidance.
The study clinical lead should be contacted if any additional guidance or clarification is 
needed.
H 9.4
Vaccination Against COVID-19
Protocol restrictions applying to live attenuated vaccines are relevant for live attenuated 
COVID-19 vaccines as well. Investigators should apply their discretion assessing the 
risk‑benefit of other types of COVID-19 vaccines for participants in clinical trials. Ideally, 
administration of the vaccine should be done on a different day other than the day of study 
drug administration to differentiate any potential AEs seen from the vaccine and study drug. 
The administration of the vaccine and any potential AEs associated with the vaccine are to be 
documented on the concomitant medication and AE eCRFs, respectively.
H 10
References
Curigliano et al 2020 
Curigliano G, Banerjee S, Cervantes A, Garassino M, Garrido P, Girard N. Managing cancer 
patients during the COVID-19 pandemic: an ESMO multidisciplinary expert consensus. Ann 
Oncol 2020;31(10):1320-35.
EMA 2020
EMA, Clinical Trials Facilitation and Coordination Group, European Commission. Guidance 
on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, 
Version 2, 27 March 2020. Available from: URL: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf. Accessed: 17 December 2020.


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Appendix I
Abbreviations
Abbreviation or special term
Explanation
AchE
Acetylcholine esterase
ACTH
Adrenocorticotropic hormone
ADL
Activities of daily living
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase 
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration versus time curve
AUCss
Area under the plasma concentration versus time curve at steady state
B7-H1
B7 homolog 1
BNP
Brain-type natriuretic peptide
BP
Blood pressure
BUN
Blood urea nitrogen
C
Cycle
cCRT
Concurrent chemoradiation therapy
CD
Cluster of differentiation
CI
Confidence interval
Cmax,ss
Maximum drug concentration at steady state
CR
Complete response
CRF
Case report form
CRP
C-reactive protein
CRT
Chemoradiation therapy
CSP
Clinical Study Protocol
CSR
Clinical study report
CT
Computed tomography
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Event
CTLA-4
Cytotoxic T-lymphocyte antigen 4
Ctrough,ss
Trough plasma concentration
DCO
Data cut-off
DILI
Drug induced liver injury
CCI
CCI




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Abbreviation or special term
Explanation
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IFN-γ
Interferon gamma
IG
Immunoglobulin
IgG
Immunoglobulin G
ILD
Interstitial lung disease 
IM
Intramuscular
imAE
Immune-mediated adverse event
International Coordinating 
Investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the Investigators and/or 
activities internationally 
I-O
Immuno-oncology
IP
Investigational product
IRB
Institutional Review Board
IV
Intravenous
IVRS
Interactive voice response system
IWRS
Interactive web response system
LDH 
Lactate dehydrogenase
LFT
Liver function test
LLN
Lower limit of normal
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MOA
Mechanism of action
MRI
Magnetic resonance imaging
NCCN
National Comprehensive Cancer Network 
NCI
National Cancer Institute
NE
Not evaluable
NED
No evidence of disease
NL
New lesion
NSCLC
Non-small cell lung cancer
NTL
Non-target lesion
ORR
Objective response rate
OS
Overall survival


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Abbreviation or special term
Explanation
OS12, OS24, OS36
Proportion of patients alive at 12 months, 24 months, 36 months, 
respectively, from first IP dose administration
PD
Progression of disease
PD-1
Programmed cell death 1
PD-L1, PD-L2
Programmed cell death ligand 1, programmed cell death 1 ligand 2
PDx
Pharmacodynamic(s)
PET
Positron emission tomography
PFS
Progression-free survival
PFS12, PFS24
Proportion of patients progression-free at 12 months and 24 months, 
respectively, from first IP dose administration
PGx
Pharmacogenetic(s)
PHL
Potential Hy’s law
PJP
Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii 
pneumonia)
PK
Pharmacokinetic(s)
PO
Per os (by mouth)
PR
Partial response
PRO
Patient-reported outcome(s)
 
 
PS
Performance status
PRAE
Possibly-related adverse event
q28d
Every 28 days
q2w ,q3w, q4w, q8w, q12w
Every 2, 3, 4, 8, 12 weeks, respectively
Q
Quarter
QoL
Quality of life
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RECIST 1.1
Response Evaluation Criteria in Solid Tumours version 1.1
RNA
Ribonucleic acid
SAE
Serious adverse event 
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SC
Steering Committee
sCRT
Sequential chemoradiation therapy
SD
Stable disease
SoA
Schedule of assessments
CCI
CCI


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Abbreviation or special term
Explanation
SoC
Standard of care
SOP
Standard Operating Procedure
SpO2
Peripheral oxygen saturation
sPD-L1
Soluble programmed cell death ligand 1
T3
Triiodothyronine
T4
Thyroxine
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
TKI
Tyrosine kinase inhibitors
TL
Target lesion
TMG
Toxicity Management Guidelines
TNF(-α)
Tumour necrosis factor (alpha)
TPV
Third-party vendor
TRAE
Treatment-related adverse event
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States
WBDC
Web-Based Data Capture
WHO
World Health Organisation
WHO/ECOG PS
World Health Organisation/Eastern Cooperative Oncology Group 
Performance Status
CCI
CCI


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d4194c00006-csp-v4
Document Title:
D4194C00006 Clinical Study Protocol version 4
Document ID:
Doc ID-003880333
Version Label:
5.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
14-Jul-2021 16:00 UTC
Content Approval
09-Jul-2021 20:04 UTC
Management Approval
09-Jul-2021 19:19 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
PPD
PPD

SAP_003.pdf: 


Statistical Analysis Plan
Study Code
D4194C00006
Edition Number
5.0
Date
22 May 2023
A Phase II, Open-Label, Multi-Centre, International Safety Study of 
Durvalumab Following Sequential Chemotherapy and Radiation Therapy 
in Patients with Stage III, Unresectable Non-Small Cell Lung Cancer 
(PACIFIC 6)


Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 2 of 71
A Phase II, Open-Label, Multi-Centre, International Safety Study of 
Durvalumab Following Sequential Chemotherapy and Radiation Therapy 
in Patients with Stage III, Unresectable Non-Small Cell Lung Cancer 
(PACIFIC 6)
Study Statistician
 (PAREXEL)
Date
PPD


Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 3 of 71
A Phase II, Open-Label, Multi-Centre, International Safety Study of 
Durvalumab Following Sequential Chemotherapy and Radiation Therapy 
in Patients with Stage III, Unresectable Non-Small Cell Lung Cancer 
(PACIFIC 6)
Statistical Science Director
 (AstraZeneca)
Date
PPD


Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 4 of 71
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................3
TABLE OF CONTENTS.....................................................................................4
LIST OF TABLES...............................................................................................7
LIST OF ABBREVIATIONS ..............................................................................8
AMENDMENT HISTORY................................................................................ 12
1.
STUDY DETAILS............................................................................................. 15
1.1
Study Objectives................................................................................................ 15
1.1.1
Primary Objective .............................................................................................. 15
1.1.2
Secondary Objectives......................................................................................... 15
1.1.3
Exploratory Objectives....................................................................................... 16
1.2
Study Design...................................................................................................... 17
1.2.1
Study Treatment................................................................................................. 18
1.2.2
Tumour Response Assessments.......................................................................... 19
1.2.3
Overall Survival Assessments ............................................................................ 19
1.3
Number of Subjects............................................................................................ 19
2.
ANALYSIS SETS ............................................................................................. 20
2.1
Definition of Analysis Sets................................................................................. 20
2.1.1
Safety Analysis Set (SAF).................................................................................. 20
2.2
Protocol Deviations............................................................................................ 20
2.2.1
Important Protocol Deviations............................................................................ 20
2.2.2
Monitoring of Important Protocol Deviations..................................................... 23
3.
ANALYSIS VARIABLES................................................................................. 23
3.1
Derivation of RECIST Visit Responses.............................................................. 23
3.1.1
Site Investigator Assessments Using RECIST 1.1 .............................................. 24
3.1.1.1
Target Lesions ................................................................................................... 24
3.1.1.2
Non-Target Lesions and New Lesions................................................................ 28
3.1.1.3
Overall Visit Response....................................................................................... 30
3.2
Safety Variables................................................................................................. 30
3.2.1
Primary Safety Endpoint .................................................................................... 30
3.2.2
Secondary Safety Endpoints............................................................................... 31
3.2.3
Adverse Events .................................................................................................. 31


Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 5 of 71
3.2.3.1
Treatment-Related Adverse Events .................................................................... 32
3.2.3.2
Adverse Events of Special Interest ..................................................................... 32
3.2.3.3
Immune-Mediated Adverse Event ...................................................................... 32
3.2.3.4
Confirmed/Suspected COVID-19 infections....................................................... 33
3.2.4
Electrocardiograms ............................................................................................ 33
3.2.5
Vital Signs ......................................................................................................... 33
3.2.6
Laboratory Data................................................................................................. 33
3.2.7
Physical Examination......................................................................................... 34
3.2.8
Exposure to Durvalumab.................................................................................... 34
3.3
Efficacy Variables.............................................................................................. 36
3.3.1
Progression-Free Survival.................................................................................. 36
3.3.2
Overall Survival................................................................................................. 37
3.3.3
Objective Response Rate.................................................................................... 37
3.3.4
Best Objective Response.................................................................................... 38
3.3.5
Duration of Response......................................................................................... 38
3.3.6
Lung Cancer Mortality....................................................................................... 38
3.4
Exploratory Variables ........................................................................................ 39
3.4.1
Patient Reported Outcomes ................................................................................ 39
3.4.1.1
..................................................... 40
3.4.1.2
..................................................... 42
3.4.1.3
..................................................... 43
3.4.2
..................................................... 43
3.5
Other Variables.................................................................................................. 44
3.5.1
Baseline Characteristics ..................................................................................... 44
3.5.2
Prior and Concomitant Medications and Therapies............................................. 44
3.5.3
Biomarkers ........................................................................................................ 44
4.
ANALYSIS METHODS.................................................................................... 45
4.1
General Principles.............................................................................................. 45
4.1.1
General Statistical Considerations ...................................................................... 45
4.1.2
General Considerations for Summary of Safety Data.......................................... 47
4.1.3
Handling of Missing Data .................................................................................. 47
4.1.4
Definitions of Visit Windows............................................................................. 48
4.1.4.1
Visit Windows for Safety and PRO Assessments ............................................... 48
4.1.4.2
Visit Windows for Tumour Assessments............................................................ 49
4.2
Study Population................................................................................................ 49
4.2.1
Patient Disposition............................................................................................. 49
4.2.2
Protocol deviations............................................................................................. 50
4.2.3
Demography and Baseline Characteristics.......................................................... 50
4.2.4
Previous and Concomitant Medications and Procedures..................................... 51
4.2.5
Study drug administration .................................................................................. 51
4.3
Analysis of Primary Safety Endpoint.................................................................. 51
4.4
Analysis of Secondary Efficacy Endpoints......................................................... 51
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Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 6 of 71
4.4.1
Progression-Free Survival.................................................................................. 51
4.4.2
Overall Survival................................................................................................. 52
4.4.3
Objective Response Rate.................................................................................... 52
4.4.4
Duration of Response......................................................................................... 52
4.4.5
Time to Lung Cancer Mortality (NSCLC-Related Death)................................... 52
4.5
Analysis of Secondary Safety Endpoints ............................................................ 53
4.5.1
Adverse Events .................................................................................................. 53
4.5.1.1
Adverse Events of Special Interest and Immune-Mediated Adverse Events........55
4.5.1.2
COVID-19 related Adverse events ..................................................................... 56
4.5.2
Electrocardiograms ............................................................................................ 57
4.5.3
Vital Signs ......................................................................................................... 57
4.5.4
Laboratory Data................................................................................................. 57
4.5.4.1
Liver Enzyme Elevations and Hy's Law ............................................................. 58
4.5.4.2
Assessment of Thyroid Function Test Results .................................................... 58
4.5.5
Exposure............................................................................................................ 59
4.5.6
Therapy following discontinuation from durvalumab ......................................... 59
4.6
Analysis of Exploratory Endpoints..................................................................... 59
4.6.1
..................................................... 59
4.6.2
..................................................... 60
4.6.3
..................................................... 60
4.6.4
..................................................... 61
4.6.5
Biomarkers ........................................................................................................ 61
5.
INTERIM ANALYSES ..................................................................................... 61
6.
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 61
7.
REFERENCES .................................................................................................. 62
8.
APPENDIX ....................................................................................................... 64
8.1
Appendix A:  Schedule of Assessments.............................................................. 64
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Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 8 of 71
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
ACS
Abnormal clinically significant
AE
Adverse event
AEPI
Adverse event of possible interest
AESI
Adverse event of special interest
AJCC
American Joint Committee on Cancer
ALT
Alanine transaminase
AST
Aspartate transaminase
ATC
Anatomical therapeutic chemical
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
CRT
Chemoradiation therapy
CS
Clinically significant
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
EA
Early assessment
ECG
Electrocardiogram
CCI
CCI


Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 9 of 71
Abbreviation or 
special term
Explanation
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
 
ePRO
Electronic patient-reported outcome assessment
ESE
Early Safety Evaluation
GI
Gastrointestinal
Gy
Gray
HL
Hy’s Law
IASLC 
International Association for the Study of Lung Cancer
IASLC 2016
IASLC Staging manual version 8
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
LLQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
msec
Milliseconds
MSSO
MedDRA Maintenance and Support Service Organization
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
ORR
Overall response rate
CCI
CCI
CCI
CCI
CCI
CCI




Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 11 of 71
Abbreviation or 
special term
Explanation
sCRT
Sequential Chemoradiotherapy
SD
Stable disease
SI
International system (of units) 
SOC
System organ class
T3
Tri-iodothyronine 
T4
Thyroxine 
TEAE
Treatment-emergent adverse event
TNM
Tumour, node and metastasis
TL
Target lesion
TRAE
Treatment-related adverse event
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
VAS
Visual analogue scale
WHO
World Health Organization




Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 13 of 71
Date
Brief description of change

the assessment of thyroid and renal function tests (Sections 4.5.4.2
and 4.5.4.3)

Extra summaries for exposure (Section 4.5.5)
1 October 2021
Version 3.0 includes the following changes from V2.0:

Added explanation for equivalence of SAF and FAS in section 2.1.1

Added shift table for Assessment of Thyroid Function Test Results to 
section 4.5.4.2

Added rule to identify two missed visits for censoring for progression-
free survival in section 3.3.1

Added estimates for Month 36 (Day 1095) in section 4.4.5

Removed Total Protein and Corrected Calcium from analysis by 
CTCAE grading in section 4.5.4

Removed section 4.5.4.3 Assessment of Renal Function Test 
Abnormalities

Added text for Covid-19 pandemic in section 3.2.3.4, 4.1.1, 4.2.1 and 
4.2.2, 4.2.3, 4.4.1, 4.4.2, 4.5.1.2

Updates from amendment to the clinical study protocol version 4.0.
22 November 2022
Version 4.0 includes the following changes from V3.0:

Section 3.2.3: Added: "AEs with unknown CTCAE Grade will not be 
imputed for the CTCAE grade, but will be counted as AE of CTCAE 
Grade 3 or 4 for the analyses. For analyses for AEs by worst CTCAE 
Grade these AEs will be counted with the grade unknown."

Section 3.2.3.2: Added: AESIs will also include AEPIs, but will further 
be mentioned as AESIs only.

Section 4.1.1: Added: Proportions will be presented as percentages (%). 

Section 4.1.1: Added: Patients with previous anti-cancer radiotherapy 
will be listed.

Section 4.1.3: Revised as: If any of the above puts the date before the 
date of the last dose of durvalumab or data cut-off date (DCO) 
respectively, a conservative approach is followed and, the date is 
imputed using the date of last dose or DCO date.

Sections 4.6.1, 4.6.2, 4.6.3: Added: Summaries will include all data 
obtained up until 90 days after the last dose of durvalumab.

Section 4.5.1.3 added for AEs of patients with history of lymphopenia.

Section 5 was revised to align with factual matter for the proposed ESE 
analysis.
22 May 2023
Version 5.0 includes the following changes from V4.0:


Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 14 of 71
Date
Brief description of change

Section 4.1.3: Added:  For imputation of a start date it is required that 
the new imputed date is sensible, eg. prior to the end date of the AE or 
medication ...  

Section 4.4.3: Added no assessment category to Best objective response 
(BoR).

Section 4.4.6 added for presentation of summary statistics for PFS, and 
OS by subgroups: main compound of previous chemotherapy regimen, 
and total treatment duration of 12 months.


Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 15 of 71
1.
STUDY DETAILS
This study is being conducted to provide safety, efficacy, and quality of life (QoL) data to 
complement the results of the PACIFIC (D4191C00001) Study, which assessed treatment with 
durvalumab (MEDI4736) in patients with unresectable Stage III non-small cell lung cancer 
(NSCLC) who had not progressed after concurrent chemoradiation therapy (cCRT).  The study 
will expand on the data currently available from the PACIFIC Study by assessing the clinical 
profile of durvalumab in patients who have not progressed after sequential chemoradiation 
therapy (sCRT), and in patients of World Health Organisation/Eastern Cooperative Oncology 
Group Performance Status 0 to 1 and 2 (WHO/ECOG PS 0 to 1 and 2).
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 
treatment-related adverse events (TRAEsa) 
within six months from the initiation of 
durvalumab treatment
Grade 3 and Grade 4 TRAEsa
Note: Toxicities will be classified as per CTCAE grading system NCI CTCAE version 4.03.
TRAE: treatment-related adverse event; CTCAE: Common Terminology Criteria for Adverse Event; NCI: National Cancer 
Institute.
a. TRAEs and PRAEs are used interchangeably and "possibly related adverse events" (PRAEs) will be reported in this SAP, 
tables, figures, listings, and CSR.
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 Tumours version 1.1 
(RECIST 1.1) as assessed by the Investigator
PFS12 and PFS24 according to RECIST 1.1 as 
assessed by the Investigator
Median OS, OS12, OS24, and OS36
To further assess the efficacy of durvalumab 
treatment in terms of objective response rate 
(ORR) and duration of response (DoR)
ORR 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






Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
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based chemotherapy contained cisplatin or carboplatin and etoposide, vinblastine, vinorelbine, a taxane (paclitaxel or 
docetaxel), or pemetrexed (ie, an agent other than gemcitabine), an overlap of 1 cycle of chemotherapy and radiation 
therapy is acceptable.
b
Treatment initiation within the first 14 days after sCRT therapy is highly encouraged.
AE: adverse event; IP: investigational product; PD: progressive disease; sCRT: sequential chemoradiotherapy; 
WHO/ECOG PS: World Health Organisation/Eastern Cooperative Oncology Group Performance Status.
Up to 150 patients will be treated with the study drug in Europe and North America in two 
cohorts: one cohort of between 100 and 120 patients with WHO/ECOG PS=0 or 1, and a second
cohort of up to 30 patients with WHO/ECOG PS=2.
Patients must not have progressed following definitive, platinum-based sCRT; radiation therapy 
must be completed within 42 days prior to first dose administration of durvalumab. The last 
dose of radiation therapy is defined as the day of the last radiation treatment session.
Patients must have histologically- or cytologically-documented NSCLC and locally-advanced, 
unresectable Stage III disease (according to the International Association for the Study of Lung 
Cancer [IASLC] Staging Manual Version 8 [IASLC 2016])
1.2.1
Study Treatment
Patients will receive 1500 mg durvalumab administered via intravenous (IV) infusion, starting 
on Week 1 after confirmation of eligibility, every four weeks (q4w) for a maximum of 24 
months from Cycle 1 Day 1. Study drug should be discontinued prior to 24 months if there is 
progressive disease according to RECIST 1.1 criteria (PD; unless the investigator considers the 
patient continues to receive benefit from the durvalumab), initiation of alternative cancer 
therapy, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is 
met.
Patients may delay dosing due to TRAEs which are either immune-mediated AEs (imAEs) or 
non-imAEs, or for reasons other than TRAEs. 

In case of a TRAE (imAEs or non-imAEs), dosing may be delayed per the Dosing 
Modification and Toxicity Management Guidelines (see annex to the protocol).

If dosing must be delayed for reasons other than TRAEs, dosing will resume as soon as 
feasible.

The duration of delays will be accounted for, as a non-exposure duration, when deriving 
actual duration of exposure to study treatment (See Section 3.2.8)
The schedule of assessments including safety, tolerability, efficacy using RECIST version 1.1 
and patient reported outcomes (PROs) based on questionnaires are detailed in the study 
assessment schedule in Appendix A.
If the dosing is delayed, the laboratory and physical assessments scheduled for that treatment 
cycle will also be delayed accordingly. The tumour efficacy and PRO assessments dates are not 
affected by dose delays and remain as originally scheduled, as they are based on the date of first 
administration of durvalumab (not the date of the study therapy per cycle).
All other scheduled assessments must be performed relative to the start of the dosing cycle such 
that all procedures required for dosing (eg, collection of laboratory samples) should be 




Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 20 of 71
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 (SAF)
The SAF will consist of all patients who received at least one dose (partial or in full) of 
durvalumab.
In this study, Full Analysis Set (FAS) will consist of all patients who received at least one dose 
(partial or in full) of durvalumab.  Therefore, the SAF and FAS would be equivalent in this 
study and for the purpose of results presentation all endpoints will be analysed using SAF.
2.2
Protocol Deviations
2.2.1
Important Protocol Deviations
According to ICH E3 guidelines version dated 1995 (ICH 1995), 
“Protocol deviations 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 CSR:
CCI


Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 21 of 71

Deviation 1: Patients who received treatment and who deviated from the following key 
entry criteria in CSP:

Inclusion Criterion 5: Histologically- or cytologically-documented NSCLC with 
locally-advanced, unresectable Stage III disease (according to the IASLC 2016]).
Positron emission tomography (PET)/CT, MRI of the brain, and endobronchial 
ultrasound with biopsy are highly encouraged at diagnosis.

Inclusion Criterion 6: Receipt of sCRT which must have been completed within 42
days prior to first dose administration of durvalumab in the study.
(a) The platinum-based chemotherapy regimen must contain cisplatin or carboplatin 
and 1 of the following agents: etoposide, vinblastine, vinorelbine, a taxane 
(paclitaxel or docetaxel), or pemetrexed, according to the local SoC regimens.
Platinum-based chemotherapy containing cisplatin or carboplatin and gemcitabine 
is permitted under certain conditions – refer to bullet point 6(b).
(b) Patients must have received at least 2 cycles of platinum-based chemotherapy 
before radiation therapy. The interval between administration of the last dose of
chemotherapy regimen and start of radiation therapy must be no more than 6 weeks.
Consolidation chemotherapy after radiation is not permitted.
(i)
If the patient’s platinum-based chemotherapy contained gemcitabine, no 
overlap between chemotherapy and radiation therapy is permitted.
(ii) If the patient’s platinum-based chemotherapy contained any of the agents 
listed in 6(a) other than gemcitabine, an overlap of 1 cycle of chemotherapy 
and radiation therapy is acceptable.
(c) Patients must have received a total dose of radiation of 60 Gray (Gy) ±10% 
(54 Gy to 66 Gy). Sites are encouraged to adhere to mean organ radiation dosing as 
follows:
(i) Mean lung dose <20 Gy and/or V20 <35%;
(ii) Mean oesophagus <34 Gy;
(iii) Heart V45 <35% or V30 <30%.
Note: Sites should be aware of the recent Radiotherapy Oncology Group (RTOG)
version 0617 (RTOG 0617) Study data 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%.

Inclusion Criterion 7: Patients must not have progressed following platinum-based 
sCRT, as per Investigator-assessed RECIST 1.1 criteria. In order to assess disease 
progression, the baseline imaging (CT/MRI) used for Screening purposes should be 
compared against the most recently performed scan that allows physician assessment 
as per RECIST 1.1 criteria (i.e. fulfils the RECIST 1.1 defined imaging acquisition 
parameters). If an intermediate scan taken between chemotherapy and radiotherapy 
is available and that scan is suitable for physician assessment as per RECIST 1.1 


Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 22 of 71
criteria, then this scan should be used.
(a) Patients with measurable disease and/or non-measurable and/or no evidence of
disease (NED) assessed at baseline by CT/MRI will be entered in this study.
(b) Prior irradiated lesions may be considered measurable and selected as TLs 
provided they fulfil the other criteria for measurability.

Inclusion Criterion 9: WHO/ECOG PS ≤2.

Exclusion Criterion 1: Patients with locally-advanced NSCLC whose disease has 
progressed following platinum-based sCRT.

Exclusion Criterion 2: Patients who have disease considered for surgical treatment 
as part of their care plan, such as Pancoast or superior sulcus tumours.

Exclusion Criterion 3: Mixed small-cell lung cancer and NSCLC histology.

Exclusion Criterion 6: Uncontrolled intercurrent illness, including but not limited to, 
ongoing or active infection, symptomatic congestive heart failure, uncontrolled 
hypertension, unstable angina pectoris, cardiac arrhythmia, Interstitial lung disease 
(ILD), serious chronic Gastrointestinal (GI) conditions associated with diarrhoea, 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 13: Patients who have received cCRT for locally-advanced 
NSCLC, or who received sCRT with at least 2 concomitant CRT cycles. Prior 
surgical resection (ie, Stage I or II) is permitted.
Note: Patients whose platinum-based chemotherapy contained gemcitabine and who 
received sCRT with at least 1 concomitant CRT cycle are excluded from this study.

Exclusion Criterion 16: Prior exposure to immune-mediated therapy, including but 
not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 
antibodies, excluding therapeutic anticancer vaccines.

Deviation 2: The patient met discontinuation criteria but did not discontinue durvalumab 
(e.g., 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.


Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 23 of 71
2.2.2
Monitoring of Important 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. 
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 database lock. 
The final classification of IPDs will be made prior to database lock or data cut-off (DCO) 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 tumour response data will be used to determine each patient’s visit 
response according to RECIST version 1.1.  It will also be used to determine, if and when a 
patient’s disease has progressed in accordance with RECIST and their best objective response 
to study treatment.  
The baseline radiological tumour assessment is part of the screening procedure and should be 
performed within 42 days after the end of sCRT, no more than 28 days before the start of 
durvalumab treatment, and ideally as close as possible to the start of study treatment.  Tumour
assessments will begin at 8 weeks ± 1 week after durvalumab initiation and continue every 
8 weeks ± 1 week through 52 weeks (relative to the date of durvalumab initiation), and then 
every 12 weeks ± 1 week thereafter until disease progression. An additional follow-up scan will 
be performed if clinically feasible.
If an unscheduled assessment is performed, and the patient’s disease has not progressed, every 
attempt should be made to perform the subsequent assessments at patients’ scheduled 
visits. This schedule is to be followed to minimise any unintentional bias caused by some 
patients being assessed at a different frequency than other patients.
Additional scans can be completed per standard practice post-disease progression.
From the investigator’s review of the imaging scans, the RECIST tumour 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 tumour 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 


Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 24 of 71
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.
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 target lesions (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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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 
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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will also be NE, unless there is a progression of non-TLs or new lesions, in which case the 
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 


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following way and once a lesion has had intervention then it should be treated as having 
intervention for the remainder of the study noting that an intervention will most likely shrink 
the size of tumours:

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 more than one third 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.


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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
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:  


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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 tumour 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 
tumour.
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 tumour


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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), 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 TRAEs (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 TRAEs 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. In the tables, listings and figures, the 
TRAEs are presented as “possibly related adverse events” as per the CRF and AZ standards.


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3.2.2
Secondary Safety Endpoints
The secondary safety endpoints of this study include:

TEAEs and SAEs

AESIs (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), pulse 
rate, temperature, and respiratory rate

Laboratory data including clinical chemistry, haematology and urinalysis

Physical Examination
3.2.3
Adverse Events
Details of all AEs and SAEs will be collected for a patient from the signing of the informed 
consent form (ICF) up to 90 days after the last dose of durvalumab. If an event starts after this 
period and the Investigator considers that it is possible that it is due to a late onset toxicity to 
durvalumab, then it should be reported as an AE or SAE.
All AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA) providing the System Organ Class (SOC) and Preferred Term (PT). 
In addition, all AEs will also be graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for AEs (CTCAE Version 4.03) allocating grades from Grade 1 
to Grade 4 which will be used for the reporting. 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
AEs with unknown CTCAE Grade will not be imputed for the grade, but will be counted as AE 
of CTCAE Grade 3 or 4 for the analyses. For analyses for AEs by worst CTCAE Grade these 
AEs will be counted with a grade as unknown.
Treatment-emergent adverse events (TEAEs) are AEs that start after the first dose of 
durvalumab or which start prior to the first dose of durvalumab but worsen following the first 
dose of durvalumab, and where the start date/date of worsening is also no later than 90 days 
after the last dose of durvalumab or the initiation of the first subsequent therapy following 
discontinuation of durvalumab (whichever occurs first). 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.


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3.2.3.1
Treatment-Related Adverse Events
A TRAE is any AE with a relatedness to durvalumab of possible or probable, or where the 
relatedness is missing.  When the relatedness of an AE is missing on the eCRF, all efforts will 
be taken to ensure that the Investigator assigns his/her assessment of relatedness prior to 
database lock. In the tables, listings and figures, the TRAEs are presented as “possibly related 
adverse events” as per the CRF and AZ standards.
If relatedness of an AE is missing at the DBL, as given in Section 4.1.2, the AE will be
considered as related to durvalumab.
3.2.3.2
Adverse Events of Special Interest
An AESI is defined as an AE of scientific and medical interest specific to durvalumab and may 
require close monitoring and rapid communication by the Investigator to the sponsor. AESIs 
will also include AEPIs, but will further be mentioned as AESIs only. An AESI can be either 
serious or non-serious. The AESIs will be programmatically derived.
An AstraZeneca medically qualified expert, after consultation with the Global Patient Safety 
Physician, has reviewed all AEs of interest and identified which PTs contribute to each AESI. 
A further review will take place prior to DBL to ensure any further terms not already included 
are captured within the categories. The final list of PTs for all AESIs will be completed before 
DBL and documented in the Study Master File. 
3.2.3.3
Immune-Mediated Adverse Event
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 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)).
Time to event analyses for imAEs will be performed for the following definitions: 

Time to first onset of imAE: Start date of first imAE episode – First dose date + 1

Time to first onset of imAE of Grade 3 or 4: First date of imAE episode that had 
CTCAE Grade 3 or 4 – First dose date + 1

Time to resolution of imAE: End date of imAE episode – Start date of imAE episode + 1

Time to resolution of Grade 3 or 4: End date of imAE episode that had 
CTCAE Grade 3 or 4 – First date imAE episode had severity of grade 3 or higher + 1
If an imAE does not resolve, then the time to resolution will be censored at earliest date of DCO, 
death date, or last dose date + 90 days. Patients who die prior to resolution of the imAE will be 
censored at the date of death.
Adjudication and statistical analysis for the imAEs will be performed by AstraZeneca. The 
results will be incorporated into and discussed in the CSR.


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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.
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 SBP (mmHg), DBP (mmHg), pulse rate (breaths/min), weight (kg), 
body temperature (degrees Celsius), and respiratory rate (breaths/min).
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 durvalumab project reference ranges will be used for 
the primary interpretation of laboratory data.
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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3.2.7
Physical Examination
A physical examination will be performed at Screening and during the study. Findings in this 
data will be reported as medical history at Screening. 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. 
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, 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 MAX[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.
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 


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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) 
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 treatment discontinuation. 
Patient 1:
PID = (9 * 1.5g)/ 13.5g = 100%
Patient 2:
PID = (8 * 1.5g)/ 13.5g = 89% 
Patient 3:
PID = (5 * 1.5g)/ 13.5g = 56% 


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Patient 4: 
PID = (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 tumour 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 RECIST 1.1 assessment prior to the two missed visits.
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. 
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 


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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 date of DCO will be censored at the last recorded
date at which the patient was known to have been alive, or at date of DCO, if known afterwards.
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 electronic case report 
form (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 
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).


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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 
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 tumour data.
3.3.6
Lung Cancer Mortality
The lung cancer mortality (NSCLC-related death) is assessed using the deaths which are 












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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, height, body mass index (BMI).

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 tumour 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 sequential chemoradiotherapy: Total dose, Radiotherapy treated 
location, Time from completion of radiotherapy to study treatment, Type of previous 
chemoradiotherapy, best response to previous chemoradiotherapy, Chemotherapy Class, 
Chemotherapy regimen used for sequential chemoradiotherapy, Number of chemotherapy 
cycles. 

Previous treatments for early stage disease (prior to definitive CRT): Radiotherapy treated 
location, Treatment status, Chemotherapy regimen used for early stage disease prior to CRT.

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.
3.5.3
Biomarkers
A mandatory, pre-treatment tumour sample will be submitted if available. Pre-treatment tumour
samples will be analysed for PD-L1 expression for all patients in the SAF for whom a tumour 


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tissue archival sample is available at the Screening visit.
The remaining exploratory biomarkers will not be covered within this SAP.
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 
the WHO/ECOG PS 0 to 1 and 2 groups. 

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 observation 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 9.3 or higher will be used for all analyses.

Exact CIs for proportions will be calculated using the Clopper-Pearson method.

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).


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
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 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 tumour 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, WHO/ECOG PS 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, WHO/ECOG PS 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, 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. 

Participants affected by the COVID-19 pandemic will be listed as recorded as protocol 
deviations, which were assessed as COVID-19 related. 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 
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. 

Proportions will be presented as percentages (%). 


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4.1.2
General Considerations for Summary of Safety Data
The following considerations are for the summary of safety data.

The missing values in vital signs, laboratory data, coagulation and urinalysis will not be 
imputed. 

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.

If the year and month are available and the day is missing, impute the day as 01 (the first 
day of the month).

If any of the above puts the date before the date of first dose of durvalumab, a conservative 
approach is followed and, the date is imputed using the date of first dose.
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.

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).

If any of the above puts the date before the date of the last dose of durvalumab or data cut-
off date (DCO) respectively, a conservative approach is followed and, the date is imputed 


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using the date of last dose or DCO date.  If DCO date is after the date of death, the date is 
imputed using the date of death.

It is not expected to have missing dates for unscheduled laboratory, diagnostics data. 
However, if there are missing dates, for any derivations, the dates should be imputed 
following the rules for concomitant medications and AEs
For imputation of a start date it is required that the new imputed date is sensible, eg. prior to the 
end date of the AE or medication.  Completely missing start dates will only be imputed to the 
first dose date unless the end date suggests it could have started prior to this in which case 
impute the 1st January of the same year as the end date. 
4.1.4
Definitions of Visit Windows
Time windows are defined for all summaries of vital signs, laboratory data, PRO around visits 
in Section 4.1.4.1 and for tumour 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 half way 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:

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 


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
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 Tumour Assessments
The following conventions will apply for tumour assessment data:

All tumour 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.

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 tumour assessments 
which are outside the visit windows will be flagged in the data listings. 
The above could result in more than one tumour 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 


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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 as recorded as 
protocol deviations, which were assessed as COVID-19 related.
4.2.2
Protocol deviations 
Important protocol deviations are defined in Section 2.2 and will be listed and summarized for 
the SAF, including a summary of those identified as resulting from the COVID-19 pandemic.
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, age group [<50, >=50-< 65, ≥ 65-<75, and ≥ 75 years], sex, race, and 
ethnicity)

Demographic characteristics in patients with confirmed/suspected COVID-19 infection.

Patient characteristics at baseline (height, weight [prior to start of sCRT, and after sCRT
at screening, and the change], weight groups [<40, >=40-< 75, ≥ 75-<90, ≥ 90-<120, and 
≥ 120 kg], body mass index (BMI) after sCRT, and BMI groups [Underweight (<18.5), 
Normal weight (=18.5 - <25.0), Overweight (=25.0 - <30.0), Obese (=30.0)]

Nicotine use and consumption 

A summary and a list of patients by site and country will be provided.

Previous disease-related sequential chemoradiotherapy
o
Sequential, no chemotherapy overlap with radiotherapy
o
Sequential, 1 cycle chemotherapy overlap with radiotherapy
o
Concurrent, >1 cycle chemotherapy overlap with radiotherapy
The number of cycles used for the classification will be derived by the number of 
days from the overlapping time interval from each specific chemotherapy regimen 
overlapping with radiotherapy, divided by 21 days, and rounded up to the next 


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integer, and will subsequently be summed up by patient. 

Previous treatments for early stage disease
Medical history and relevant surgical history are coded using MedDRA and will be summarized 
by SOC and PT. Medical history will also be summarized for patients with confirmed/suspected 
COVID-19 infection.
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 will be summarized by 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.
Patients with previous anti-cancer radiotherapy will be listed.
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 TRAEs (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 TRAEs 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 TRAEs, 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 WHO/ECOG PS 
0/1 and PS 2 groups. This summary will also be graphically presented as a bar chart. The number 
and percentages of patients with NCI CTCAE Grade 3 or Grade 4 TRAEs 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, PFS12 (Day 365) and PFS24 (Day 730).
Summaries of the number (%) of patients experiencing a PFS event (overall and also at Month 
12 and Month 24) and the type of event (disease progression or death) will be provided.
All summary statistics will be presented with the appropriate 95% CI.


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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 12month (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), OS24 (Day 
730) and OS36 (Day 1095). 
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, NE, and no assessment). 
4.4.4
Duration of Response
A Kaplan-Meier plot and descriptive statistics will be provided for the DoR and the respective 
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 Month 12 (Day 365) 
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 


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mortality. Summaries will include the lower and upper quartile and median lung cancer 
mortality and estimates at Month12 (Day 365), Month 24 (Day 730), and Month 36 (Day 1095). 
All summary statistics will be presented with the appropriate 95% CI.
4.4.6
Additional subgroup analyses
The summary statistics for PFS, and OS will also be presented by subgroups, as by:

Main compound of previous chemotherapy regimen: 
o
Main compound carboplatin only: patient received previous anti-cancer 
chemotherapy CARBOPLATIN but no CISPLATIN
o
Main compound cisplatin only: patient received previous anti-cancer 
chemotherapy CISPLATIN but no CARBOPLATIN.

Total treatment duration of 12 months:
o
Total treatment duration (<= 12 months)
o
Total treatment duration (> 12 months)
Total treatment duration categories <= 12 months / > 12 months refer to durations of <= 365.25 
days / > 365.25 days, respectively.
The number of patients per subgroup will be presented with the baseline characteristics and 
exposure tabulations, as appropriate. 
4.5
Analysis of Secondary Safety Endpoints
4.5.1
Adverse Events
All AEs 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 AEs 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, TRAEs, SAEs, AESIs, imAEs, AEs with 
outcome of death, AEs leading to discontinuation of durvalumab, AEs leading to 
discontinuation of study. Listings of AESIs 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:


Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 54 of 71

At least one AE

At least one TRAE

At least one AE of CTCAE Grade 3 or Grade 4

At least one TRAE of CTCAE Grade 3 or Grade 4

At least one SAE

At least one Serious TRAE

At least one AE leading to discontinuation of study treatment

At least one TRAE leading to discontinuation of study treatment

At least one AE leading to treatment interruption

At least one TRAE leading to treatment interruption

At least one AE with outcome of death

At least one TRAE with outcome of death

At least one AESI

At least one TRAE of special interest (AESI)

At least one imAE (and exact Clopper-Pearson 95% CI)

At least one immune-mediated TRAEs
The following summaries including the number and percent of patients by SOC and PT will be 
presented separately:

All AEs / TRAEs

All AEs / TRAEs of CTCAE Grade 3 or Grade 4

All TRAEs of CTCAE Grade 3 or Grade 4 occurring within the six months of first dosed 
date

All TRAEs which starts within 90 days after 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 3.2.8) 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 / TRAEs with outcome of death

All SAEs / Serious TRAEs

All AEs / TRAEs leading to discontinuation from durvalumab (Note: Reason for 
discontinuation recorded on the patient disposition page)

All AEs / TRAEs 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 


Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 55 of 71
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
and prior to initiation of first subsequent therapy

Number of deaths occurring more than 90 days after the last dose 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 Immune-Mediated Adverse Events
The following summaries of AESIs will be presented by AESI category and PT:

All AESIs / TRAEs of special interest 

All serious AESIs

All AESIs by maximum CTCAE Grade

All AESIs by outcome

All AESIs leading to treatment interruption

All AESIs leading to treatment discontinuation

All AESIs / TRAEs of special interest with fatal outcome

All AESIs which required treatment 

All AESIs which required treatment with systemic steroids, and high dose steroids

All AESIs which required treatment with immunosuppressants

All AESIs which required treatment with endocrine therapy
Overall summaries will present the numbers and percentages of patients with at least one 
immune-mediated AE (imAE) by the following categories:

AEs / TRAEs,

AEs / TRAEs of CTCAE Grade 3 or Grade 4

SAEs / Serious TRAEs

AEs / TRAEs with outcome of death

AEs which required treatment 

AEs which required treatment with systemic steroids, and high dose steroids

AEs which required treatment with immunosuppressants

AEs which required treatment with endocrine therapy

AEs leading to treatment discontinuation

AEs by outcome 
Using the same categories above similar summaries will be presented by preferred term, and by 
SOC and PT.
Time to event analyses for immune-mediated AE (imAE) will be performed by AESI categories, 


Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 56 of 71
for: 

Time to first onset of imAE

Time to first onset of imAE of Grade 3 or 4 

Time to resolution of imAE

Time to resolution of Grade 3 or 4
For patients with imAEs having multiple PTs within an AESI category the AEs will be collapsed 
to one event if the difference between end date of an imAE and subsequent start date of the next 
imAE is <=3 days. The time to onset will be based upon the first PT, whereas time to resolution 
used for KM analysis will be based on time of the worst imAE episode from that given patient.
At the AESI grouped term level for time to resolution outputs the worst imAE is defined in the 
order of the following:

imAE with worst (highest) grade first

For more than one imAE with the same highest grade take imAE which did not resolve 
before imAE which did resolve

If multiple imAE and all resolved take imAE with longest duration
Summaries for imAEs and related data will be presented by imAE category and PT:

At least one imAE

At least one serious imAE

At least one imAE by outcome

At least one imAE leading to treatment interruption 

At least one imAE leading to treatment discontinuation

At least one imAE by maximum CTCAE Grade

At least one imAE causally related to study medication

At least one imAE with fatal outcome
Post-baseline medications associated with imAEs will be presented by number and percent of 
patients by ATC-classification and PT.
Length of intervention with steroids, immunosuppressants and/or hormone replacement therapy 
for imAEs will be calculated based on treatment start and stop dates. Total treatment times will 
then be combined for each patient and summarised for patients experiencing at least one 
treatment-emergent imAE.
4.5.1.2
COVID-19 related Adverse events
The following summaries of AE data will be presented including the number and percentage of 
patients with:

AEs in patients with confirmed/suspected COVID-19 infection

AEs in patients without confirmed/suspected COVID-19 infection

AEs by SOC, PT and maximum CTCAE grade in patients with confirmed/suspected 
COVID-19 infection


Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 57 of 71

AEs by SOC, PT and maximum CTCAE grade in patients without confirmed/suspected 
COVID-19 infection

AEs associated with COVID-19 infection by SOC and PT

AEs excluding AEs associated with COVID-19 infection by SOC and PT

AEs with confirmed/suspected COVID-19 infection by SOC and PT

AEs excluding confirmed COVID-19 infection by SOC and PT

AEs associated with COVID-19 infection and with outcome of death by SOC and PT

AEs excluding associated with COVID-19 infection and with outcome of death by SOC 
and PT

AEs associated with COVID-19 infection leading to discontinuation of investigational 
product by SOC and PT

AEs excluding associated with COVID-19 infection leading to discontinuation of 
investigational product by SOC and PT
The summaries for COVID-19 related adverse events will only be performed when there is 
sufficient number of patients (e.g. ≥5 and/or ≥2% of the patient population) have 
confirmed/Suspected Covid-19 infection.
4.5.1.3
Adverse Events of Patients with History of Lymphopenia
AEs of patients with a history of lymphopenia will be listed. Patients with history of 
lymphopenia will be obtained from the medical history records.
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.
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 after last dose 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:


Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 58 of 71

Haematology: Haemoglobin, Leukocytes, Lymphocytes (absolute count), Neutrophils 
(absolute count), Platelets

Clinical chemistry: Alanine transaminase (ALT), Aspartate transaminase (AST), Alkaline 
phosphatase (ALP), Total bilirubin, Sodium (hypo- and hyper-), Potassium (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, >10x – ≤20x and >20x upper limit of 
normal (ULN) during the study

AST ≥ 3x – ≤ 5x, > 5x – ≤8x, > 8x – ≤10x, >10x – ≤20x 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, >10x – ≤20x and >20x ULN during 
the study

ALT or AST ≥3x ULN and total bilirubin ≥2x ULN during the study (Potential Hy’s 
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. Individual patient data 
where ALT or AST (ie, ≥ 3x ULN) plus Total bilirubin (ie, ≥ 2x ULN) are elevated at any time 
will also be listed. 
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
Shift table for TSH test, baseline versus maximum value on treatment will be produced for the 
categories:












Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 64 of 71
8.
APPENDIX
8.1
Appendix A:  Schedule of Assessments
Table 7 Schedule of Assessments for Screening and Treatment Period
Screening
C1a
C2a
C3a
C4a
C5 to PD (max. 24 
months)a,b
Final visit
Week
-4 to -1
1
q4w ±3 days unless dosing needs to be held for 
toxicity reasons
Day
-28 to -1
1
q28d ±3 days unless dosing needs to be held for 
toxicity reasons
Informed consent
Informed consent: Study procedures
X
Informed consent: Genetic sample and analysis 
(optional)c
X
Study procedures
Physical examination (full)
X
Targeted physical examinations 
(symptomatic patients only)
X
X
X
X
X
X
Assessment of early toxicities (phone call)d
X
X
X
Vital signs (temperature, respiratory rate, blood 
pressure, and pulse), body weight, and heighte
X
X
X
X
X
X
X
ECGf
X
As clinically indicated
Concomitant medications
Medical history
X
Demography, including baseline characteristics and 
tobacco use
X


Statistical Analysis Plan 
Study Code D4194C00006
Edition Number 5.0
Date 22 May 2023
Page 65 of 71
Screening
C1a
C2a
C3a
C4a
C5 to PD (max. 24 
months)a,b
Final visit
Week
-4 to -1
1
q4w ±3 days unless dosing needs to be held for 
toxicity reasons
Day
-28 to -1
1
q28d ±3 days unless dosing needs to be held for 
toxicity reasons
Eligibility criteria
X
X
Laboratory assessments
Clinical chemistry
X
Xg
Xh
Xh
Xh
Xh
X
Haematology
X
Xg
Xh
Xh
Xh
Xh
X
Coagulation
Xi
As clinically indicated
TSH (reflex free T3 or free T4)g,j,k
X
Xk
X
X
X
X
X
Urinalysis 
X
As clinically indicated
Hepatitis B and C, HIV, and tuberculosis
X
Pregnancy testl
X
X
X
X
X
X
X
Monitoring
X
X
X
X
X
X
X
AE/SAE assessmentm
Drug accountability
X
All visits
IP administration
Durvalumab (MEDI4736)n
X
X
X
X
X
X
QoL assessments
 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biomarker assessments
CCI
CCI
CCI














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Document Title:
Statistical Analysis Plan Edition 5
Document ID:
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