Conditions: Non-Small Cell Lung Cancer
Keywords: Locally advanced Unresectable Non-Small Cell Lung Cancer MEDI4736 PD-L1 Stage III Non-Small Cell Lung Cancer Chemoradiation Immune-mediated cancer therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 713
Healthy volunteers: no

Brief summary:
A Global Study to Assess the Effects of MEDI4736 following concurrent chemoradiation in Patients with Stage III Unresectable Non-Small Cell Lung Cancer.

Detailed description:
A Phase III, Randomised, Double-blind, Placebo-controlled, Multi-centre, International Study of MEDI4736 as Sequential Therapy in Patients with Locally Advanced, Unresectable Non-Small Cell Lung Cancer (Stage III) Who Have Not Progressed Following Definitive, Platinum-based, Concurrent Chemoradiation Therapy (PACIFIC)

Arms:
arm 1: MEDI4736 (intravenous infusion) arm 2: Placebo (matching placebo for intravenous infusion)

Interventions: intervention 1: MEDI4736 intervention 2: PLACEBO
Intervention descriptions: intervention 1: MEDI4736 by intravenous infusion. Treatment from Day 1 for a maximum of 12 months or study drug withdrawal if this occurs earlier . The 2:1 ratio (MEDI4736 to placebo). intervention 2: PLACEBO by intravenous infusion. Treatment from Day 1 for a maximum of 12 months or study drug withdrawal if this occurs earlier . The 2:1 ratio (MEDI4736 to placebo).

Protocol document:
Prot_004.pdf: 


Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
2 (167) 
Administrative 
Change No. 
 Date of Administrative 
Change 
 
Local Administrative 
Change No. 
 
Date of Local 
Administrative Change 
01 
 30 October 2014 
 
 
 
 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
 




Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
4(167) 
Secondary Objective: 
Outcome Measure: 
To further assess the efficacy of MEDI4736 
compared with placebo in terms of: OS24, ORR, 
DoR, APF12, APF18, PFS2, and TTDM 
OS24 
ORR using BICR assessments according to RECIST 
1.1a 
DoR using BICR assessments according to RECIST 
1.1a 
APF12 and APF18 using BICR assessments 
according to RECIST 1.1 
PFS2 as defined by local standard clinical practice 
TTDM using BICR assessments according to 
RECIST 1.1a 
To assess the safety and tolerability profile of 
MEDI4736 compared with placebo 
AEs, physical examinations, vital signs including 
blood pressure, pulse, electrocardiograms, and 
laboratory findings including clinical chemistry, 
haematology and urinalysis 
To assess the PK of MEDI4736  
Concentration of MEDI4736 in blood and 
non-compartmental PK parameters (such as peak 
concentration and trough, as data allow) (sparse 
sampling) 
To investigate the immunogenicity of MEDI4736  
ADA (confirmatory results: positive or negative; 
titres [ADA neutralising antibodies will also be 
assessed])  
To assess symptoms and health-related quality of life 
in patients treated with MEDI4736 compared with 
placebo using EORTC QLQ-C30 v3 and LC13 
EORTC QLQ-C30: Time to symptom deterioration 
(fatigue, pain, nausea/vomiting, dyspnoea, loss of 
appetite, insomnia, constipation, and diarrhoea).  
Time to QoL/function deterioration (physical 
function; role function; emotional function; cognitive 
function; social function and global health 
status/QoL) 
LC13: Time to symptom deterioration (dyspnoea, 
cough, haemoptysis, chest pain, arm/shoulder pain, 
other pain) 
Changes in World Health Organization Performance 
Status will also be assessed 
Analysis of ORR and DoR will be based upon BICR assessment according to RECIST 1.1.  See the statistical methods 
section for further details. 
Note: Prior irradiated lesions may be considered measurable and selected as target lesions providing they fulfil the other 
criteria for measurability. 
ADA  Anti-drug antibody; AE  Adverse event; APF12  Proportion of patients alive and progression free at 12 months from 
randomisation; APF18  Proportion of patients alive and progression free at 18 months from randomisation; BICR  Blinded 
Independent Central Review; DoR  Duration of response; EORTC QLQ-C30  European Organisation for Research and 
Treatment of Cancer 30-item core quality of life questionnaire; LC13  Lung Cancer Module; ORR Objective response rate; 
OS24  Proportion of patients alive at 24 months from randomisation; PFS2  Time from randomisation to second progression; 
PK  Pharmacokinetic(s); QoL  Quality of Life; RECIST  Response Evaluation Criteria In Solid Tumours; TTDM  Time to 
death or distant metastasis. 
 


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
5(167) 
Exploratory Objective: 
Outcome Measure: 
To explore irRC criteria as an assessment 
methodology for clinical benefit of MEDI4736 
compared with placebo by BICR 
PFS and ORR using BICR assessments according to 
irRC 
To investigate the relationship between MEDI4736 
PK exposure and clinical outcomes, efficacy, AEs 
and/or safety parameters, if deemed appropriate  
A graphical and/or a data modelling approach will be 
used to analyse MEDI4736 PK exposure and the 
relationship with clinical outcomes, efficacy, AEs 
and/or safety parameters, as deemed appropriate 
To describe and evaluate resource use associated with 
MEDI4736 treatment and underlying disease 
Health resource utilisation measures including 
hospitalization, outpatient visits, or emergency 
department visits 
To explore the impact of treatment and disease state 
on health state utility using the EQ-5D-5L 
The EQ-5D-5L health state utility index will be used 
to derive health state utility based on patient reported 
data 
To investigate the relationship between a patient’s 
PD-L1 expression and spatial distribution within the 
tumour microenvironment and efficacy outcomes 
with MEDI4736  
Tumoural expression of PD-L1 and spatial 
distribution within the tumour microenvironment 
relative to efficacy outcomes (OS, PFS and ORR)  
To collect blood and tissue samples for analysis of 
peripheral and tumoural biomarkers 
 
Biomarker analysis of blood and tissue to assess 
exploratory markers which may include but is not 
limited to: immune cell gene expression profiles 
within the peripheral and tumoural compartments, the 
presence of IFN-ȖWXPRXUQHFURVLVIDFWRU-Į,/-2, 
IL-6, IL-10, IL-8, and IL-12 as well as antibodies 
against tumour, self, or viral antigens, expression of 
PD-L1 and the number and phenotype of immune 
cells such as T-cells 
To explore the relationship(s) between a patient’s 
biomarker status and MEDI4736 PK exposure and 
clinical outcomes before and after treatment 
Biomarker status before and after treatment and 
MEDI4736 PK exposure and relationship with 
clinical outcomes, efficacy, AEs and/or safety 
parameters, as deemed appropriate 
To explore potential biomarkers in residual biological 
samples (eg, tumour, plasma and/or serum), which 
may influence the progression of cancer (and 
associated clinical characteristics) and/or 
prospectively identify patients likely to respond to 
MEDI4736 treatment 
Correlation of biomarkers with response to 
MEDI4736 treatment and/or the progression of cancer 
To collect and store DNA according to each country’s 
local and ethical procedures for future exploratory 
research into genes/genetic variation that may 
influence response (ie, distribution, safety, tolerability 
and efficacy) to study drugs and/or susceptibility to 
disease (optional) 
Correlation of polymorphisms with variation in PK, 
PDx, safety or response parameters observed in 
patients treated with MEDI4736 and/or susceptibility 
to disease 
AE  Adverse event; BICR  Blinded Independent Central Review; EQ-5D-5L  EuroQoL 5-dimension, 5-level health state 
utility index; IFN  Interferon; IL  Interleukin; irRC  Immune-related response criteria; ORR Objective response rate; OS  
Overall survival; PD-L1  Programmed death ligand 1; PDx  Pharmacodynamic(s); PFS  Progression free survival; PK  
Pharmacokinetic(s); T-cell  T lymphocyte.   
 


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
6(167) 
Study design   
This is a Phase III, randomised, double-blind, placebo-controlled, multi-centre study assessing 
the efficacy and safety of MEDI4736 (also referred to as durvalumab) compared with placebo, 
as sequential therapy in male and female patients with locally advanced, unresectable NSCLC 
(Stage III), who have not progressed following definitive, platinum-based, concurrent 
chemoradiation therapy. 
Approximately 1000 patients will be enrolled and 702 patients randomised (patients will be in 
CR, PR or have SD following definitive, platinum-based, concurrent chemoradiation therapy) 
at 260 to 330 sites worldwide, in a 2:1 ratio (MEDI4736 to placebo) to 1 of 2 arms: 
x 
MEDI4736 (10 mg/kg every 2 weeks [Q2W] intravenous [iv] for up to 12 months)  
x 
Placebo (matching placebo for infusion Q2W iv for up to 12 months). 
Randomisation will be stratified by: DJHDWUDQGRPLVDWLRQYHUVXV\HDUVRIDJHsex 
(male versus female), and smoking history (smoker versus non-smoker).  Patients must 
complete their last dose of radiation therapy within 1 to 42 days prior to randomisation in the 
study (the last dose of radiation therapy is defined as the day of the last radiation treatment 
session).  For patients who are recovering from toxicities associated with prior treatment, 
randomisation may be delayed by up to 42 days from the end of the chemoradiation therapy.  
For those patients randomised to the placebo arm no cross-in to the MEDI4736 arm is 
permitted and similarly those patients randomised to the MEDI4736 arm no cross-in to the 
placebo arm is permitted. 
The primary objective of this study is to assess the efficacy of MEDI4736 treatment compared 
with placebo in terms of overall survival (OS) and progression free survival (PFS) per 
RECIST 1.1 as assessed by Blinded Independent Central Review (BICR).   
Tumour assessments will be performed using computed tomography/magnetic resonance 
imaging.  The baseline assessment is part of the screening procedures and should be 
performed within 0 to 42 days after the end of chemoradiation therapy and before the start of 
study drug.  Efficacy for all patients will be assessed by objective tumour assessments every 
8 weeks (relative to the date of randomisation) for the first 12 months, then every 12 weeks 
thereafter, until confirmed objective disease progression as defined by Response Evaluation 
Criteria in Solid Tumours (RECIST) 1.1 (irrespective of the reason for stopping study drug 
and/or subsequent therapy).  If an unscheduled assessment is performed, and the patient has 
not progressed, every attempt should be made to perform the subsequent assessments at their 
scheduled visits.  A BICR will be conducted.  
Following completion or discontinuation of study drug, patients will enter a follow-up period.   
Once a patient has had objective progression recorded and has discontinued study drug, the 
patient will be followed up for survival status every 2 months until death, withdrawal of 
consent or the end of the study. 


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
7(167) 
There will be 4 DCO time points in the study.  The first analysis DCO will occur when it is 
expected that 367 PFS events have occurred (52% maturity, approximately 30 months after 
the first patient is randomised).  The second analysis DCO will occur at the time of the 
primary PFS analysis when it is expected that 458 PFS events have occurred (65% maturity, 
approximately 36 months after the first patient is randomised), and the first OS interim 
analysis will be conducted at the same time (with approximately 285 events, 41% maturity).  
The third analysis DCO will occur at the time of the second OS interim analysis when it is 
expected that 393 OS events have occurred (56% maturity, approximately 47 months after the 
first patient is randomised).  The fourth analysis DCO will occur at the time of the primary OS 
analysis when it is expected that 491 OS events have occurred (70% maturity, at 
approximately 62 months).  If the study achieves statistical significance for the co-primary 
endpoints of PFS and/or OS at one of the planned interim analyses, then that will be 
considered the final analysis for that endpoint.  Further analyses for that particular endpoint 
may occur based on the needs for long term follow-up with more mature data.    
See the Statistical methods section (Section 12.2) for further details. 
At the time of Amendment 07 finalisation, the study endpoints had been met and the planned 
analysis portion of the study had been concluded.  Details on long-term follow up, including 
data collection for patients in follow-up or in re-treatment, are provided in the Long-term 
follow up section (Section 9.5). 
Safety review and Independent Data Monitoring Committee (IDMC) 
An IDMC will be convened, and will meet approximately 3 months after the study has started, 
or once 75 patients have been randomised whichever occurs first, to review safety assessments 
and make recommendations to continue, amend, or stop the study based on safety findings.  
The first three efficacy analyses will also be assessed by the IDMC.  The committee will then 
meet again 3 months later and then at least every 6 months thereafter up to the decision to 
unblind the study.  Serious adverse events, adverse events, and other safety data will be 
reviewed and individual and aggregated safety data will be evaluated by the IDMC.  In 
addition the IDMC will review the unblinded interim analysis summaries of efficacy data.  
Full details of the IDMC procedures and processes can be found in the IDMC Charter. 
Target patient population 
Male or female patients aged 18 years or older with histologically- or 
cytologically-documented NSCLC who present with locally advanced, unresectable 
(Stage III) disease (according to Version 7 of the International Association for the Study of 
Lung Cancer Staging Manual in Thoracic Oncology).  Patients must not have progressed 
following definitive, platinum-based, concurrent chemoradiation therapy; the last session of 
radiation therapy must be completed within 1 to 42 days prior to randomisation in the study.  
For patients who are recovering from toxicities associated with prior treatment, randomisation 
may be delayed by up to 42 days from the end of the chemoradiation therapy.  Patients must 
have World Health Organization Performance Status of 0 or 1. 


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
8(167) 
Investigational product, dosage and mode of administration 
Patients enrolled to the MEDI4736 arm will receive MEDI4736 10 mg/kg via a 60-minute iv 
infusion Q2W ± 3 days for up to 12 months (maximum of 26 doses, last dose at Week 50).   
Comparator, dosage and mode of administration 
Patients enrolled to the placebo arm will receive matching placebo via a 60-minute iv infusion 
Q2W ± 3 days for up to 12 months (maximum of 26 doses, last dose at Week 50).   
Duration of treatment 
Patients enrolled in the study will receive either MEDI4736 10 mg/kg or placebo via iv 
infusion Q2W ± 3 days.  Administration of study drug (ie, investigational product MEDI4736 
or placebo) will commence on Day 1 following randomisation to MEDI4736 or placebo after 
confirmation of eligibility and will continue on a Q2W schedule for a maximum duration of 
12 months.  The final administration of study drug will be at the Week 50 visit.  Study drug 
should be discontinued prior to 12 months if there is confirmed progression of disease (PD) 
(unless the Investigator considers the patient continues to receive benefit from study drug), 
initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or other 
reasons to discontinue study drug occur.   
Disease progression requires confirmation.  The confirmation scan should be acquired at the 
next regularly scheduled imaging visit and no earlier than 4 weeks after the prior 
determination of tumour progression.  In the absence of clinically significant deterioration the 
investigational site is advised to continue the patient on study drug until progression has been 
confirmed. 
If progression is not confirmed, then the patient should continue study drug and on treatment 
assessments. 
Patients who achieve and maintain disease control (CR, PR, no evidence of disease or SD) 
through to the end of the 12-month treatment period will enter follow-up.  Upon evidence of 
PD (according to RECIST 1.1), with or without confirmation, during follow-up after 
completion of 12 months of treatment, patients initially treated with MEDI4736 may restart 
and continue on study drug for as long as the Investigator judges that they are gaining clinical 
benefit with the same treatment guidelines followed during the initial 12-month treatment 
period.  If the patient continues to receive re-treatment after the final DCO for the study, they 
should have tumour assessment scans and other assessments as per local clinical practice.  
Patients will only be able to restart study drug once.  Once the study has been unblinded, then 
only patients who were randomised to the durvalumab (MEDI4736) treatment arm and who 
fulfil the eligibility criteria for re-treatment will be able to restart study drug. 
Patients who have a dose interruption due to toxicity at any point in the first 12 months of 
treatment may resume and complete the 12-month treatment period. 


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
9(167) 
Patients who have confirmed PD during the 12-month initial treatment period or after 
re-restarting study drug, and cannot continue to receive study drug, will enter follow-up. 
Patients with confirmed PD that continue to receive study drug at the discretion of the 
Investigator (following consultation with the sponsor) can receive study drug for a maximum 
of 12 months during the initial treatment period but for as long as the Investigator judges they 
are gaining clinical benefit if they are a re-treatment patient.   
Study drug should be discontinued if there is confirmed progression of disease (PD) following 
a previous response (PR or CR) to study drug.  
For all patients who receive study drug through disease progression or patients who achieve 
disease control and restart study drug upon evidence of PD (according to RECIST 1.1) during 
follow-up, 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 and re-treatment as specified in the protocol and also 
reconsent to continue or restart treatment.  These patient informed consent documents will 
specify that treatment beyond initial evidence of PD or re-treatment following progression 
during follow up is not the standard of care and that alternative treatment options, either 
locally licensed treatments or other clinical trials, are available for this patient population.  
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.  
Patients who progress during the first 12 months of treatment are not eligible for re-treatment 
at any time.  
Outcome variable(s):  
See Objectives. 


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
10(167) 
Statistical methods 
The primary objective of this study is to assess the efficacy of MEDI4736 treatment compared 
with placebo in terms of OS and PFS.  OS is defined as the time from the date of 
randomisation until death due to any cause.  PFS (per RECIST 1.1 as assessed by BICR) will 
be defined as the time from the date of randomisation until the date of objective disease 
progression or death (by any cause in the absence of progression) regardless of whether the 
patient withdraws from randomised therapy or receives another anti-cancer therapy prior to 
progression.  Thus, the two co-primary endpoints of this study are OS and PFS.  To control for 
type-I error, a significance level of 2.5% will be used for analysis of OS and a significance 
level of 2.5% will be used for analysis of PFS.  The study will be considered positive (a 
success) if either the PFS analysis results and/or the OS analysis results are statistically 
significant. 
Secondary efficacy variables include: the proportion of patients alive at 24 months from 
randomisation, objective response rate, duration of response, the proportion of patients alive 
and progression free at 12 and 18 months from randomisation, the time from randomisation to 
second progression, time to relapse and time to death or distant metastasis.   
Efficacy data will be summarised and analysed on an Intent-to-Treat (ITT) basis including all 
treated patients and will compare the treatment arms on the basis of randomised treatment, 
regardless of the treatment actually received.  Patients who were randomised but did not 
subsequently go on to receive study drug are included in the ITT population.   
Approximately 702 patients will be randomised 2:1 to MEDI4736 or placebo.  There will be 
4 DCO time points in the study. The DCO for the interim PFS analysis (first analysis) will be 
done when 367 PFS events have occurred (52% maturity).  The interim PFS analysis will be 
assessed by an IDMC (further details are given in the IDMC charter).  It is expected that 
recruitment will have completed prior to the results of the interim PFS analysis being 
available. 
The DCO for the primary PFS analysis (second analysis) and first interim OS analysis will be 
done when at least 458 PFS events have occurred (65% maturity).  If the true PFS hazard ratio 
(HR) is 0.67, this number of events in the study will provide at least 95% power to 
demonstrate a statistically significant difference for PFS with a 2-sided significance level of 
2.5% in the ITT population; this translates to a 5-month benefit in median PFS over 10 months 
on placebo if PFS is exponentially distributed.  The smallest treatment difference that would 
be statistically significant is a HR of 0.8. In addition, the first OS interim analysis will be 
performed for superiority, at the time of the primary PFS analysis. Approximately 285 death 
events (41% maturity) will be available for the first interim OS analysis (assuming OS 
HR=0.73).  This interim OS analysis will also be assessed by an IDMC. 
The DCO for the second OS interim analysis (third analysis) will occur when it is expected 
that 393 OS events have occurred (56% maturity).  


Revised Clinical Study Protocol Synopsis 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
11(167) 
The DCO for the primary OS analysis (fourth analysis) will occur when 491 OS events have 
occurred (70% maturity). If the true OS HR is 0.73, this number of death events will provide 
at least 85% power to demonstrate a statistically significant difference for OS, assuming a 
2.5% 2-sided significance level in the ITT population; this translates to an 8-month benefit in 
median OS over 22 months on placebo if OS is exponentially distributed.  The smallest 
treatment difference that would be statistically significant is a HR of 0.81. 
OS will be analysed using a stratified log-rank test (age at randomisation [<65 years versus 
\HDUVRIDJH@VH[>PDOHYHUVXVIHPDOH@DQGVPRNLQJVWDWXV>VPRNHUYHUVXVQRQ-smoker]).  
The effect of treatment will be estimated by the HR together with its corresponding 97.5% 
confidence interval (CI) and p-value for the ITT population.   
PFS, based on the programmatically derived PFS from BICR assessments, will be analysed 
using a stratified log-rank test.  The effect of treatment will be estimated by the HR together 
with its corresponding 97.5% CI and p-value for the ITT population.   
Safety data will be summarised descriptively and will not be formally analysed. 
End of Analysis Portion of Study 
Once the planned statistical analyses have been performed for both the primary analysis of 
PFS and OS endpoints of the study, data collection will be reduced.  Please refer to 
Section 9.5.1 for more information.  
Once the final DCO of the study for long term follow-up has been reached, patients in OS and 
PFS follow-up will be considered to have completed the study.  At the time of the final DCO 
(anticipated to be approximately 5 years following the last patient randomised) any patient 
who is still in progression-free follow up will have been progression free for approximately 
5 years following the start of their chemoradiation; as such, they will be considered cured and 
will no longer be considered eligible for re-treatment within this protocol.  Those patients who 
are still actively in retreatment, and continuing to receive clinical benefit, will have the option 
to continue on study drug on an alternate rollover or extension protocol.  Please refer to 
Section 9.5.2 for more information. 
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
12(167) 
TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ........................................................................................................... 1 
PROTOCOL SYNOPSIS ......................................................................................... 3 
TABLE OF CONTENTS ....................................................................................... 12 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................... 19 
1. 
INTRODUCTION ................................................................................................. 23 
1.1 
Background ............................................................................................................ 23 
1.1.1 
Non-small cell lung cancer .................................................................................... 23 
1.1.2 
Immunotherapies .................................................................................................... 23 
 
Clinical data for agents targeting PD-1 and PD-L1 ............................................... 25 
1.1.3 
MEDI4736 ............................................................................................................. 27 
1.1.4 
Non-clinical experience with MEDI4736 .............................................................. 27 
1.1.5 
Clinical experience with MEDI4736 ..................................................................... 28 
1.1.6 
Safety pharmacology summary .............................................................................. 30 
1.1.7 
Genetic data ........................................................................................................... 30 
1.2 
Research hypothesis ............................................................................................... 30 
1.3 
Rationale for conducting this study ....................................................................... 31 
1.4 
Benefit/risk and ethical assessment........................................................................ 33 
1.4.1 
Unmet need and potential role of immunotherapies in NSCLC ............................ 33 
1.4.2 
Summary of MEDI4736 data and potential benefits and risks .............................. 34 
1.4.3 
Summary of potential benefits and risks of other immunotherapy agents ............. 34 
1.4.4 
Summary benefit: risk statement ........................................................................... 35 
2. 
STUDY OBJECTIVES .......................................................................................... 35 
2.1 
Primary objective ................................................................................................... 35 
2.2 
Secondary objectives ............................................................................................. 36 
2.3 
Exploratory objectives ........................................................................................... 37 
3. 
STUDY PLAN AND PROCEDURES .................................................................. 38 
3.1 
Overall study design and flow chart ...................................................................... 38 
3.2 
Rationale for study design, doses and control groups ............................................ 55 
3.2.1 
Unmet need and potential role of immunotherapies in NSCLC ............................ 55 
3.2.2 
Potential role for MEDI4736 in the treatment of NSCLC ..................................... 56 
3.2.3 
Study design rationale ............................................................................................ 56 
 
Timing of treatment with MEDI4736 relative to concurrent chemoradiation 
therapy .................................................................................................................... 56 
 
Dose justification ................................................................................................... 56 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
13(167) 
 
Predictive biomarkers and rationale for an unselected population in Study 
D4191C00001 ........................................................................................................ 57 
 
Rationale for study endpoints (efficacy) ................................................................ 58 
 
Rationale for study endpoints (other exploratory endpoints) ................................ 59 
 
Rationale for re-treatment beyond 12 months ....................................................... 60 
4. 
PATIENT SELECTION CRITERIA ..................................................................... 61 
4.1 
Inclusion criteria .................................................................................................... 61 
4.2 
Exclusion criteria ................................................................................................... 63 
4.3 
Criteria for treatment through progression of disease and re-treatment ................ 66 
5. 
STUDY CONDUCT .............................................................................................. 69 
5.1 
Restrictions during the study ................................................................................. 69 
5.2 
Patient enrolment and randomisation ..................................................................... 70 
5.2.1 
Procedures for randomisation ................................................................................ 70 
5.3 
Procedures for handling patients incorrectly enrolled or randomised or 
initiated on study drug ........................................................................................... 71 
5.4 
Blinding and procedures for unblinding the study ................................................. 72 
5.4.1 
Methods for ensuring blinding ............................................................................... 72 
5.4.2 
Methods for unblinding the study .......................................................................... 72 
5.5 
Treatments .............................................................................................................. 73 
5.5.1 
Identity of investigational product(s) ..................................................................... 73 
 
Product preparation of MEDI4736 ........................................................................ 73 
5.5.2 
Doses and treatment regimens ............................................................................... 74 
 
Study drug administration ...................................................................................... 76 
5.5.3 
Management of toxicity ......................................................................................... 76 
 
MEDI4736 adverse events of special interest ........................................................ 77 
5.5.4 
Additional study drug ............................................................................................ 79 
5.5.5 
Labelling ................................................................................................................ 79 
5.5.6 
Storage ................................................................................................................... 80 
5.6 
Concomitant and post-study treatment(s) .............................................................. 80 
5.7 
Treatment compliance ............................................................................................ 80 
5.7.1 
Accountability ........................................................................................................ 81 
5.8 
Discontinuation of investigational product ............................................................ 81 
5.8.1 
Procedures for discontinuation of a patient from investigational product ............. 82 
5.9 
Withdrawal from study .......................................................................................... 83 
6. 
COLLECTION OF STUDY VARIABLES ........................................................... 85 
6.1 
Recording of data ................................................................................................... 85 
6.2 
Data collection at enrolment and follow-up ........................................................... 85 
6.2.1 
Enrolment procedures ............................................................................................ 85 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
14(167) 
6.2.2 
Follow-up procedures ............................................................................................ 87 
 
Survival follow-up ................................................................................................. 87 
 
Second progression ................................................................................................ 88 
6.3 
Efficacy .................................................................................................................. 88 
6.3.1 
Central reading of scans ......................................................................................... 91 
6.4 
Safety ..................................................................................................................... 91 
6.4.1 
Definition of adverse events .................................................................................. 91 
6.4.2 
Definitions of serious adverse event ...................................................................... 91 
6.4.3 
Recording of adverse events .................................................................................. 92 
6.4.4 
Reporting of serious adverse events....................................................................... 97 
6.4.5 
Laboratory safety assessment ................................................................................ 98 
6.4.6 
Physical examination ........................................................................................... 100 
6.4.7 
Electrocardiogram ................................................................................................ 100 
6.4.8 
Vital signs ............................................................................................................ 101 
 
Pulse and blood pressure ...................................................................................... 101 
 
Temperature, respiratory rate and oxygen saturation........................................... 102 
6.4.9 
Other safety assessments ...................................................................................... 102 
6.5 
Patient reported outcomes .................................................................................... 102 
6.5.1 
EORTC QLQ-C30 ............................................................................................... 103 
6.5.2 
Lung Cancer Module (LC13) ............................................................................... 103 
6.5.3 
EuroQoL 5-dimension, 5-level health state utility index (EQ-5D-5L) ................ 103 
6.5.4 
Administration of patient reported outcomes questionnaires .............................. 104 
6.6 
Pharmacokinetics and ADA ................................................................................. 105 
6.6.1 
Collection of PK samples and determination of drug concentration ................... 105 
6.6.2 
Collection of samples to measure for the presence of ADA and ADA 
neutralising antibodies ......................................................................................... 105 
6.7 
Biomarker analysis ............................................................................................... 106 
6.7.1 
Collection of patient selection biomarker data .................................................... 106 
6.7.2 
Blood borne biomarkers ....................................................................................... 107 
6.7.3 
Tumour samples (immune-related or response-related markers) ........................ 107 
6.7.4 
Genomic analysis ................................................................................................. 107 
6.7.5 
Management of biomarker data ........................................................................... 107 
6.8 
Pharmacogenetics ................................................................................................ 108 
6.8.1 
Collection of pharmacogenetic samples .............................................................. 108 
6.9 
Health economics ................................................................................................. 108 
7. 
BIOLOGICAL SAMPLING PROCEDURES ..................................................... 108 
7.1 
Volume of blood .................................................................................................. 108 
7.2 
Handling, storage and destruction of biological samples .................................... 110 
7.2.1 
Pharmacokinetic, immunogenicity and/or pharmacodynamic (soluble PD-
L1) samples .......................................................................................................... 110 
7.2.2 
Pharmacogenetic samples .................................................................................... 110 


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7.3 
Labelling and shipment of biohazard samples ..................................................... 110 
7.4 
Chain of custody of biological samples ............................................................... 111 
7.5 
Withdrawal of informed consent for donated biological samples ....................... 111 
8. 
ETHICAL AND REGULATORY REQUIREMENTS ....................................... 112 
8.1 
Ethical conduct of the study ................................................................................. 112 
8.2 
Patient data protection .......................................................................................... 112 
8.3 
Ethics and regulatory review................................................................................ 112 
8.4 
Informed consent ................................................................................................. 113 
8.5 
Changes to the protocol and informed consent form ........................................... 114 
8.6 
Audits and inspections ......................................................................................... 115 
9. 
STUDY MANAGEMENT BY ASTRAZENECA .............................................. 115 
9.1 
Pre-study activities ............................................................................................... 115 
9.2 
Training of study site personnel ........................................................................... 115 
9.3 
Monitoring of the study ....................................................................................... 116 
9.3.1 
Source data ........................................................................................................... 116 
9.4 
Study agreements ................................................................................................. 116 
9.4.1 
Archiving of study documents ............................................................................. 116 
9.5 
Study timetable and end of study ......................................................................... 117 
9.5.1 
Data collection after the primary analysis of PFS and OS ................................... 117 
9.5.2 
Data collection after the final DCO for the study ................................................ 123 
10. 
DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE .................... 123 
11. 
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA, OR DELEGATE ................................................................... 124 
11.1 
Calculation or derivation of efficacy variable(s) ................................................. 124 
11.1.1 
RECIST 1.1 based endpoints ............................................................................... 124 
 Blinded Independent Central Review of RECIST 1.1-based assessments .......... 124 
 Investigator RECIST 1.1-based assessments ....................................................... 125 
11.1.2 
Blinded Independent Central Review of irRC-based assessments ...................... 125 
11.1.3 
Co-primary endpoints .......................................................................................... 125 
 Overall survival .................................................................................................... 125 
 Progression free survival ...................................................................................... 125 
11.1.4 
Proportion of patients alive at 24 months ............................................................ 126 
11.1.5 
Objective response rate ........................................................................................ 127 
11.1.6 
Duration of response ............................................................................................ 127 
11.1.7 
Proportion of patients alive and progression free at 12 months ........................... 127 
11.1.8 
Proportion of patients alive and progression free at 18 months ........................... 128 
11.1.9 
Time from randomisation to second progression (PFS2) .................................... 128 
11.1.10 
Time to death or distant metastasis ...................................................................... 128 


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11.2 
Calculation or derivation of safety variable(s) ..................................................... 128 
11.2.1 
Adverse events ..................................................................................................... 128 
11.2.2 
Other significant adverse events (OAEs) ............................................................. 129 
11.2.3 
Safety assessments ............................................................................................... 129 
11.3 
Calculation or derivation of patient reported outcome variables ......................... 129 
 EORTC QLQ-C30 ............................................................................................... 130 
 LC13 .................................................................................................................... 133 
 Calculation or derivation of health state utility (EQ-5D-5L) ............................... 134 
11.4 
Calculation or derivation of pharmacokinetic variables ...................................... 135 
11.4.1 
PK non-compartmental analysis .......................................................................... 135 
11.4.2 
Population PK and exposure-response/safety analysis ........................................ 135 
11.4.3 
Immunogenicity analysis ..................................................................................... 135 
11.5 
Calculation or derivation of biomarker variable(s) .............................................. 135 
11.6 
Calculation or derivation of pharmacogenetic variables...................................... 135 
11.7 
Calculation or derivation of health economic variables....................................... 135 
12. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
BY ASTRAZENECA .......................................................................................... 136 
12.1 
Description of analysis sets .................................................................................. 136 
12.1.1 
Full analysis set .................................................................................................... 136 
12.1.2 
Safety analysis set ................................................................................................ 137 
12.1.3 
PK analysis set ..................................................................................................... 137 
12.2 
Methods of statistical analyses ............................................................................. 137 
12.2.1 
Multiple testing strategy ...................................................................................... 139 
12.2.2 
Co-primary endpoints .......................................................................................... 141 
 Overall survival .................................................................................................... 141 
 Progression free survival ...................................................................................... 143 
12.2.3 
Proportion of patients alive at 24 months (OS24) ............................................... 145 
12.2.4 
Objective response rate ........................................................................................ 145 
12.2.5 
Duration of response ............................................................................................ 145 
12.2.6 
Proportion of patients alive and progression free at 12 months (APF12) ............ 145 
12.2.7 
Proportion of patients alive and progression free at 18 months (APF18) ............ 146 
12.2.8 
Time from randomisation to second progression (PFS2) .................................... 146 
12.2.9 
Time to death or distant metastasis ...................................................................... 146 
12.2.10 
Patient reported outcomes .................................................................................... 146 
 EORTC QLQ-C30 ............................................................................................... 146 
 LC13 .................................................................................................................... 147 
 EuroQol-5-Dimension 5-Level questionnaire ...................................................... 148 
12.2.11 
Healthcare resource use ....................................................................................... 148 
12.2.12 
Safety data ............................................................................................................ 148 
12.2.13 
PK data ................................................................................................................. 149 
 Immunogenicity analysis ..................................................................................... 149 
12.2.14 
PK/PDx relationships ........................................................................................... 149 


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12.2.15 
Biomarker data ..................................................................................................... 149 
12.2.16 
Interim analysis .................................................................................................... 149 
 PFS interim analysis ............................................................................................ 150 
 OS interim analyses ............................................................................................. 150 
12.3 
Determination of sample size ............................................................................... 151 
12.4 
Independent data monitoring committee.............................................................. 151 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ................................................................................................ 153 
13.1 
Medical emergencies, AstraZeneca/MedImmune and IQVIA contacts .............. 153 
13.2 
Overdose .............................................................................................................. 154 
13.3 
Pregnancy ............................................................................................................. 155 
13.3.1 
Maternal exposure ................................................................................................ 155 
13.3.2 
Paternal exposure ................................................................................................. 156 
14. 
LIST OF REFERENCES ..................................................................................... 157 
 
LIST OF TABLES 
Table 1 
Schedule of study procedures: Screening and Treatment Period 
(up to 12 months, maximum of 26 doses, last infusion at Week 50) ....... 44 
Table 2 
Schedule of study procedures: follow-up for patients who have 
completed the treatment period for study drug and achieved 
disease control (until confirmed progression of disease) and 
patients who have discontinued study drug due to toxicity or a 
reason other than confirmed progression of disease ................................. 49 
Table 3 
Schedule of study procedures: follow-up for patients who have 
discontinued study drug due to confirmed progression of disease ........... 52 
Table 4 
Effective methods of contraception (two methods must be used) ............ 69 
Table 5 
Haematology ............................................................................................. 98 
Table 6 
Clinical chemistry (serum or plasma) ....................................................... 98 
Table 7 
Urinalysis .................................................................................................. 99 
Table 8 
Volume of blood to be drawn from each patient in the first 
3 months on-treatment ............................................................................ 109 
Table 9 
eCRFs to be completed during long-term follow up .............................. 120 
Table 10 
Concomitant medications/Supportive Care therapy of interest 
during safety follow up ........................................................................... 121 


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Table 11 
Schedule of study procedures: Long-term follow-up and re-
treatment period after primary PFS and OS analyses ............................. 122 
Table 12 
Mean change and visit response in health related quality of life ............ 131 
Table 13 
Visit Response for HRQoL and disease-related symptoms ................... 133 
Table 14 
Summary of outcome variables and analysis populations ...................... 136 
Table 15 
Formal statistical analyses to be conducted and pre-planned 
sensitivity analyses ................................................................................. 138 
 
LIST OF FIGURES 
Figure 1 
Study design schema ................................................................................ 39 
Figure 2 
Study flow chart ....................................................................................... 42 
Figure 3 
Multiple testing procedures for controlling the type 1 error rate ........... 141 
 
LIST OF APPENDICES 
Appendix A 
Signatures 
Appendix B 
Additional Safety Information  
Appendix C 
IATA 6.2 Guidance document 
Appendix D 
Pharmacogenetics Research 
Appendix E 
Actions required in cases of combined increase of Aminotransferase and 
Total Bilirubin – Hy’s Law 
Appendix F 
Guidelines for Evaluation of Objective Tumour Response Using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumours) 
Appendix G 
Patient Reported Outcomes: EORTC QLQ-C30, LC13 and EQ-5D-5L 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
aa 
Amino acid 
ADA 
Anti-drug antibody 
AE 
Adverse event (see definition in Section 6.4.1) 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
APC 
Antigen presenting cell 
APF12 
Proportion of patients alive and progression free at 12 months from 
randomisation 
APF18 
Proportion of patients alive and progression free at 18 months from 
randomisation  
APTT 
Activated partial thromboplastin time  
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
B-cell 
B lymphocyte 
BICR 
Blinded Independent Central Review 
BoR 
Best objective response 
BP 
Blood pressure 
B7-H1 
B7 homolog 1 
cCTRT 
Concurrent chemoradiation 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CL 
Clearance 
CR 
Complete response 
CRF 
Case report form 
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 


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Abbreviation or 
special term 
Explanation 
Cyno 
Cynomolgus monkey 
DCO 
Data cut-off 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid  
DoR 
Duration of response 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDoR 
Expected Duration of Response 
EGFR 
Epidermal growth factor receptor 
EOI 
End of infusion 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer 30-item core 
quality of life questionnaire 
EQ-5D 
EuroQoL 5 dimension utility index 
EQ-5D-5L 
EuroQoL 5 dimension, 5 level health state utility index  
ESMO 
European Society for Medical Oncology 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FFPE 
Formalin fixed paraffin embedded 
FTIH 
First-Time-In-Human 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
HRQoL 
Health Related Quality of Life 
IASLC 
International Association for the Study of Lung Cancer 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
IFN 
Interferon 
Ig 
Immunoglobulin 
IL 
Interleukin 


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Abbreviation or 
special term 
Explanation 
imAE 
immune-mediated adverse event  
INR 
International normalised ratio  
International 
Co-ordinating 
Investigator 
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the Investigators and/or 
activities internationally.  
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
irRC 
Immune-related response criteria 
irRECIST 1.1 
Immune-related response criteria modified 
ITT 
Intent-to-Treat  
iv 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LC13 
Lung Cancer Module; 13-item self-administered questionnaire from the 
EORTC for lung cancer  
LIMS 
Laboratory Information Management System 
MedDRA 
Medical Dictionary for Regulatory Activities 
miRNA 
Micro RNA 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger RNA 
MTD 
Maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network  
NE 
Not evaluable 
NED 
No evidence of disease 
NSCLC 
Non-small cell lung cancer 
OAE 
Other significant adverse event (see definition in Section 11.2.2) 
ORR 
Objective response rate 
OS 
Overall survival 
OS24 
Proportion of patients alive at 24 months from randomisation 
PD 
Progression of disease 
PD-1 
Programmed death 1 
PD-L1 
Programmed death ligand 1 
PDx 
Pharmacodynamic(s) 


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Abbreviation or 
special term 
Explanation 
PFS 
Progression free survival 
PFS2 
Time from randomisation to second progression 
PGx 
Pharmacogenetic(s) 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PRO 
Patient reported outcome(s) 
Q2W 
Every 2 weeks 
QoL 
Quality of Life 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
r 
Recombinant  
R&D 
Research and Development 
RECIST 
Response Evaluation Criteria In Solid Tumours 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event (see definition in Section 6.4.2). 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
sPD-L1   
Soluble programmed death ligand 1 
SUSAR 
Suspected Unexpected Serious Adverse Reaction(s) 
t½ 
Half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
T-cell 
T lymphocyte 
TMGs 
Toxicity Management Guidelines 
TSH 
Thyroid stimulating hormone 
TTDM 
Time to death or distant metastasis 
ULN 
Upper limit of normal 
US 
United States 
WBDC 
Web Based Data Capture 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
Investigators should be familiar with the MEDI4736 Investigator’s Brochure (IB). 
1.1 
Background 
1.1.1 
Non-small cell lung cancer 
Lung cancer has been the most common cancer in the world for several decades, and by 2008, 
there were an estimated 1.61 million new cases, representing 12.7% of all new cancers.  It was 
also the most common cause of death from cancer, with 1.38 million deaths (18.2% of the 
total) (GLOBOCAN 2008).  Non-small cell lung cancer (NSCLC) represents approximately 
80% to 85% of all lung cancers and 30% of patients present with Stage III disease.  Standard 
treatment for patients with a good performance status and unresectable Stage III NSCLC is 
platinum-based doublet chemotherapy and radiotherapy administered with curative intent.  A 
meta-analysis of concurrent versus sequential chemoradiotherapy showed better outcomes 
with concurrent therapy, but even with concurrent chemoradiotherapy 5-year overall survival 
(OS) is only approximately 15% (Butts et al 2014). 
Therefore, sequential/maintenance (consolidation) therapy has been and continues to be 
explored in an attempt to prolong a favourable clinical state after delivery of definitive 
chemoradiotherapy.   
1.1.2 
Immunotherapies 
The immune system can identify tumour-associated antigens and eliminate the cancerous cells 
expressing them and thus plays an important role in preventing and combating the growth of 
tumours.  This process of tumour immune surveillance is believed to result in a co-evolution 
of the tumour and immune response termed immunoediting, which is thought to follow 
3 stages (Swann and Smyth 2007).   
x 
During the initial phase of elimination, the innate and adaptive immune systems 
detect and eliminate tumour cells.  Elimination can result in complete clearance of 
tumour cells as is seen in rare cases of spontaneous regression of melanoma 
(Kalialis et al 2009).   
x 
However, if elimination is incomplete, the immune system and tumour may enter a 
state of equilibrium.  During this second phase of immunoediting, the immune 
response selectively eliminates susceptible tumour cells and may prevent tumour 
progression.  As the equilibrium phase persists, the tumour may evolve mechanisms 
to avoid or attenuate the immune response.   


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x 
The emergence of tumour cells with reduced immunogenicity or enhanced 
immunosuppressive mechanisms leads to the escape phase of immunoediting.  
During the escape phase, many factors may contribute to the failure of the immune 
system to control tumour growth including the expression of immune-inhibitory 
molecules, presence of immunosuppressive regulatory T lymphocytes (T-cells) or 
immunosuppressive cytokines within the tumour microenvironment, and 
down-regulation of major histocompatibility molecules and tumour antigens leading 
to reduced antigen presentation and recognition.  
Blockade of negative regulatory signals to T-cells such as cytotoxic T-lymphocyte antigen 4 
(CTLA-4) and programmed death ligand 1 (PD-L1) has also shown promising clinical 
activity.  Ipilimumab binds to CTLA-4 and prevents the interaction of CTLA-4 with cluster of 
differentiation (CD) 80 and CD86, resulting in enhanced T-cell activation and proliferation 
(Lipson and Drake 2011).  Ipilimumab was granted United States (US) Food and Drug 
Administration (FDA) approval in 2011 for the treatment of metastatic melanoma and is 
currently under investigation for several other malignancies. 
PD-L1 (B7 homolog 1 [B7-H1], CD274) is part of a complex system of receptors and ligands 
that are involved in controlling T-cell activation.  In normal tissue, PD-L1 is expressed on 
T-cells, B lymphocytes (B-cells), dendritic cells, macrophages, mesenchymal stem cells, bone 
marrow-derived mast cells, as well as various nonhaematopoietic cells (Keir et al 2008).  The 
normal function of PD-L1 is to regulate the balance between T-cell activation and tolerance 
through interaction with 2 receptors, programmed death 1 (PD-1, CD279) and CD80 (B7-1).  
PD-L1 is also expressed by tumours and acts at multiple sites to help tumours evade detection 
and elimination by the host immune system.  In the lymph nodes, PD-L1 on antigen 
presenting cells (APCs) binding to PD-1 (CD279) or CD80 (B7-1) on activated T-cells, 
delivers an inhibitory signal to the T-cell (Keir et al 2008, Park et al 2010).  Likewise, binding 
of CD80 on APCs to PD-L1 on T-cells leads to inhibitory signalling in the T-cell.  These and 
bidirectional interactions between CD80 and PD-L1, expressed on both APCs and T-cells, 
lead to further inhibition of T-cell activation.  These interactions result in reduced T-cell 
activation and fewer activated T-cells in the circulation.  In the tumour microenvironment, 
PD-L1 expressed on tumour cells binds to PD-1 on activated T-cells reaching the tumour.  
This delivers an inhibitory signal to those T-cells, preventing them from killing the target 
tumour cells, and thus protecting the tumour from immune elimination (Zou and Chen 2008).  
PD-L1 is expressed in a broad range of cancers with a high frequency, up to 88% in some 
types of cancer.  In a number of these cancers, including lung (Mu et al 2011), renal 
(Krambeck et al 2007, Thompson et al 2005, Thompson et al 2006), pancreatic  
(Loos et al 2008, Nomi et al 2007, Wang et al 2010), and ovarian cancers  
(Hamanishi et al 2007), the expression of PD-L1 is associated with reduced survival and an 
unfavourable prognosis.  In ovarian cancer, for example, the 5-year survival rate in patients 
with low levels of PD-L1 was 80.2%, compared with 52.6% in patients with high levels of 
PD-L1 (Hamanishi et al 2007).  In lung cancer, only 20% of patients with tumours expressing 
PD-L1 survived for more than 3 years, compared with 49% of patients with tumours lacking 
PD-L1 (Mu et al 2011).  Based on these data, and on data for expression of PD-L1 on the 
surface of human tumours generated using proprietary immunohistochemistry methods for 


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assessment, MEDI4736 has the potential to affect multiple types of solid tumours, including 
those with a high incidence rate and some less common types with limited treatment options 
and poor outcomes.  
The levels of tumour-infiltrating lymphocytes, and more specifically cytotoxic T-cells, have 
been correlated to improved prognosis in a number of cancers including colorectal, melanoma, 
and lung cancers (Pagès et al 2010), suggesting that an anti-tumour immune response is 
beneficial to patients.  In vitro, an antibody that blocks the interaction between PD-L1 and its 
receptors can relieve PD-L1-dependent immunosuppressive effects and enhance the cytotoxic 
activity of anti-tumour T-cells (Blank et al 2006).  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 several preclinical studies using mouse tumour models support this 
hypothesis, where antibodies directed against PD-L1, or its receptor PD-1, showed 
anti-tumour activity (Hirano et al 2005, Iwai et al 2002, Okudaira et al 2009,  
Zhang et al 2008). 
Blocking PD-L1 is a similar approach to that taken by ipilimumab, but has some potential 
advantages.  Firstly, the expression of CTLA-4 and its ligands is restricted to the 
haematopoietic system; thus, the site of action for molecules targeting CTLA-4 is solely the 
peripheral lymphoid organs.  In contrast, PD-L1 is expressed not only on cells of the 
haematopoietic system but also on a range of tumour types.  Targeting of PD-L1 could 
therefore have additional effects within the tumour microenvironment.  Secondly, CTLA-4 
plays an early and critical role in controlling T-cell activation.  This is reflected in the 
phenotype of CTLA-4 knockout mice, which die at an age of between 3 weeks and 4 weeks 
due to lymphoproliferative disease and tissue destruction.  In contrast PD-L1, via binding to 
PD-1, acts later in the process of T-cell activation (Fife and Bluestone 2008) and is considered 
more dispensable for the control of initial T-cell activation.  This is reflected in the phenotype 
of PD-L1 knockout mice, which are viable and have normal T-cell numbers and activation 
levels, but that have increased T-cell activation in response to antigen and increased 
susceptibility in certain autoimmunity models (Dong et al 2004, Latchman et al 2004).  Based 
on these data, inhibition of PD-L1 would be expected to have reduced toxicity relative to 
inhibition of CTLA-4.  In support of this, recent Phase I clinical studies testing the tolerability 
of agents targeting PD-1 have shown a more favourable toxicity profile than ipilimumab 
(Berger et al 2008, Brahmer et al 2010, Wolchok et al 2009). 
 
Clinical data for agents targeting PD-1 and PD-L1 
A Phase I clinical study of the anti-PD-1 antibody nivolumab(BMS-936558/MDX-1106) was 
recently conducted in 39 patients (Brahmer et al 2010).  No dose limiting toxicities (DLTs) 
were observed and a maximum tolerated dose (MTD) was not identified.  Efficacy data for 
nivolumab indicate an objective response rate (ORR) of 19% for NSCLC patients with 
squamous histology and 15% for NSCLC patients with non-squamous histology  
(Brahmer et al 2013).  In a large Phase I study of nivolumab in 296 patients, treatment-related 
adverse events (AEs) were observed at all dose levels studied (Topalian et al 2012). The most 
frequent treatment-related AEs of any grade observed during this study were fatigue (24%), 
rash (12%), diarrhoea (11%) and pruritus (10%).  Immune-PHGLDWHG$(VRI*UDGH


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occurred in 6% of patients and included pneumonitis (1%), diarrhoea (1%), alanine 
aminotransferase (ALT) increased (1%), and aspartate aminotransferase (AST) increased 
(1%).  Of note, 3 deaths due to pneumonitis were assessed as related to study drug. 
MK-3475, another anti-PD-1 monoclonal antibody, is being evaluated in Phase I and II 
studies, with data from a study of 135 patients with advanced melanoma recently reported 
(Hamid et al 2013).  Efficacy data for MK-3475 in NSCLC has indicated an ORR of 24% by 
immune-related response criteria (irRC) (21% by Response Evaluation Criteria In Solid 
Tumours [RECIST]) after 2 previous NSCLC treatment regimens.  Preliminary median OS 
was 51 weeks (unpublished data presented by E Garon at The World Conference on Lung 
Cancer 2013).  The most frequent treatment-related AEs of any grade observed in the study of 
135 patients with advanced melanoma recently reported by Hamid et al 2013 were fatigue 
(30%), rash and pruritus (21% each), diarrhoea (20%), myalgia (12%), headache, asthenia, 
nausea, and elevated AST (10% each).  Grade 3 or higher treatment-related AEs were reported 
in 13% of patients and included rash (2%), pruritus, hypothyroidism, diarrhoea, abdominal 
pain, fatigue, decreased appetite, elevated AST and renal failure (1% each). 
Clinical data have also been reported from a Phase I clinical study of the anti-PD-L1 antibody, 
BMS-936559 (MDX-1105).  Preliminary data for BMS-936559 (MDX-1105) indicates an 
ORR of 8% for NSCLC patients with squamous histology and 11% for NSCLC patients with 
non-squamous histology.  The most frequently observed treatment-related AEs of any grade 
were similar to those observed with BMS-936558 and included fatigue (16%), 
infusion-related reaction (10%), diarrhoea (9%), rash (7%), arthralgia (7%), pruritus (6%) and 
nausea (6%) (Brahmer et al 2012).  Immune-PHGLDWHG$(VRI*UDGHRFFXUUHGLQRI
patients.  Pneumonitis was not reported in this study. 
Data for MPDL3280A, another anti-PD-L1 antibody in development in NSCLC patients, was 
presented by L Horn at The World Conference on Lung Cancer 2013.  These data showed an 
ORR in smokers of 26%; versus 10% in never smokers and 23% in patients with epidermal 
growth factor receptor (EGFR) wild type mutation status and 23% in patients who were EGFR 
mutation positive.  Safety data from 171 patients enrolled in a Phase I study of MPDL3280A, 
has also been recently presented (Herbst et al 2013).  In this ongoing study, the most 
frequently reported AEs, regardless of causality, were fatigue (43%), cough (26%), diarrhoea 
(26%), nausea (25%), decreased appetite (25%), headache (25%), constipation (23%), 
dyspnoea (23%), pyrexia (22%), arthralgia (19%), rash (18%), and insomnia (18%).  Grade 3 
or 4 treatment-related AEs were reported in 13% of patients.  No DLTs were observed and an 
MTD was not identified. 
Studies of other agents targeting the PD-1/PD-L1 pathway are also in early stage development 
with limited data available.  CT-011 (an anti-PD-1 monoclonal antibody), has been evaluated 
in a Phase I study in advanced haematologic malignancies (Berger et al 2008).  In this study of 
17 patients, CT-011 was well tolerated and no treatment-related toxicities were reported.  
No MTD was identified in this population.  The most frequent AE was diarrhoea, which 
occurred in 2 patients.  


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1.1.3 
MEDI4736 
MEDI4736 is a human monoclonal antibody of the immunoglobulin (Ig) G1 kappa subclass 
that inhibits binding of PD-L1 (B7-H1, CD274) to PD-1 (CD279) and CD80 (B7-1).  
MEDI4736 is composed of 2 identical heavy chains and 2 identical light chains, with an 
overall molecular weight of approximately 149 kDa.  MEDI4736 contains a triple mutation in 
the constant domain of the Ig G1 heavy chain that reduces binding to complement protein C1q 
and the fragment crystallizable gamma receptors involved in triggering effector function.   
1.1.4 
Non-clinical experience with MEDI4736 
For full details of the non-clinical information, please refer to the current IB. 
MEDI4736 binds with high affinity and specificity to human PD-L1 and blocks its interaction 
with PD-1 and CD80.  In vitro studies demonstrate that MEDI4736 antagonizes the inhibitory 
effect of PD-L1 on primary human T-cells, resulting in restored proliferation and release of 
interferon (IFN) gamma.  Additionally, MEDI4736 demonstrates a lack of 
antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in cell-based 
functional assays.  In vivo studies show that MEDI4736 inhibits tumour growth in a xenograft 
model via a T-cell dependent mechanism.  An anti-mouse PD-L1 antibody has also 
demonstrated improved survival in a syngeneic tumour model when MEDI4736 was given as 
a monotherapy and resulted in complete tumour regression in >50% of treated mice when 
given in combination with chemotherapy. 
Cynomolgus monkeys were selected as the only relevant species for evaluation of the 
pharmacokinetics (PK)/pharmacodynamics (PDx) and potential toxicity of MEDI4736.  This 
conclusion was based on:  
x 
The high amino acid (aa) sequence identity shared by the extracellular domains of 
cynomolgus monkey (cyno) PD-L1 and human PD-L1 
x 
The conservation of an aa in cynoPD-L1 that is essential for the binding of 
MEDI4736 to recombinant (r)PD-L1 
x 
The similar affinity for binding of MEDI4736 to rcynoPD-L1 and rPD-L1.  
In addition, the PDx of MEDI4736 was demonstrated in vivo in cynomolgus monkeys.  
Mouse and rat were not considered relevant nonclinical species due to: 
x 
The much lower aa sequence identity shared by the extracellular domains of mouse 
PD-L1 or rat PD-L1 and human PD-L1 
x 
Rat PD-L1 and mouse PD-L1 lack the aa that is essential for the binding of 
MEDI4736 to human PD-L1 
x 
Lack of binding of MEDI4736 to the extracellular domains of mouse PD-L1. 


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Following intravenous (iv) administration, the PK of MEDI4736 in cynomolgus monkeys was 
non-linear.  Systemic clearance (CL) decreased and half-life (t½) increased with increasing 
doses, suggesting saturable target binding-mediated CL of MEDI4736.  No apparent gender 
differences in PK profiles were observed for MEDI4736. 
In general, there were no MEDI4736-related adverse effects in toxicology studies conducted 
in cynomolgus monkeys that were considered to be of relevance to humans.  Adverse findings 
in the non-Good Laboratory Practice (GLP) PK/PDx and dose range-finding study (4 doses 
over 5 weeks), and a GLP 4-week repeat-dose toxicity study were consistent with anti-drug 
antibody (ADA)-associated morbidity and mortality in individual animals.  The death of a 
single animal in the non-GLP, PK/PDx, and dose range-finding study was consistent with an 
ADA-associated acute anaphylactic reaction based on the presence of ADA within days of the 
first dose, acuteness and timing (after repeated dosing) of the death, clinical signs consistent 
with an anaphylactic reaction, lack of remarkable effects on other study parameters, and lack 
of histopathologic findings consistent with any other cause of death.  In addition, the spectrum 
of findings, especially the microscopic pathology, in a single animal in the GLP, 4-week, 
repeat-dose study was also consistent with ADA-associated immune complex deposition.  
Similar effects have been observed by MedImmune in cynomolgus monkeys administered 
human monoclonal antibodies unrelated to MEDI4736: ADA immune-complexes were 
identified in the affected animal in a subsequent investigative study.  Given that 
immunogenicity of human monoclonal antibodies in nonclinical species is not generally 
predictive of responses in humans, the ADA-associated morbidity and mortality were not 
taken into consideration for the determination of the no-observed-adverse-effect level of 
MEDI4736 in these studies.  Finally, interim audited data from the dosing phase of the pivotal 
3-month GLP toxicity study in cynomolgus monkeys, showed that subchronic dosing of 
MEDI4736 was not associated with any adverse effects.  Therefore, the no-observed adverse 
effect level of MEDI4736 in all the general toxicity studies was considered to be 100 mg/kg, 
the highest dose tested in these studies. 
1.1.5 
Clinical experience with MEDI4736 
For full details of the clinical information, please refer to the current IB. 
MEDI4736 has been given to humans as part of ongoing studies where it is given either as a 
single drug or in combination with other drugs.  The majority of the safety data currently 
available for MEDI4736 are based on the first-time-in-human (FTIH), single agent study 
(CD-ON-MEDI4736-1108) in patients with advanced solid tumours.  As of 18 February 2014, 
a total of 198 patients have entered into this study of which 177 had received MEDI4736 at 
10 mg/kg given every 2 weeks (Q2W).  The most frequently reportHGRIVXEMHFWV
treatment-emergent AEs (all grades) were fatigue, dyspnoea, nausea, constipation and 
decreased appetite.  The majority of these treatment-emergent AEs were Grades 1 to 2 in 
severity and manageable by the general treatment guidelines as described in the current 
MEDI4736 study protocols.  
Grade 3 or higher treatment-emergent AEs were noted in 44/177 subjects (24.9%).  These 
events occurring in more than 1 subject included dyspnoea (9 subjects); dehydration 


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(4 subjects); abdominal pain, fatigue, sepsis, increased AST and increased gamma 
glutamyltransferase (3 subjects); and hyperbilirubinemia, back pain, pulmonary embolism, 
respiratory failure and hypotension (2 subjects each).  The Grade 3 or higher 
treatment-emergent AEs that were considered by the Investigator to be related to MEDI4736 
were increased AST (2 subjects), and hypothyroidism, vomiting, fatigue, infusion related 
reaction, troponin, dehydration and arthralgia (1 subject each).  
Treatment-related AEs were reported for 52/177 subjects (29.4%).  The most frequently 
reported (2 or more subjects) treatment-related AEs (all grades) were fatigue (11.3%); nausea 
(5.6%); dyspnoea (4.0%); diarrhoea, vomiting and pyrexia (3.4% each); myalgia (2.8%); 
hypothyroidism, decreased appetite, dizziness, cough, pruritus and rash (2.3% each), 
abdominal pain, increased AST and arthralgia (1.7% each); and asthenia, influenza-like 
illness, oedema peripheral, increased ALT, headache and dry skin (1.1% each).  No DLTs 
have been reported.  
Serious adverse events (SAEs; not necessarily related to MEDI4736) that were reported in this 
study and observed in 3 or more subjects at 10 mg/kg Q2W include dyspnoea (2.8%), 
dehydration (2.3%), abdominal pain (1.7%) and sepsis (1.7%).  Treatment-related SAEs noted 
at the 10mg/kg Q2W dosing schedule were observed in 3 patients: pneumonitis, pleural 
effusion, arthralgia, right-hand weakness and rule out cord compression. 
Of the 198 subjects enrolled, 28 subjects have died (25 subjects treated with MEDI4736 
10 mg/kg Q2W, and 1 subject in each of the 0.1, 0.3 and 3.0 mg/kg Q2W cohorts).  No 
subjects died on treatment.  None of the deaths were considered related to MEDI4736 by the 
Investigator and all deaths were “due to disease” with the exception of 1 subject (cause of 
death was reported as “disease under treatment”).  
Of the 177 subjects treated with MEDI4736 10 mg/kg Q2W, 77 have had at least one 
post-baseline disease assessment as of 18 February 2014.  No subjects had a CR.  Four 
subjects (5.2%) had a best response of PR (unconfirmed) assessed by irRC: 1 subject with 
advanced cutaneous melanoma, 1 subject with squamous cell carcinoma of the head and neck, 
1 subject with squamous NSCLC, and 1 subject with non-squamous NSCLC.  In addition, 
36 subjects (46.8%) had stable disease (SD), 20 subjects (26.0%) had confirmed PD, 
14 subjects (18.2%) had unconfirmed PD, and 3 subjects (3.9%) were not evaluable. 
Twelve of the 15 subjects in the 0.1, 0.3, 1.0 mg/kg, and 3.0 mg/kg Q2W dose-escalation 
cohorts had at least one post-baseline disease assessment as of 18 February 2014.  Two 
subjects in each of the 0.3 and 1.0 mg/kg cohorts had a best response of PR (3 confirmed and 
1 unconfirmed) assessed by irRC (Wolchok et al 2009).  All 6 subjects in the 15 mg/kg Q3W 
cohort had at least one post-baseline disease assessment as of 18 February 2014.  No subjects 
had CR or PR, 4 subjects had a best response of SD, 1 subject had confirmed PD, and 
1 subject had unconfirmed PD. 


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1.1.6 
Safety pharmacology summary 
Refer to the latest version of the IB for the latest information on identified and potential risks 
associated with MEDI4736.   
There are a number of potential/possible risks based on the mechanism of action of 
MEDI4736 and related molecules including immune-mediated reactions such as enterocolitis, 
dermatitis, hepatotoxicity, endocrinopathy, and neuropathy. 
A hypothetical risk exists for agents that activate the immune system by delivering agonistic 
signals through activating receptors, such as CD28 (Suntharalingam et al 2006).  Such agents 
have an increased potential to trigger systemic, nonspecific activation of T-cells since they can 
exert their effects in the absence of any antigen-specific T-cell receptor signals.  In contrast, 
agents that act via antagonism of an inhibitory pathway modulate an existing antigen-specific 
T-cell receptor signal and have a limited potential to drive systemic, nonspecific activation of 
T-cells.  This is exemplified clinically by molecules targeting CTLA-4 and PD-1, which are 
not associated with acute, severe adverse effects, such as a cytokine storm (Berger et al 2008, 
Brahmer et al 2010, Wolchok et al 2010).  Like these molecules, MEDI4736 antagonizes an 
inhibitory receptor (PD-L1).  As such, in the absence of an antigen-specific T-cell receptor 
signal, inhibition of function of PD-L1 is not anticipated to elicit any response.  This 
expectation is supported by published data showing no effect for anti-PD-L1 antibodies in the 
absence of a T-cell receptor stimulus (Dong et al 2003).   
To assess directly the potential of MEDI4736 to induce a release of cytokines, cytokine 
release assays were conducted in human whole blood.  MEDI4736 did not induce release of 
any cytokine from any donor at any concentration tested.  These results support that, 
consistent with its mechanism of action as a PD-L1 antagonist, MEDI4736 is not expected to 
induce acute cytokine release in humans.  Nevertheless, the MEDI4736 FTIH study design 
took into account the unlikely possibility of a cytokine release event by having a low starting 
dose, extensive monitoring, and cytokine sampling. 
1.1.7 
Genetic data 
The pharmacogenetic (PGx) research elements of this study (relating to DNA) are optional.  
Refer to Appendix D. 
1.2 
Research hypothesis 
The research hypothesis for this study is: MEDI4736 (10 mg/kg Q2W via iv infusion) will 
show improved efficacy compared with placebo when given as sequential therapy to patients 
with locally advanced, unresectable NSCLC (Stage III) who have not progressed following 
definitive, platinum-based, concurrent chemoradiation therapy. 
This will be assessed via the primary objective of this study, which is to assess the efficacy of 
MEDI4736 treatment compared with placebo in terms of OS and progression free survival 
(PFS).  Secondary efficacy objectives include evaluation of the proportion of patients alive at 
24 months from randomisation (OS24), ORR, DoR, the proportion of patients alive and 


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progression free at 12 months from randomisation (APF12) and the proportion of patients 
alive and progression free at 18 months from randomisation (APF18), the time from 
randomisation to second progression (PFS2), and time to death or distant metastasis (TTDM).  
Other secondary objectives include an assessment of safety and tolerability, MEDI4736 PK 
exposure, immunogenicity and patient reported outcomes (PRO).  Exploratory objectives are 
also included.   
Section 12.3 provides information on how the sample size for the study was determined. 
1.3 
Rationale for conducting this study 
The rationale for combining chemotherapy and radiotherapy is to combine the benefits of 
radiotherapy in terms of local regional control with the benefits of chemotherapy in terms of 
reducing the risks of metastatic disease.  With concurrent chemoradiation (cCTRT) there is 
the potential for chemotherapy, given during a course of radiotherapy, to enhance the 
effectiveness of radiotherapy (ie, radiosensitisation) (O'Rourke et al 2010). 
For patients with unresectable Stage IIIA or Stage IIIB disease, combined modality therapy 
(chemoradiation) is superior to radiation alone and cCTRT is superior to sequential therapy 
(NCCN Guidelines 2014).  Concurrent chemoradiation regimens that may be used for all 
histologies for initial treatment include cisplatin/etoposide, cisplatin/vinblastine or 
carboplatin/paclitaxel (TAXOL®).  For non-squamous NSCLC other cCTRT regimens include 
cisplatin/pemetrexed (ALIMTA®) (NCCN Guidelines 2014).  The guidelines for the treatment 
of patients with unresectable Stage IIIA or Stage IIIB NSCLC in Europe  
(Vansteenkiste et al 2013) and Japan (Saijo et al 2010) are in line with those used in the US. 
However, the majority of patients inevitably progress (PFS is usually short; approximately 
8 months) and 5-year OS is approximately 15% (Butts et al 2014). 
Whilst advances have been made in improving survival from Stage III NSCLC by optimising 
local control, evidence suggests that cCTRT does not reduce the risk of distant relapse.  With 
fewer cycles and, in some cases, lower doses of chemotherapy being delivered in the 
concurrent setting, several studies have assessed whether delivering induction or consolidation 
treatment will improve survival.  A pooled analysis of 41 Phase II/III trials confirmed that 
there remains no evidence to suggest that consolidation chemotherapy after cCTRT improves 
survival for patients with Stage III NSCLC and current guidelines continue to recommend 
cCTRT alone for the treatment of inoperable Stage III NSCLC (Bayman et al 2014).  There is 
still therefore a significant unmet medical need for additional treatment options for use in this 
patient population to improve on PFS and OS (see Section 1.1.1). 
The sequential/consolidation setting post cCTRT may be ideal to evaluate the efficacy of 
immunotherapy, which is aimed at boosting the ability of the patient immune system to 
eliminate cancer cells.  
Tumours that are poorly immunogenic or that have become immunosuppressive can likely be 
made immunogenic through administration of pro-immunogenic therapies designed to 


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increase antigen release from the cancer cell.  Potential priming agents for immunotherapy 
agents include chemotherapy and radiotherapy.  Some cytotoxic therapies, such as 
anthracyclines or ionizing 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 
towards a pro-inflammatory phenotype and increase priming towards T helper 1 anti-tumour 
T-cells and away from regulatory T-cells (Vanneman and Dranoff 2012).  Additionally, a 
recent Phase II trial in patients with Stage IIIb/IV NSCLC or extensive-disease small-cell lung 
cancer investigated whether  the anti-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 trial 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 (Drake 2012). 
The therapeutic application of ionizing radiation has been largely based on its cytocidal power 
combined with the ability to selectively target tumours.  Radiotherapy effects on survival of 
cancer patients are generally interpreted as the consequence of improved local control of the 
tumour, directly decreasing systemic spread.  Experimental data from multiple cancer models 
have provided sufficient evidence to propose a paradigm shift, whereby some of the effects of 
ionizing radiation are recognised as contributing to systemic antitumour immunity.  
Interventions such as radiotherapy that promote the release of tumour neoantigens in an 
immunogenic way, together with strategies to overcome dominant immunosuppressive 
pathways, offer opportunities to recover effective immune reactivity  
(Formenti and Demaria 2013).  By coupling release and/or expression of new antigens with 
immune adjuvant-like effects, radiotherapy engages both the innate and adaptive arms of the 
immune system, with the potential to convert the irradiated cancer into an in situ vaccine that 
elicits tumour-specific T-cells.  Once vaccinated, the host is endowed with immune memory, a 
powerful weapon active against synchronous non-irradiated tumour sites and potentially 
against cancer cells that emerge from dormancy during the life of the host.  Such immune 
memory may explain radiotherapy’s repercussions on the final outcome of irradiated patients.  
Radiotherapy’s effect on local tumour control is associated with an effect on metastatic 
recurrence and eventual cancer survival.  For instance, two meta-analyses of prospective, 
randomised trials in breast cancer demonstrated a direct contribution of adjuvant radiotherapy 
to patients’ long-term survival.  The effect was independent of the stage and extent of surgery 
(Formenti and Demaria 2013). 
In addition, the clinical observation of the abscopal effect of tumour regression outside the 
irradiated field may be a result of radiation induced antigen and cytokine release and the 
subsequent immune response against the tumour.  Anecdotes have been published describing 
the abscopal effect with ipilimumab.  In addition it has been shown than fractionated 
radiotherapy induces an abscopal effect when in combination with an anti–CTLA-4 antibody 


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in two non-clinical carcinoma models (Dewan et al 2009).  In syngeneic mice models of 
cancer the combination of radiotherapy and anti-CTLA-4 resulted in successful 
T-cell-mediated antitumour responses, whereas anti-CTLA-4 treatment by itself was 
ineffective.  Inhibition of early lung metastases and responses of bulky tumours outside the 
radiation field were observed in mice with established poorly immunogenic mammary and 
colorectal carcinomas (Formenti and Demaria 2013).  Initial evidence in lung and breast 
carcinoma and glioma suggests that antibodies that target other checkpoint receptors on 
T-cells and/or co-stimulatory molecules such as CD137 can also be successfully combined 
with radiotherapy (Formenti and Demaria 2013).  Both chemotherapy and radiotherapy can 
up-regulate the expression of PD-L1 (Zhang et al 2008b, Deng et al 2014) due to the release 
of cytokines and other inflammatory molecules, which could therefore make such tumours 
sensitive to a PD-L1 directed therapy. 
MEDI4736, an antibody that blocks the interaction between PD-L1 and its receptors, may 
relieve PD-L1-dependent immunosuppressive effects and therefore enhance the cytotoxic 
activity of anti-tumour T-cells.  This hypothesis is supported by emerging clinical data from 
other monoclonal antibodies targeting the PD-L1/PD-1 pathway (see Section 1.1.2), which 
provide early evidence of clinical activity and a manageable safety profile superior to the 
anti-CTLA-4 class.  
1.4 
Benefit/risk and ethical assessment 
Refer to the IB for information on the potential benefits of MEDI4736 and an assessment of 
the potential and known risks.   
1.4.1 
Unmet need and potential role of immunotherapies in NSCLC 
Non-small cell lung cancer (NSCLC) represents approximately 80% to 85% of all lung 
cancers and 30% of patients present with Stage III disease.  Standard treatment for patients 
with a good performance status and unresectable Stage III NSCLC is platinum-based doublet 
chemotherapy and radiotherapy administered with curative intent.  A meta-analysis of 
concurrent versus sequential chemoradiotherapy showed better outcomes with concurrent 
therapy, but even with concurrent chemoradiotherapy 5-year OS is only approximately 15% 
(Butts et al 2014). 
Whilst advances have been made in improving survival from Stage III NSCLC by optimising 
local control, evidence suggests that cCTRT does not reduce the risk of distant relapse.  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.  A pooled analysis of 41 Phase II/III trials confirmed that there remains 
no evidence to suggest that consolidation chemotherapy after cCTRT improves survival for 
patients with Stage III NSCLC and current guidelines continue to recommend cCTRT alone 
for the treatment of inoperable Stage III NSCLC (Bayman et al 2014).  Given the lack of 
persuasive evidence for an active comparator, the use of a placebo comparator is justified in 
the proposed sequential/consolidation setting in this study. 


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The sequential/consolidation setting post-cCTRT may be ideal to evaluate the efficacy of 
immunotherapy, which is aimed at boosting the ability of the patient immune system to 
eliminate cancer cells.  Chemoradiotherapy often induces initial tumour shrinkage followed by 
eventual PD as the tumours find mechanisms to bypass the chemoradiotherapy-induced 
growth inhibition.  The initial tumour shrinkage observed in some patients following 
chemoradiotherapy is the result of cell death and tumour damage.  
Chemoradiotherapy-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.  
Therefore, triggering or augmenting an antigenic antitumour response with 
chemoradiotherapy 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 antitumour activity by improving local control and 
decreasing systemic spread. 
1.4.2 
Summary of MEDI4736 data and potential benefits and risks 
MEDI4736, a human monoclonal antibody directed against human PD-L1, may offer benefit 
to this patient population.  MEDI4736 has a high affinity for human PD-L1 and is able to 
completely block the interaction of recombinant human PD-L1 with both recombinant human 
PD-1 and recombinant human CD80 in a biochemical assay.  In vitro, MEDI4736 enhances 
the proliferation and activation of primary human T-cells cultured in the presence of rPD-L1. 
Nonclinical studies demonstrate that MEDI4736 inhibits tumour growth in mouse xenograft 
models.  This activity is shown to be dependent upon the presence of human T-cells, 
supporting the hypothesis that PD-L1 blockade can enhance anti-tumour immune response.  
No MEDI4736-associated risks have been reported in nonclinical safety studies in 
cynomolgus monkeys.  Please refer to Section 1.1.5 and the current IB for clinical experience 
with MEDI4736. 
Important potential risks associated with MEDI4736, as with the administration of any foreign 
protein and/or other biologic agents, include anaphylaxis/anaphylactoid/hypersensitivity 
reactions, serious infections, infusion reactions, immune complex disease, and the 
development of ADAs.  Anti-drug antibodies could result in immune complex disease with 
manifestations such as arthralgias, serum sickness, and vasculitis and/or could result in altered 
MEDI4736 levels or activity. 
1.4.3 
Summary of potential benefits and risks of other immunotherapy agents 
Other monoclonal antibodies targeting the PD-1/PD-L1 pathway are currently in clinical 
development.  Among the most frequent treatment-related AEs noted in these antibodies are 
fatigue, rash, diarrhoea and pruritus.  Immune-PHGLDWHG$(VRI*UDGHUHSRUWHGLQFOXGH
pneumonitis, diarrhoea, ALT increased and AST increased. 
Other relevant risks include those associated with biological and immunotherapy agents.  
Ipilimumab and tremelimumab are both immunomodulatory antibodies that target CTLA-4 
and have been studied extensively across multiple tumour types.  Ipilimumab is marketed for 


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the treatment of metastatic or unresectable melanoma based on improvements in OS as a 
single agent and in combination with chemotherapy.  Immune-mediated AEs of *UDGH 3 
observed during Phase III studies of ipilimumab occurred in 15% of patients and included 
enterocolitis (7%), hepatitis (2%), dermatitis (2.5%) and endocrinopathy (1.8%)  
(YERVOY™ prescribing information).  Adverse events similar to those reported with 
ipilimumab were observed during the clinical development of tremelimumab in melanoma, 
with diarrhoea (40%), pruritus (23%), rash (22%), nausea (22%) and fatigue (17%) being the 
most common (Kirkwood et al 2010).  Grade 3 or higher AEs observed were diarrhoea (11%), 
fatigue (2%), rash (1%), nausea (1%), vomiting (1%) and anorexia (1%). 
Promising evidence of clinical activity has been observed for molecules similar to MEDI4736, 
including other monoclonal antibodies targeting the PD-1/PD-L1 pathway.  In these studies, 
encouraging response rates and durable responses have been observed across a range of 
tumour types (Berger et al 2008, Brahmer et al 2010, Gordon et al 2013, Robert et al 2011, 
Topalian et al 2012).  The experience to date with anti-PD-1/PD-L1 monoclonal antibodies 
suggests that these agents can provide significant clinical activity with a manageable safety 
profile that is superior to that of the anti-CTLA-4 class. 
1.4.4 
Summary benefit: risk statement 
In summary, the potential for clinical benefit associated with inhibition of the PD-1/PD-L1 
pathway, supported by objective responses observed in earlier studies in patients with 
NSCLC, outweighs the known and potential risks based on the AEs reported in patients 
treated with MEDI4736 and other PD-1/PD-L1 inhibitors.  Thus, the benefit/risk assessment, 
favours the conduct of this proposed study.   
The safety of patients in this study will be assessed by an Independent Data Monitoring 
Committee (IDMC) via ongoing safety assessments and formal interim analyses of safety data 
at 3 months, 6 months and then at least every 6 months thereafter. 
2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
Primary Objective: 
Outcome Measure: 
To assess the efficacy of MEDI4736 treatment 
compared with placebo in terms of OS and PFS 
OS 
PFS using BICR assessments according to 
RECIST 1.1a 
a 
The co-primary analysis of PFS will be based on programmatically derived PFS using BICR assessments according to 
RECIST 1.1.  See Section 12.2.2 for further details. 
BICR  Blinded Independent Central Review; OS  Overall survival; PFS  Progression free survival; RECIST  Response 
Evaluation Criteria In Solid Tumours. 
 


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2.2 
Secondary objectives 
Secondary Objective: 
Outcome Measure: 
To further assess the efficacy of MEDI4736 
compared with placebo in terms of: OS24, ORR, 
DoR, APF12, APF18, PFS2 and TTDM 
OS24 
ORR using BICR assessments according to RECIST 
1.1a 
DoR using BICR assessments according to RECIST 
1.1a 
APF12 and APF18 using BICR assessments 
according to RECIST 1.1a 
PFS2 as defined by local standard clinical practice 
TTDM using BICR assessments according to 
RECIST 1.1a 
To assess the safety and tolerability profile of 
MEDI4736 compared with placebo 
AEs, physical examinations, vital signs including 
blood pressure, pulse, electrocardiograms, and 
laboratory findings including clinical chemistry, 
haematology and urinalysis 
To assess the PK of MEDI4736  
Concentration of MEDI4736 in blood and 
non-compartmental PK parameters (such as peak 
concentration and trough, as data allow) (sparse 
sampling) 
To investigate the immunogenicity of MEDI4736  
ADA (confirmatory results: positive or negative; 
titres [ADA neutralising antibodies will also be 
assessed])  
To assess symptoms and health-related quality of life 
in patients treated with MEDI4736 compared with 
placebo using EORTC QLQ-C30 v3 and LC13 
EORTC QLQ-C30: Time to symptom deterioration 
(fatigue, pain, nausea/vomiting, dyspnoea, loss of 
appetite, insomnia, constipation, and diarrhoea).  
Time to QoL/function deterioration (physical 
function; role function; emotional function; cognitive 
function; social function and global health 
status/QoL) 
LC13: Time to symptom deterioration (dyspnoea, 
cough, haemoptysis, chest pain, arm/shoulder pain, 
other pain) 
Changes in World Health Organization Performance 
Status will also be assessed 
a 
Analysis of ORR and DoR will be based upon BICR assessment according to RECIST 1.1.  See Sections 12.2.3 and 
12.2.5 for further details. 
Note: Prior irradiated lesions may be considered measurable and selected as target lesions providing they fulfil the other 
criteria for measurability. 
ADA  Anti-drug antibody; AE  Adverse event; APF12  Proportion of patients alive and progression free at 12 months from 
randomisation; APF18  Proportion of patients alive and progression free at 18 months from randomisation; BICR  Blinded 
Independent Central Review; DoR  Duration of response; EORTC QLQ-C30  European Organisation for Research and 
Treatment of Cancer 30-item core quality of life questionnaire; LC13  Lung Cancer Module; ORR Objective response rate; 
OS24  Proportion of patients alive at 24 months from randomisation; PFS2  Time from randomisation to second progression; 
PK  Pharmacokinetic(s); QoL  Quality of Life; RECIST  Response Evaluation Criteria In Solid Tumours; TTDM  Time to 
death or distant metastasis. 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
37(167) 
2.3 
Exploratory objectives 
Exploratory Objective: 
Outcome Measure: 
To explore irRC criteria as an assessment 
methodology for clinical benefit of MEDI4736 
compared with placebo by BICR 
PFS and ORR using BICR assessments according to 
irRC 
To investigate the relationship between MEDI4736 
PK exposure and clinical outcomes, efficacy, AEs 
and/or safety parameters, if deemed appropriate  
A graphical and/or a data modelling approach will be 
used to analyse MEDI4736 PK exposure and the 
relationship with clinical outcomes, efficacy, AEs 
and/or safety parameters, as deemed appropriate 
To describe and evaluate resource use associated with 
MEDI4736 treatment and underlying disease 
Health resource utilisation measures including 
hospitalisation, outpatient visits, or emergency 
department visits 
To explore the impact of treatment and disease state 
on health state utility using the EQ-5D-5L 
The EQ-5D-5L health state utility index will be used 
to derive health state utility based on patient reported 
data 
To investigate the relationship between a patient’s 
PD-L1 expression and spatial distribution within the 
tumour microenvironment and efficacy outcomes 
with MEDI4736  
Tumoural expression of PD-L1 and spatial 
distribution within the tumour microenvironment 
relative to efficacy outcomes (OS, PFS and ORR) 
To collect blood and tissue samples for analysis of 
peripheral and tumoural biomarkers 
 
Biomarker analysis of blood and tissue to assess 
exploratory markers which may include but is not 
limited to: immune cell gene expression profiles 
within the peripheral and tumoural compartments, the 
presence of IFN-ȖWXPRXUQHFURVLVIDFWRU-Į,/-2, 
IL-6, IL-10, IL-8, and IL-12 as well as antibodies 
against tumour, self, or viral antigens, expression of 
PD-L1 and the number and phenotype of immune 
cells such as T-cells 
To explore the relationship(s) between a patient’s 
biomarker status and MEDI4736 PK exposure and 
clinical outcomes before and after treatment 
Biomarker status before and after treatment and 
MEDI4736 PK exposure and relationship with 
clinical outcomes, efficacy, AEs and/or safety 
parameters, as deemed appropriate 
To explore potential biomarkers in residual biological 
samples (eg, tumour, plasma and/or serum), which 
may influence the progression of cancer (and 
associated clinical characteristics) and/or 
prospectively identify patients likely to respond to 
MEDI4736 treatment 
Correlation of biomarkers with response to 
MEDI4736 treatment and/or the progression of cancer 
To collect and store DNA according to each country’s 
local and ethical procedures for future exploratory 
research into genes/genetic variation that may 
influence response (ie, distribution, safety, tolerability 
and efficacy) to study drugs and/or susceptibility to 
disease (optional) 
Correlation of polymorphisms with variation in PK, 
PDx, safety or response parameters observed in 
patients treated with MEDI4736 and/or susceptibility 
to disease 
AE  Adverse event; BICR  Blinded Independent Central Review; EQ-5D-5L  EuroQoL 5 dimension, 5 level health state 
utility index; IFN  Interferon; IL  Interleukin; irRC  Immune-related response criteria; ORR Objective response rate; PD-L1  
Programmed death ligand 1; PDx  Pharmacodynamic(s); PFS  Progression free survival; PK  Pharmacokinetic(s); T-cell  T 
lymphocyte.   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
38(167) 
PD-L1 expression determined by immunohistochemistry will be reported in the Clinical Study 
Report (CSR).  Other exploratory biomarker and PGx research will be reported outside the 
CSR.  Data relating to the exploratory objectives of PRO and Health Related Quality of Life 
(HRQoL) will be reported in the CSR. 
3. 
STUDY PLAN AND PROCEDURES 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures. 
3.1 
Overall study design and flow chart 
This study is a Phase III, randomised, double-blind, placebo-controlled, multi-centre study 
assessing the efficacy and safety of MEDI4736 compared with placebo as sequential therapy 
in male and female patients with locally advanced, unresectable NSCLC (Stage III) who have 
not progressed following definitive, platinum-based, concurrent chemoradiation therapy. 
Approximately 880 patients with locally advanced, unresectable non-small cell lung cancer 
(NSCLC; Stage III) will be recruited and 702 patients randomised at 260 to 330 sites in 
Australia, Asia, Europe, North and South America and South Africa.  These patients will be in 
complete response (CR), PR, or have SD following definitive, platinum-based, concurrent 
chemoradiation therapy.   
Patients must have histologically- or cytologically-documented NSCLC who present with 
locally advanced, unresectable (Stage III) disease (according to Version 7 of the International 
Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology  
[IASLC Staging Manual in Thoracic Oncology]).   
Patients will be randomised in a 2:1 ratio (MEDI4736 to placebo) to 1 of 2 arms: 
x 
MEDI4736 (10 mg/kg Q2W iv for up to 12 months).   
x 
Placebo (matching placebo for infusion Q2W iv for up to 12 months).   
Randomisation will be stratified by: DJHDWUDQGRPLVDWLRQYHUVXV\HDUVRIDJHVH[
(male versus female), and smoking history (smoker versus non-smoker).  Patients must not 
have progressed following definitive, platinum-based, concurrent chemoradiation therapy; 
radiation therapy must be completed within 1 to 42 days prior to randomisation in the study 
(the last dose of radiation therapy is defined as the day of the last radiation treatment session).  
For patients who are recovering from toxicities associated with prior treatment, randomisation 
may be delayed by up to 42 days from the end of the chemoradiation therapy.  For those 
patients randomised to the placebo arm no cross-in to the MEDI4736 arm is permitted and 
similarly those patients randomised to the MEDI4736 arm no cross-in to the placebo arm is 
permitted. 




Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
40(167) 
approximately 36 months after the first patient is randomised), and the first OS interim 
analysis will be conducted at the same time (with approximately 285 events, 41% maturity).  
The third analysis DCO will occur at the time of the second OS interim analysis when it is 
expected that 393 OS events have occurred (56% maturity, approximately 47 months after the 
first patient is randomised).  The fourth analysis DCO will occur at the time of the primary OS 
analysis when it is expected that 491 OS events have occurred (70% maturity, at 
approximately 62 months).  Further analyses for that particular endpoint may occur based on 
the needs for long term follow-up with more mature data.  See Section 12.3 for further details. 
Sensitivity analyses will be performed on PFS and ORR using Investigator tumour data based 
on all scans upon RECIST 1.1 and site Investigator tumour data based on all scans upon 
RECIST 1.1 modified for confirmation of progression.  Exploratory analysis of PFS and ORR 
will also be performed for data obtained from the BICR on a subset 250 evaluable patients 
using irRC.  See Section 6.3 and Appendix F for further information regarding RECIST 
tumour assessments in this study.   
The study flow chart is presented in Figure 2.   
The schedule of study procedures at Screening and during the Treatment Period is presented 
in Table 1.  The schedule of study procedures during follow-up for patients who have 
completed the Treatment Period and achieved disease control (until confirmed PD) and 
patients who have discontinued study drug due to toxicity or a reason other than confirmed PD 
is presented in Table 2.  The schedule of study procedures during follow-up for patients who 
have discontinued study drug due to confirmed PD is presented in Table 3.  The schedule of 
study procedures for all patients during long-term follow up is presented in Table 11.   
Guidelines for the management of toxicities are described in Section 5.5.3.   
Details of the PGx component of the study (relating to DNA) are provided in Appendix D. 
End of Analysis Portion of Study 
Once the planned statistical analyses have been performed for both the primary analysis of 
PFS and OS endpoints of the study, data collection will be reduced.  Please refer to 
Section 9.5.1 for more information. 
 
Once the final DCO of the study for long-term follow-up has been reached, patients in OS and 
PFS follow-up will be considered to have completed the study.  At the time of the final DCO 
(anticipated to be approximately 5 years following the last patient randomised) any patient 
who is still in progression free follow up will have been progression free for approximately 
5 years following the start of their chemoradiation; as such, they will be considered cured and 
will no longer be considered eligible for re-treatment within this protocol.  Those patients who 
are still actively in re-treatment, and continuing to receive clinical benefit, will have the option 
to continue on study drug on an alternate rollover or extension study.  Please refer to 
Section 9.5.2 for more information. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
41(167) 
Independent Data Monitoring Committee 
An IDMC will be convened and will meet approximately 3 months after the study has started, 
or once 75 patients have been randomised whichever occurs first, to review safety assessments 
and make recommendations to continue, amend, or stop the study the study based on safety 
findings.  The first two efficacy analyses will also be assessed by the IDMC.  The committee 
will then meet again 3 months later and then at least every 6 months thereafter up to the 
decision to unblind the study.  All patients who receive a dose of study drug will be evaluated 
for safety and tolerability.  Enrolment will continue unless there is an unexpected safety 
concern.  The study may be adjusted or suspended depending on the IDMC review outcome.  
In addition, the IDMC will review the unblinded interim analysis summaries of efficacy data. 
Details on the IDMC are provided in Section 12.4 and full details of the IDMC procedures and 
processes can be found in the IDMC Charter. 




Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
43(167) 
d 
Patients with confirmed PD that continue to receive study drug at the discretion of the Investigator (following 
consultation with the sponsor) can receive study drug for a maximum of 12 months during the initial treatment period 
but for as long as the Investigator judges that they are gaining clinical benefit if they are a re-treatment patient.  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 
and re-treatment as specified in Section 4.3.  The same exceptions as noted in footnote b apply.  Patients will follow the 
assessments in Table 1 including tumour assessments every 8 weeks (relative to the date of randomisation) until study 
drug is stopped.  Patients who continue to receive re-treatment after the final 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 MEDI4736 in order to manage AEs in accordance with the MEDI4736 TMGs (refer to Section 5.5.3).  
Study drug should be discontinued if there is confirmed PD following a previous response (PR or CR) to study drug. 
e 
Patients with confirmed PD that discontinue study drug, should have scans conducted according to local standard 
clinical practice (see Section 6.2.2.2) that are submitted for BICR until the patient commences a new treatment (these 
scans are optional). 
Note: At final DCO for the study, patients who are receiving study drug can either choose to discontinue from the study or 
where the Investigator judges that patients are gaining clinical benefit, patients may continue to receive study drug.  For 
patients who do continue to receive study drug beyond the time of the final DCO, Investigators must continue to report all 
SAEs to AstraZeneca Patient Safety until 90 days after study drug is discontinued Any non-serious AEs occurring or ongoing 
after the time of this DCO are to be followed up at the Investigator’s discretion and per local standard of care. 
AE  Adverse event; BICR  Blinded Independent Central Review; CR  Complete response; DCO  Data cut-off; PD  
Progression of disease; PR  Partial response; RECIST  Response Evaluation Criteria In Solid Tumours; SAE  Serious adverse 
event; SD  Stable disease.   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
44(167) 
Table 1 
Schedule of study procedures: Screening and Treatment Period (up to 12 months, maximum of 26 doses, 
last infusion at Week 50) 
Visit   
(Assessments to be performed at the times stipulated 
and as clinically required in the management of the 
patient.) 
 
All assessments to be performed pre-infusion unless stated otherwise 
Screening 
Randomisation 
 
Every  
2 Weeks 
Every  
4 Weeks 
Every 
8 Weeks 
Day 
-42 to -1 
1 
15 
29 
43 
57 
Day 1 of the week 
Week 
-6 to -1 
0 
2 
4 
6 
8 
10, 12,  
14, 16 etc 
12, 16, 20,  
24, 28, etc  
16, 24, 32, 40  
and 48 
(±3 days) 
(±7 days) 
Written informed consent/assignment of patient 
identification number (Note: Patients are required to 
re-consent to continue study drug when treated 
through progression and to restart study drug 
following initial disease control [See Section 8.4]) 
X 
 
 
 
 
 
 
 
 
Verify eligibility criteria 
X 
X 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
Demography and history of tobacco and alcohol use 
X 
 
 
 
 
 
 
 
 
Patient questionnaires (patient reported outcomes) 
X 
X 
 
X 
 
X 
 
 
X 
Health resource use 
 
X 
 
X 
 
X 
 
X 
 
Medical and surgical history (including all treatments 
for NSCLC) 
X 
 
 
 
 
 
 
 
 
Hepatitis B and C; HIV 
X 
 
 
 
 
 
 
 
 
8ULQHK&*RUVHUXPȕK&* 
X 
X 
X 
X 
X 
X 
X 
 
 
Kit assignment and MEDI4736 or placebo 
administration 
 
X 
X 
X 
X 
X 
X 
(last dose 
Week 50) 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
 
X 
 
Vital signs (BP, pulse [pre- and post-infusion], 
respiratory rate, temperature and oxygen saturation; 
see Section 6.4.8) 
X 
X 
X 
X 
X 
X 
X 
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
45(167) 
Table 1 
Schedule of study procedures: Screening and Treatment Period (up to 12 months, maximum of 26 doses, 
last infusion at Week 50) 
Visit   
(Assessments to be performed at the times stipulated 
and as clinically required in the management of the 
patient.) 
 
All assessments to be performed pre-infusion unless stated otherwise 
Screening 
Randomisation 
 
Every  
2 Weeks 
Every  
4 Weeks 
Every 
8 Weeks 
Day 
-42 to -1 
1 
15 
29 
43 
57 
Day 1 of the week 
Week 
-6 to -1 
0 
2 
4 
6 
8 
10, 12,  
14, 16 etc 
12, 16, 20,  
24, 28, etc  
16, 24, 32, 40  
and 48 
(±3 days) 
(±7 days) 
Weight 
X 
X 
 
X 
 
X 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
Electrocardiograma 
X 
As clinically indicated 
Adverse event/serious adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
 
World Health Organization performance status 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum chemistryb 
X 
X 
X 
X 
X 
X 
X 
 
 
Amylase, lipase (where available)b 
X 
X 
 
X 
 
X 
 
X 
 
Thyroid function tests (TSH and T3 and T4) 
X 
X 
X 
X 
X 
X 
 
X 
 
Haematologyb 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysisc 
X 
X 
 
X 
 
X 
 
X 
 
Coagulation parametersd 
X 
 
 
 
 
 
 
 
 
PK assessmente  
 
X  
(pre and EOI) 
 
 
 
X (pre) 
 
 
X 
(only at Week 24 [pre 
and EOI] and at 
Week 48 [pre])) 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
46(167) 
Table 1 
Schedule of study procedures: Screening and Treatment Period (up to 12 months, maximum of 26 doses, 
last infusion at Week 50) 
Visit   
(Assessments to be performed at the times stipulated 
and as clinically required in the management of the 
patient.) 
 
All assessments to be performed pre-infusion unless stated otherwise 
Screening 
Randomisation 
 
Every  
2 Weeks 
Every  
4 Weeks 
Every 
8 Weeks 
Day 
-42 to -1 
1 
15 
29 
43 
57 
Day 1 of the week 
Week 
-6 to -1 
0 
2 
4 
6 
8 
10, 12,  
14, 16 etc 
12, 16, 20,  
24, 28, etc  
16, 24, 32, 40  
and 48 
(±3 days) 
(±7 days) 
Immunogenicity assessment (ADA sampling 
[including ADA neutralising antibodies] to identify 
ADA responses in patient circulation)e 
 
X 
(pre) 
 
 
 
X (pre) 
 
 
X 
(only at Week 24 
[pre] and at Week 48 
[pre]) 
sPD-L1 concentration (to assess target engagement)e 
 
X 
 
 
 
X (pre) 
 
 
X 
(only at Week 24 
[pre] and at Week 48 
[pre]) 
Circulating soluble factors (to assess cytokines, 
chemokines, growth factors and antibodies against 
tumour and self antigens in circulation) 
 
X 
 
X 
 
 
 
X 
(only at 
Week 12) 
 
miRNA/mRNA (to examine immune cell gene 
expression profiles in circulation) 
 
X 
 
 
 
X 
 
 
X  
(only at Week 48) 
Archival tumour tissue sample 
X 
 
 
 
 
 
 
 
 
Tumour biopsy (optional) (see Section 6.7) 
X 
 
  
 
 
 
 
 
 
PGx sample (optional [DNA element]) 
X 
 
 
 
 
 
 
 
 
Tumour assessment (CT or MRI)f,g,h 
X 
 
 
 
 
Xi 
 
 
X 
a 
Electrocardiograms are to be performed in triplicate at Screening.  ECGs should be performed at other time if clinically indicated.  Any clinically significant 
abnormalities detected require triplicate ECG results. 
b 
Results for urea and electrolytes, full blood count and liver function tests must be available before commencing an infusion.  If screening laboratory assessments are 
performed within 3 days prior to Day 1, they do not need to be repeated at Day 1. Gamma glutamyltransferase tested at Screening, Day 1 and as clinically indicated.  
Creatinine clearance, magnesium, amylase, lipase, and uric acid tested at Screening and every 4 weeks thereafter. 
c 
Urinalysis performed at Screening, Day 1, every 4 weeks and as clinically indicated.  


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
47(167) 
d 
Coagulation tests at Screening: prothrombin time, APTT and INR – only performed at Screening and as clinically indicated. 
e 
For ADA, sPD-L1: These assessments will be performed pre-infusion on Day 1, Week 8, Week 24 and Week 48. PK samples should be collected on Day 1, Week 8, 
Week 24 and Week 48. Only on Day 1 (randomisation visit) and at Week 24 before and after the infusion. At Week 8 and Week 48, only a pre-dose sample will be 
collected. Pre-dose samples can be taken within 60 minutes before infusion and the end-of-infusion samples within 10 minutes after the end of infusion. Circulating 
soluble factors assessment will be performed pre-infusion on Day 1, Week 4 and Week 12. For miRNA/mRNA the assessment will be performed pre-infusion on 
Day 1, Week 8 and Week 48. 
f 
RECIST assessments will be performed using CT/MRI assessments of the chest and abdomen (including liver and adrenal glands).  Additional anatomy should be imaged 
based on signs and symptoms of individual patients, including new lesions at follow-up.  The baseline assessment is part of the screening procedures and should be 
performed within 0 to 42 days after the end of chemoradiation therapy and no more than 28 days before the start of study drug.  For patients who are recovering from 
toxicities associated with prior treatment, randomisation may be delayed by up to 42 days from the end of the chemoradiation therapy.  Follow-up assessments will be 
performed every 8 weeks for the first 48 weeks (relative to the date of randomisation) while on treatment until confirmed objective disease progression per RECIST 1.1.  
The confirmatory scans should be performed to preferably occur at the next scheduled visit (relative to the date of randomisation) and no less than 4 weeks after the initial 
assessment of PD (in the absence of clinically significant deterioration).  If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits (relative to the date of randomisation).  All confirmatory scans should be databased.  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 and re-treatment as specified in Section 4.3.  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.    
g 
Patients who achieve and maintain disease control (ie, CR, PR, NED, or SD) through to the end of the 12-month treatment period may restart study drug upon evidence of 
PD (according to RECIST 1.1), with or without confirmation, during follow-up.  Before restarting study drug, the Investigator should ensure patients still meet all of the 
inclusion criteria and none of the exclusion criteria for this study including re-consenting to study drug.  To restart study drug the patient must not have received an 
intervening systemic anti-cancer therapy post study drug discontinuation.  Patients should have a baseline tumour assessment within 28 days of restarting study drug, all 
further scans should occur every 8 weeks (relative to the date of restarting study drug), or, if they receive re-treatment after the final DCO, patients 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 in order to manage AEs in accordance with the durvalumab TMGs 
(refer to Section 5.5.3). 
h 
Patients with confirmed PD who continue to receive study drug at the discretion of the Investigator (following consultation with the sponsor) can receive study drug for 
as long as the Investigator judges that they are gaining clinical benefit.  Patients will have scans every 8 weeks (relative to the date of randomisation) while on study drug, 
or, if they receive re-treatment after the final DCO, patients 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 in order to manage AEs in accordance with the durvalumab TMGs (refer to Section 5.5.3).  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.  Study drug should be discontinued if there is confirmed progression of disease (PD) following a 
previous response (PR or CR) to study drug.  
i 
At Week 8 the allowed window for the tumour assessment is ±7 days.  
Note: If a patient has a delay to an infusion of study drug all assessments should be conducted relative to the date of randomisation. 
Note: Patients should commence study drug as soon as possible after randomisation (ie, on the same day after randomisation in the IVRS system) and no later than 24 hours 
after randomisation. 
Note: For ‘re-treatment’ patients who go on to have a subsequent treatment prior to the final DCO, the same assessments should be done as in the first 12-month treatment 
period with the exception of  the PK, ADA, and sPD-L1 assessments which do not need to be collected a second time. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
48(167) 
ADA  Anti-drug antibody; APTT  Activated partial thromboplastin time; BP  Blood pressure; CT  Computed tomography; ECG  Electrocardiogram; EOI  End of infusion; hCG  
Human chorionic gonadotropin; HIV  Human immunodeficiency virus; INR  International normalised ratio; miRNA  Micro RNA; MRI  Magnetic resonance imaging; mRNA  
Messenger RNA; NED  No evidence of disease; NSCLC  Non-small cell lung cancer; PD  Progression of disease; PGx  Pharmacogenetic(s); PK  Pharmacokinetic(s); RECIST  
Response Evaluation Criteria In Solid Tumours; sPD-L1  Soluble programmed death ligand 1; T3  Triiodothyronine; T4  Thyroxine; TSH  Thyroid stimulating hormone.   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
49(167) 
Table 2 
Schedule of study procedures: follow-up for patients who have completed the treatment period for study 
drug and achieved disease control (until confirmed progression of disease) and patients who have 
discontinued study drug due to toxicity or a reason other than confirmed progression of disease 
Evaluation 
Time Since Last Dose of Study Drug 
Day (±3) 
Months (±1 week) 
12 Months and Every 6 Months 
Thereafter 
(±2 weeks)d 
30 
2 
3 
4 
6 
8 
10 
Patient questionnaires (patient reported 
outcomes) and health resource use 
For patients who achieve disease control following 12 months of treatment, patient questionnaires 
and information related to health resource use should be completed every 12 weeks relative to the date 
of randomisation until confirmed PD by RECIST 1.1 by investigational site review.   
For patients who discontinue study drug due to toxicity or a reason other than confirmed PD, 
patient questionnaires and information related to health resource use should be completed relative to the 
date of randomisation as follows: every 8 weeks for the first 48 weeks (per Table 1), then every 
12 weeks thereafter until confirmed PD by RECIST 1.1 by investigational site review.   
Physical examination 
X 
 
 
 
 
 
 
 
Vital signs (BP, pulse, respiratory rate, 
temperature, oxygen saturation; see 
Section 6.4.8) 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
AE/SAE assessment 
X 
X 
X 
 
 
 
 
 
Concomitant medications 
X 
 
 
 
 
 
 
 
World Health Organization performance statusa 
X 
Xa 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Subsequent anticancer therapy 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status: phone contact with patients who 
refuse to return for evaluations and agree to be 
contacted 
 
X 
X 
X 
X 
X 
X 
X (every 2 months) 
Haematology 
X 
X 
X 
X 
 
 
 
X 
Serum chemistry  
X 
X 
X 
 
 
 
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
50(167) 
Table 2 
Schedule of study procedures: follow-up for patients who have completed the treatment period for study 
drug and achieved disease control (until confirmed progression of disease) and patients who have 
discontinued study drug due to toxicity or a reason other than confirmed progression of disease 
Evaluation 
Time Since Last Dose of Study Drug 
Day (±3) 
Months (±1 week) 
12 Months and Every 6 Months 
Thereafter 
(±2 weeks)d 
30 
2 
3 
4 
6 
8 
10 
Amylase, lipase (where available) 
X 
X 
X 
 
 
 
 
 
Thyroid function tests (TSH, and T3 and T4)  
X 
 
 
 
 
 
 
 
Coagulation parametersb 
As clinically indicated   
Urinalysis 
As clinically indicated   
Pharmacokinetic assessment  
 
 
X 
 
 
 
 
 
Immunogenicity assessment (ADA sampling 
[including ADA neutralising antibodies] to 
identify ADA responses in patient circulation) 
 
 
X 
 
X 
 
 
 
sPD-L1 concentration (to assess target 
engagement) 
 
 
X 
 
 
 
 
 
Circulating soluble factors (to assess cytokines, 
chemokines, growth factors and antibodies 
against tumour and self antigens in circulation) 
X 
 
 
 
X 
 
 
 
miRNA/mRNA (to examine immune cell gene 
expression profiles in circulation) 
X 
 
 
 
 
 
 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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Table 2 
Schedule of study procedures: follow-up for patients who have completed the treatment period for study 
drug and achieved disease control (until confirmed progression of disease) and patients who have 
discontinued study drug due to toxicity or a reason other than confirmed progression of disease 
Evaluation 
Time Since Last Dose of Study Drug 
Day (±3) 
Months (±1 week) 
12 Months and Every 6 Months 
Thereafter 
(±2 weeks)d 
30 
2 
3 
4 
6 
8 
10 
Tumour assessment (CT or MRI)c 
For patients who achieve disease control following 12 months of treatment, tumour assessments 
should be performed every 12 weeks relative to the date of randomisation until confirmed PD by 
RECIST 1.1 by investigational site review.  Please refer to Table 1 for timings of confirmatory scans.   
For patients who discontinue study drug due to toxicity or a reason other than confirmed PD, 
tumour assessments should be performed relative to the date of randomisation as follows: every 
8 weeks for the first 48 weeks (per Table 1), then every 12 weeks thereafter until confirmed PD by 
RECIST 1.1 by investigational site review.  Please refer to Table 1 for timings of confirmatory scans.   
Upon confirmed PD, scans should be conducted according to local standard clinical practice and 
submitted for central review until a new treatment is started (these scans are optional).  
a 
World Health Organization performance status should also be collected at other site visits that the patient attends, if appropriate site staff are available to collect such 
information.  In addition, please provide World Health Organization performance status when information on subsequent anticancer therapy is provided, where possible. 
b 
Coagulation tests: prothrombin time, APTT and INR will be performed if clinically indicated. 
c 
RECIST assessments will be performed using CT/MRI assessments of the chest and abdomen (including liver and adrenal glands).  Additional anatomy should be imaged 
based on signs and symptoms of individual patients, including new lesions at follow-up.  Following the final DCO for the study, patients continuing on the study who 
remain potentially eligible for future durvalumab re-treatment should receive tumour assessment scans and other assessments as per local clinical practice, but in such 
way that will allow confirmation of re-treatment eligibility criteria per Section 4.3.  See Table 11 for tumour assessments done following approval of CSP Amendment 7. 
d 
Patients on survival follow-up at the time of final DCO for the study will be considered to have completed the study and will continue to receive treatment per local 
standard of care.  
. 
ADA  Anti-drug antibody; AE  Adverse event; APTT  Activated partial thromboplastin time; BP  Blood pressure; CT  Computed tomography; INR  International normalised 
ratio; miRNA  Micro RNA; MRI  Magnetic resonance imaging; mRNA  Messenger RNA; PD  Progression of disease; RECIST  Response Evaluation Criteria In Solid 
Tumours; SAE  Serious adverse event; sPD-L1  Soluble programmed death ligand 1; T3  Triiodothyronine; T4  Thyroxine; TSH  Thyroid stimulating hormone. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
52(167) 
Table 3 
Schedule of study procedures: follow-up for patients who have discontinued study drug due to confirmed 
progression of disease  
Evaluation 
Time Since Last Dose of Study Drug 
Day (±3) 
Months (±1 week) 
12 Months and Every 6 Months  
Thereafter 
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Patient questionnaires (patient reported outcomes) and 
the health resource use  
For patients who continue on study drug post confirmed progression at the Investigator’s 
discretion (following consultation with the sponsor), patient questionnaires and information related 
to health resource use should be completed relative to the date of randomisation per Table 1 until 
study drug is stopped. 
For patients who discontinue study drug following confirmed progression, patient questionnaires 
and information related to health resource use should be completed at the Day 30 assessment only. 
Physical examination 
X 
 
 
 
 
 
 
 
Vital signs (BP, pulse, respiratory rate, temperature, 
oxygen saturation; see Section 6.4.8) 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
AE/SAE assessment 
X 
X 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
 
 
 
 
 
World Health Organization performance statusa 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Subsequent anticancer therapy 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status: phone contact with patients who refuse 
to return for evaluations and agree to be contacted 
 
X 
X 
X 
X 
X 
X 
X (every 2 months) 
Haematology 
X 
X 
X 
 
 
 
 
 
Serum chemistry  
X 
X 
X 
 
 
 
 
 
Amylase, lipase (where available) 
X 
X 
X 
 
 
 
 
 
Thyroid function tests (TSH, and T3 and T4) 
X 
 
 
 
 
 
 
 
Coagulation parametersb 
As clinically indicated   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
53(167) 
Table 3 
Schedule of study procedures: follow-up for patients who have discontinued study drug due to confirmed 
progression of disease  
Evaluation 
Time Since Last Dose of Study Drug 
Day (±3) 
Months (±1 week) 
12 Months and Every 6 Months  
Thereafter 
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Urinalysis 
As clinically indicated   
Pharmacokinetic assessment  
 
 
X 
 
 
 
 
 
Immunogenicity assessment (ADA sampling 
[including ADA neutralising antibodies] to identify 
ADA responses in patient circulation) 
 
 
X 
 
 
 
 
 
sPD-L1 concentration (to assess target engagement) 
 
 
X 
 
 
 
 
 
Circulating soluble factors (to assess cytokines, 
chemokines, growth factors and antibodies against 
tumour and self antigens in circulation) 
X 
 
 
 
 
 
 
 
miRNA/mRNA (to examine immune cell gene 
expression profiles in circulation) 
X 
 
 
 
 
 
 
 
Tumour biopsy (optional)  
An optional tumour biopsy upon evidence of PD should be performed according to institutional 
practice.  It is accepted that any biopsy procedure should be technically feasible and not associated 
with unacceptable clinical risk (see Section 6.7) 
Time to second progressionc 
For patients who continue on study drug post confirmed progression at the Investigator’s 
discretion (following consultation with the sponsor), tumour assessments should be performed 
relative to the date of randomisation per Table 1 until study drug is stopped. 
Patients who discontinue study drug following confirmed progression, will be assessed every 
12 weeks for a second progression (using the patient’s status at first progression as the reference for 
assessment of second progression).  A patient’s progression status is defined according to local 
standard clinical practice and may involve any of: objective radiological, symptomatic progression 
or death.   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
54(167) 
Table 3 
Schedule of study procedures: follow-up for patients who have discontinued study drug due to confirmed 
progression of disease  
Evaluation 
Time Since Last Dose of Study Drug 
Day (±3) 
Months (±1 week) 
12 Months and Every 6 Months  
Thereafter 
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Tumour assessment (CT or MRI)c 
For patients who continue on study drug after confirmed progression at the Investigator’s 
discretion (following consultation with the sponsor), tumour assessments should be performed 
relative to the date of randomisation per Table 1 until study drug is stopped. 
For patients who discontinue study drug following confirmed progression, scans should be 
conducted according to local clinical practice and submitted for central review until a new 
treatment is started (these scans are optional).   
a 
World Health Organization performance status should also be collected at other site visits that the patient attends, if appropriate site staff are available to collect such 
information.  In addition, please provide World Health Organization performance status when information on subsequent anti-cancer therapy is provided, where possible. 
b 
Coagulation tests: prothrombin time, APTT and INR will be performed if clinically indicated. 
c 
Study drug should be discontinued if there is confirmed progression of disease (PD) following a previous response (PR or CR) to study drug. 
ADA  Anti-drug antibody; AE  Adverse event; APTT  Activated partial thromboplastin time; BP  Blood pressure; CT  Computed tomography; INR  International normalised 
ratio; miRNA  Micro RNA; MRI  Magnetic resonance imaging; mRNA  Messenger RNA; PD  Progression of disease; SAE  Serious adverse event; sPD-L1  Soluble 
programmed death ligand 1; T3  Triiodothyronine; T4  Thyroxine; TSH  Thyroid stimulating hormone. 
 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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3.2 
Rationale for study design, doses and control groups 
3.2.1 
Unmet need and potential role of immunotherapies in NSCLC 
For patients with unresectable Stage IIIA or Stage IIIB disease combined modality therapy 
(chemoradiation) is superior to radiation alone and cCTRT is superior to sequential therapy 
(NCCN Guidelines 2014).  Concurrent chemoradiation regimens that may be used for all 
histologies for initial treatment include cisplatin/etoposide or cisplatin/vinblastine.  For 
non-squamous NSCLC other cCTRT regimens include cisplatin/pemetrexed  
(NCCN Guidelines 2014). 
However, the majority of patients inevitably progress (PFS is usually short; approximately 
8 months) and 5-year OS is approximately 15% (Butts et al 2014).  There is still therefore a 
significant unmet medical need for additional treatment options for use in this patient 
population to improve on OS and PFS (see Section 1.1.1).   
Whilst advances have been made in improving survival from Stage III NSCLC by optimising 
local control, evidence suggests that cCTRT does not reduce the risk of distant relapse.  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.  A pooled analysis of 41 Phase II/III trials confirmed that there remains 
no evidence to suggest that consolidation chemotherapy after cCTRT improves survival for 
patients with Stage III NSCLC and current guidelines continue to recommend cCTRT alone 
for the treatment of inoperable Stage III NSCLC (Bayman et al 2014).  Given the lack of 
persuasive evidence for an active comparator, the use of a placebo comparator is justified in 
the proposed sequential/consolidation setting in this study. 
The sequential/consolidation setting post-cCTRT may be ideal to evaluate the efficacy of 
immunotherapy, which is aimed at boosting the ability of the patient immune system to 
eliminate cancer cells.  Chemoradiotherapy often induces initial tumour shrinkage followed by 
eventual PD as the tumours find mechanisms to bypass the chemoradiotherapy-induced 
growth inhibition.  The initial tumour shrinkage observed in some patients following 
chemoradiotherapy is the result of cell death and tumour damage.  
Chemoradiotherapy-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.  
Therefore, triggering or augmenting an antigenic antitumour response with 
chemoradiotherapy 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 antitumour activity by improving local control and 
decreasing systemic spread. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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3.2.2 
Potential role for MEDI4736 in the treatment of NSCLC 
Currently available data from the MEDI4736 FTIH study (Section 1.1.5 and MEDI4736 IB), 
indicates encouraging response rates and DoR, with a manageable safety profile in patients 
with a variety of solid malignancies, including patients with NSCLC.  These are advanced 
patients who have failed multiple lines of therapy.  These emerging data, along with non-
clinical and clinical data around combining an immune-modulator with chemotherapy and 
radiotherapy support the proposed investigation of sequential MEDI4736 in a controlled Phase 
III setting following cCTRT in patients with unresectable Stage IIIA or IIIB NSCLC.  
Updated safety and efficacy data from this FTIH study (CD ON MEDI4736 1108) was 
presented at international oncology conferences (Rizvi et al 2015).   
3.2.3 
Study design rationale 
 
Timing of treatment with MEDI4736 relative to concurrent chemoradiation 
therapy 
Non-clinical data shows that both chemotherapy and ionising radiation up-regulate PD-L1 
expression (Deng et al 2014, Zhang et al 2008b). 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 MEDI4736 as close as possible to the completion of 
the cCTRT when antigen release and PD-L1 expression is most likely to be at its maximum 
will hopefully result in the most optimal benefit. 
 
Dose justification 
Based on an analysis of the dose-escalation data from the ongoing FTIH study, a dose of 
10 mg/kg Q2W administered for up to a maximum of 12 months is recommended for further 
development.  This dosing regimen is expected to provide a level of PD-L1 inhibition that is 
predicted to result in a high probability of clinical response in the majority of patients.   
This recommendation is supported by multiple lines of evidence including: in-vitro data, 
nonclinical activity, clinical PK-PDx, clinical biomarkers, and clinical activity data collected 
from the FTIH study.  Based on the FTIH data, MEDI4736 exhibited non-linear 
(dose-dependent) PK consistent with target mediated drug disposition.  A dose-dependent 
decrease in peripheral soluble PD-L1 was observed over the dose range of 0.1 to 10 mg/kg 
Q2W; consistent with engagement of MEDI4736 with PD-L1.  Significant soluble PD-L1 
!VXSSUHVVLRQDWWURXJKZDVREVHUYHGZLWKGRVHVPJNJ4:3.SDUDPHWHUV
such as dose-normalised area under the drug concentration-time curve and t½ increased over 
the dose range of 0.1 to 10 mg/kg Q2W and approached linearity at 3 mg/kg Q2W; suggesting 
near complete target saturation (membrane bound and soluble PD-L1) with 3 mg/kg Q2W. 
The expected mean trough concentration following 3 mg/kg Q2W MEDI4736 is ~50 μg/mL.  
Although clinical activity has been observed at lower doses, and DLTs have not been 
observed at the highest dose studied (10 mg/kg Q2W), this dose/schedule is anticipated to 
maintain levels above a target median trough concentration (100 μg/mL).  The target trough 
serum concentration of 100 μg/mL accounts for the variability in PK (~50%), PDx response 
and clinical activity (up to 100%) anticipated in a diverse cancer patient population and to 
maintain sufficient PK exposure in case of an ADA impact.  The target serum concentration of 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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100 μg/mL can be maintained with the 10 mg/kg Q2W dosing regimen.  Data generated 
during the dose escalation phase of the FTIH study also suggest that higher doses (ie, 
10 mg/kg Q2W) may be associated with better clinical activity while still providing an 
acceptable safety profile.  Dose-related changes in a variety of peripheral biomarkers have 
been observed over the dose range of 0.1 to 3 mg/kg Q2W.  Thus far, a low level of 
immunogenicity has been observed.  Screening for ADA has detected 4 positive samples from 
3 patients out of a total of 86 samples from 19 patients, with evidence for an impact on PK 
and target suppression in 1 individual.  Thus, the clinical activity observed coupled with the 
safety profile, translational science correlates, and non-clinical data supports further 
development with a dose of 10 mg/kg Q2W.  
 
Predictive biomarkers and rationale for an unselected population in Study 
D4191C00001 
For this study, we propose not to restrict enrolment to any biomarker defined sub-population 
but where possible to carefully assess these patient characteristics in the context of this study, 
and other studies. 
Tumour biopsies and viable tissue may be difficult to obtain post cCTRT.  Tumours evolve 
with time and in response to treatment, and PD-L1 expression is likely to be different, 
post-cCTRT.  In addition, non-clinical data shows that both chemotherapy and ionising 
radiation up-regulate PD-L1 expression (Deng et al 2014, Zhang et al 2008b).  Therefore, 
PD-L1 expression from a biopsy sample prior to cCTRT may not accurately reflect the state of 
disease at the time the patient enrols in this study and is randomised to either MEDI4736 or 
placebo.  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, we propose not to restrict inclusion in this study based on PD-L1 
expression from any tissue samples available.  If it is feasible, biopsies will be taken 
post-CTRT and upon disease progression after randomisation to MEDI4736 or placebo.  If 
possible based on the number and viability of the samples collected we will retrospectively 
assess 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 3 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 at the American Society of Clinical Oncology (ASCO) conference 2013 
(Powderly et al 2013) suggests that PD-L1 expression on infiltrating lymphocytes in NSCLC, 
melanoma, and renal cell carcinoma patient cohorts is associated with greater clinical benefit 
from anti-PD-L1 treatment.  Using a proprietary assay for PD-L1 immunohistochemistry, they 
found a 36% ORR in PD-L1-positive patients with 50% of patients who were PD-L1-positive 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
58(167) 
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 at ASCO 2013 by Bristol-Myers Squibb (Grosso et al 2013) 
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).  They 
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 than PD-L1 negative (21 months versus 12 months).  
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 trials and may not 
permit us to distinguish between prognostic factors or predictive markers for response to 
PD-L1 and PD-L1 therapies.   
In conclusion, in this study biopsies immediately prior to randomisation to MEDI4736 or 
placebo and post-cCTRT will be difficult to obtain, in addition, biopsy material obtained prior 
to cCTRT may not accurately reflect PD-L1 status post-cCTRT as non-clinical data shows 
that both radiation and chemotherapy up-regulate PD-L1 expression.  Therefore, we propose 
not to restrict enrolment to any biomarker defined sub population. 
 
Rationale for study endpoints (efficacy) 
The primary aim of this study is to determine the efficacy of MEDI4736 (10 mg/kg Q2W via 
iv infusion) compared with placebo in terms of OS and PFS.  Progression free survival may 
serve as a surrogate endpoint for OS when differences between treatment groups are of 
sufficient magnitude and clinically important (FDA Guidance 2011, Pazdur 2008).  In certain 
settings, 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 in second- and third-line squamous NSCLC.  It is 
anticipated that these agents may be approved or become available for use through 
expanded-access mechanisms or additional clinical studies while this study is ongoing.  This 
poses challenges in being able to fully characterize effects on OS if patients subsequently 
receive these immunotherapeutic agents.  However, given that tumour response to 
immunotherapy may differ from typical responses, both PFS and OS are co-primary endpoints 
with the study powered for OS.   
Antitumour activity will be assessed according to RECIST v1.1 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/progressive disease (see Section 6.3).  The co-primary analysis of PFS will be 
based on programmatically derived PFS based upon BICR assessments.  Sensitivity analyses 
will also be performed using data from site Investigators tumour data from all scans based 


Revised Clinical Study Protocol 
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Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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upon RECIST 1.1 and site Investigator tumour data from all scans based upon RECIST 1.1 
modified for confirmation of progression.Exploratory analysis will also be performed for 
data obtained from the BICR on a subset of 250 evaluable patients scans using irRC.   
This is because the response to immunotherapy may differ from typical responses observed 
with cytotoxic chemotherapy including the following (per Wolchok et al 2009): 
1. 
Response to immunotherapy may be delayed 
2. 
Response to immunotherapy may occur after PD by conventional criteria 
3. 
SD while on immunotherapy may be durable and represent clinical benefit. 
To account for these differences, RECIST will be modified so that PD must be confirmed at 
the next scheduled visit, preferably, and no earlier than 4 weeks after the initial assessment of 
PD in the absence of clinically significant deterioration.  Administration of study drug will 
continue between the initial assessment of progression and confirmation for progression.   
In addition, patients may continue to receive study drug beyond confirmed PD in the absence 
of clinically significant deterioration and if Investigators consider that patients continue to 
receive benefit from treatment.  Modification of RECIST as described may discourage the 
early discontinuation of study drug and provide a more complete evaluation of its antitumour 
activity than would be seen with conventional response criteria.  Nonetheless, the efficacy 
analysis will be conducted by programmatically deriving each efficacy endpoint based on 
RECIST 1.1 criteria. 
Of note, clinically significant deterioration is considered to be a rapid tumour progression that 
necessitates treatment with anti-cancer therapy other than MEDI4736 or with symptomatic 
progression that requires urgent medical intervention (eg, central nervous system metastasis, 
respiratory failure due to tumour compression, spinal cord compression). 
 
Rationale for study endpoints (other exploratory endpoints) 
Biological samples will be used to explore potential biomarkers in tumour, plasma and/or 
serum, which may influence the progression of cancer (and associated clinical characteristics) 
and/or response. 
Blood samples will be taken to allow for future exploratory research into genes/genetic factors 
that may influence response of MEDI4736 and/or agents used in combination and/or as 
comparators (PGx optional [DNA element]).   
The assessment of health economic resource use data and derivation of health state utility will 
provide important information for payers and will be used within economic evaluations of 
MEDI4736. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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Rationale for re-treatment beyond 12 months 
Justification for re-treatment beyond 12 months of MEDI4736: 
x 
Targeted therapies have significantly increased both the rate and durability of 
response in patients with biomarker-enriched subsets of cancers including advanced 
NSCLC (eg, gefitinib and erlotinib in EGFR mutation positive, and crizotinib in 
ALK translocation positive) as well as in metastatic or unresectable melanoma 
(vemurafenib and dabrafenib in BRAF V600E mutation, trametinib in both V600E 
and V600K) (Maemondo et al 2010, Mok et al 2009, Mitsudomi et al 2010,  
Rosell et al 2011, Shaw et al 2013).  Nevertheless, responses are mostly partial, and 
relapses are inevitable once resistance mechanisms emerge.  Furthermore, the 
potential for tumour “addiction” and rapid clinical deterioration at the time of 
withdrawal and/or progression has been described (Asami et al 2013,  
Yoshimura et al 2013, Kim et al 2011, Yang et al 2013, Rizos et al 2014). 
x 
In contrast to targeted therapy, responses have been observed upon re-treatment 
with immune-mediated therapy.  Responses with immune-mediated therapy are no 
different than responses to initial treatment in terms of time to response, duration of 
response, or maintenance of response beyond treatment discontinuation  
(Hodi et al 2010, Forde et al 2014). 
Therefore, patients who achieve and maintain disease control (ie, CR, PR or SD) through to 
the end of the 12-month study drug treatment period may also re-start treatment with study 
drug upon evidence of disease progression during follow-up.  
The patient must not have received an intervening systemic anti-cancer therapy after 
discontinuing study drug and should have a baseline tumour assessment within 28 days of 
re-starting treatment with study drug (see Table 11). 


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Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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4. 
PATIENT SELECTION CRITERIA 
The patient population should be selected without bias. 
Investigator(s) should keep a record, the patient screening log, of patients who entered 
pre-study screening. 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule. 
4.1 
Inclusion criteria 
For inclusion in the study patients should fulfil the following criteria: 
1. 
Provision of signed, written and dated informed consent prior to any study specific 
procedures 
2. 
Male or female aged 18 years or older 
3. 
Patients must have histologically- or cytologically-documented NSCLC who 
present with locally advanced, unresectable (Stage III) disease (according to 
Version 7 of the International Association for the Study of Lung Cancer Staging 
Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology]), 
AND  
4. 
Patients must have received at least 2 cycles of platinum-based chemotherapy 
concurrent with radiation therapy, which must be completed within 1 to 42 days 
prior to first dose of investigational product in the study.  For patients who are 
recovering from toxicities associated with prior treatment, first dose of 
investigational product may be delayed by up to 42 days from the end of the 
chemoradiation therapy.   
Sites are strongly encouraged to complete screening within the first 14 days of the 
42-day screening period. 
x 
The platinum-based chemotherapy regimen must contain one of the following 
agents: etoposide, vinblastine, vinorelbine, a taxane (paclitaxel or docetaxel), or 
pemetrexed, according to the local standard of care regimens. 
x 
The final chemotherapy cycle must end prior to, or concurrently with, the final dose 
of radiation.  Consolidation chemotherapy after radiation is not permitted but 
administration of chemotherapy prior to concurrent chemoradiation is acceptable. 
x 
Where possible, chemotherapy regimens should be given according to National 
Comprehensive Cancer Network (NCCN) Guidelines or European Society for 
Medical Oncology (ESMO) Guidelines. 


Revised Clinical Study Protocol 
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Study Code D4191C00001 
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Date 04 September 2019 
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x 
Patients must have received a total dose of radiation of 60 Gy ±10% (54 Gy to 
66 Gy) to be randomised as part of the chemoradiation therapy.  Sites are 
encouraged to adhere to mean organ radiation dosing as follows: 
 
Mean lung dose must be <20 Gy and/or V20 must be <35% 
 
Mean eosophagus dose must be <34 Gy 
 
Heart V45 <35% or V30 <30%. 
x 
Sites should be aware of the recent RTOG 0617 Trial data demonstrating that doses 
higher than 60 Gy may be associated with greater toxicity and worse efficacy. 
5. 
Patients must have not progressed following definitive, platinum-based, concurrent 
chemoradiation therapy.   
6. 
Tumour sample requirements: 
x 
Provision of an archived tumour tissue block (or at least 10 newly cut unstained 
slides) where such samples exist in a quantity sufficient to allow for analysis (refer 
to Section 6.7.1 and the Laboratory Manual for details) 
x 
A recent (3 months) tumour biopsy (taken following completion of the most recent 
therapy) is an optional requirement, provided that a biopsy procedure is technically 
feasible and the procedure is not associated with unacceptable clinical risk   
7. 
/LIHH[SHFWDQF\ZHHNVat Day 1 
8. 
World Health Organization (WHO) Performance Status of 0 or 1  
9. 
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 are amenorrheic for 12 months without an alternative medical cause.  The 
following age-specific requirements apply:  
x 
Women <50 years old would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and with luteinizing hormone and follicle-stimulating hormone levels in 
the post-menopausal range for the institution 
x 
Women  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, radiation-induced oophorectomy with last menses >1 year ago, 
chemotherapy-induced menopause with >1 year interval since last menses, or 
surgical sterilisation (bilateral oophorectomy or hysterectomy).   


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10. 
Adequate organ and marrow function as defined below:  
x 
Absolute neutrophil count >1.5 x 109/L (1500 per mm3) 
x 
Platelets >100 x 109/L (100,000 per mm3) 
x 
Haemoglobin 9.0 g/dL (5.59 mmol/L) 
x 
Serum creatinine CL >40 mL/min by the Cockcroft-Gault formula  
(Cockcroft and Gault 1976) or by 24-hour urine collection for determination of 
creatinine clearance: 
Males: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age) 
72 x serum creatinine (mg/dL) 
Females: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age) 
x 0.85 
72 x serum creatinine (mg/dL) 
 
x 
6HUXPELOLUXELQ[XSSHUOLPLWRIQRUPDO8/17KLVZLOOQRWDSSO\WRSDWLHQWV
with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinaemia that 
is predominantly unconjugated in the absence of evidence of haemolysis or hepatic 
pathology) who will be allowed in consultation with their physician. 
x 
AST and AL7[8/1. 
Genetics research study (optional) 
For inclusion in the optional (DNA) genetics research study patients must fulfil the following 
criteria: 
x 
Provide informed consent for the genetic sampling and analyses. 
If a patient declines to participate in the genetics research, there will be no penalty or loss of 
benefit to the patient.  A patient who declines genetics research participation will not be 
excluded from any other aspect of the main study. 
4.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca/MedImmune staff and/or staff at the study site). 
2. 
Either: 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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x Previous drug assignment in the present study 
or 
x Prior randomisation or treatment in a previous durvalumab (MEDI4736) and/or 
tremelimumab clinical study regardless of treatment arm assignment 
3. 
Participation in another clinical study with an investigational product during the last 
4 weeks. 
4. 
Concurrent enrolment in another clinical study, unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional 
study. 
5. 
Mixed small cell and non-small cell lung cancer histology. 
6. 
Patients who receive sequential chemoradiation therapy for locally advanced 
NSCLC. 
7. 
Patients with locally advanced NSCLC who have progressed whilst definitive 
platinum based, concurrent chemoradiation therapy. 
8. 
Receipt of any immunotherapy, or investigational drug within 4 weeks prior to the 
first dose of study drug; and in the case of monoclonal antibodies 6 weeks prior to 
the first dose of study drug. 
9. 
Current or prior use of immunosuppressive medication within 28 days before the 
first dose of study drug, with the exceptions of intranasal and inhaled 
corticosteroids or systemic corticosteroids at physiological doses, which are not to 
exceed 10 mg/day of prednisone, or an equivalent corticosteroid.  Systemic steroid 
administration required as prophylaxis against or to manage toxicities arising from 
chemotherapy and/or radiotherapy delivered as part of the chemoradiation therapy 
for locally advanced NSCLC is allowed. 
10. 
Prior exposure to any anti-PD-1 or anti-PD-L1 antibody. 
11. 
Any unresolved toxicity CTCAE >Grade 2 from the prior chemoradiation therapy.  
Patients with irreversible toxicity that is not reasonably expected to be exacerbated 
by study drug may be included (eg, hearing loss) after consultation with the 
AstraZeneca/MedImmune medical monitor.   
12. 
Patients with grade 2 pneumonitis from prior chemoradiation therapy. 
13. 
$Q\SULRU*UDGHLPPXQH-related adverse event (irAE) while receiving any 
previous immunotherapy agent, or any unresolved irAE >Grade 1. 


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Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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14. 
Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for 
cancer treatment.   
15. 
Recent major surgery within 4 weeks prior to entry into the study (excluding the 
placement of vascular access) that would prevent administration of study drug. 
16. 
Active or prior documented autoimmune disease within the past 2 years.  
NOTE: Patients with vitiligo, Grave’s disease, or psoriasis not requiring systemic 
treatment (within the past 2 years) are not excluded. 
17. 
Active or prior documented inflammatory bowel disease (eg, Crohn’s disease, 
ulcerative colitis). 
18. 
History of primary immunodeficiency. 
19. 
History of allogeneic organ transplant. 
20. 
History of hypersensitivity to MEDI4736 or any excipient. 
21. 
Mean QT LQWHUYDOFRUUHFWHGIRUKHDUWUDWH47FPVFDOFXODWHGIURP
3 electrocardiograms (ECGs) using Bazett’s Correction. 
22. 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active 
bleeding diatheses including any patient known to have evidence of acute or chronic 
hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric 
illness/social situations that would limit compliance with study requirements or 
compromise the ability of the patient to give written informed consent. 
23. 
Active infection of tuberculosis, as determined by clinical signs and symptoms. 
24. 
Receipt of live attenuated vaccination within 30 days prior to study entry or within 
30 days of receiving study drug. 
25. 
History of another primary malignancy except for: 
x 
Malignancy treated ZLWKFXUDWLYHLQWHQWDQGZLWKQRNQRZQDFWLYHGLVHDVH years 
before the first dose of study drug and of low potential risk for recurrence 
x 
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence 
of disease 
x 
Adequately treated carcinoma in situ without evidence of disease eg, cervical cancer 
in situ. 


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Drug Substance Durvalumab (MEDI4736)  
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Edition Number 01.1 
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26. 
Female patients who are pregnant, breast-feeding or male or female patients of 
reproductive potential who are not employing an effective method of birth control. 
27. 
Any condition that, in the opinion of the Investigator, would interfere with 
evaluation of the study drug or interpretation of patient safety or study results. 
Genetics research study (optional) 
Exclusion criteria for participation in the optional (DNA) genetics research component of the 
study: 
x 
Previous allogeneic bone marrow transplant 
x 
Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection. 
Procedures for withdrawal of incorrectly enrolled patients are provided in Section 5.3. 
4.3 
Criteria for treatment through progression of disease and re-
treatment 
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 for continuing study drug.   
For all patients who completed the first 12-month period of treatment with study drug and had 
CR, PR or SD at completion, re-treatment during follow up would be offered on the basis of a 
patient having objective RECIST 1.1 disease progression with or without confirmation.   
For all patients who are treated through progression, or patients who achieve disease control 
[ie, CR, PR, or SD] at 12 months and restart treatment upon evidence of PD during follow-up, 
the Investigator should ensure patients do not have any significant, unacceptable or 
irreversible toxicities that indicate continuing or restarting treatment would not further benefit 
the patient. In addition, the Investigator should ensure patients meet the following inclusion 
criteria (criteria number from Section 4.1): 
x 
The patient must provide signed, written and dated re-treatment or treatment 
through progression informed consent (criterion 1).  These consent documents will 
specify that treatment beyond initial evidence of PD or re-treatment upon 
progression during follow up is not the standard of care and that alternative 
treatment options, either locally licensed treatments or other clinical trials, are 
available for this patient population.  
x 
Meet serum creatinine CL >40 mL/min by the Cockcroft-Gault formula (or by 
24-hour urine collection as defined by the formula in protocol inclusion 
criterion 10) and the criterion for AST/ALT.   


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Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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The patient should not enter re-treatment if any of the following exclusion criteria are 
fulfilled: 
x 
Concurrent enrolment in another clinical study, unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional study 
(criterion 4) 
x 
Current or prior use of immunosuppressive medication within 28 days before the 
first dose of study drug, with the exceptions of intranasal and inhaled 
corticosteroids or systemic corticosteroids at physiological doses, which are not to 
exceed 10 mg/day of prednisone, or an equivalent corticosteroid (criterion 9) 
x 
Any unresolved toxicity CTCAE >Grade 2 from previous anti-cancer therapy.  
Patients with irreversible toxicity that is not reasonably expected to be exacerbated 
by the investigational product may be included (eg, hearing loss) after consultation 
with the AstraZeneca/MedImmune study physician (criterion 11)   
x 
$Q\SULRU*UDGHLU$(ZKLOHpreviously receiving study treatment, or any 
unresolved irAE >Grade 1 (criterion 13) 
x 
Be currently receiving, or have received in the interim period after stopping study 
drug, any chemotherapy, immunotherapy, biologic or hormonal therapy for cancer 
treatment.  Note: Local treatment of isolated lesions, excluding target lesions, for 
palliative intent is acceptable (eg, by local surgery or radiotherapy) (drawn from 
criterion 14)  
x 
Recent major surgery within 4 weeks prior to dosing (excluding the placement of 
vascular access) that would prevent administration of investigational product 
(criterion 15) 
x 
Active or prior documented autoimmune disease within the past 2 years (patients 
with vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment within 
the past 2 years are not excluded) (criterion 16) 
x 
Active or prior documented inflammatory bowel disease (eg, Crohn’s disease, 
ulcerative colitis) (criterion 17) 
x 
History of primary immunodeficiency (criterion 18) 
x 
History of allogeneic organ transplant (criterion 19) 
x 
History of hypersensitivity to MEDI4736 or any excipient (criterion 20) 
x 
0HDQ47LQWHUYDOFRUUHFWHGIRUKHDUWUDWH47FPVFDOFXODWHGIURP
3 electrocardiograms (ECGs) using Bazett’s Correction (criterion 21) 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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x 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active 
bleeding diatheses including any patient known to have evidence of acute or chronic 
hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric 
illness/social situations that would limit compliance with study requirements or 
compromise the ability of the patient to give written informed consent (criterion 22) 
x 
Active infection of tuberculosis, as determined by clinical signs and symptoms 
(criterion 23) 
x 
Receipt of live attenuated vaccination within 30 days prior to dosing or within 
30 days of receiving study drug (criterion 24) 
x 
Female patients who are pregnant, breast-feeding or male or female patients of 
reproductive potential who are not employing an effective method of birth control 
(criterion 26) 
x 
Any condition that, in the opinion of the Investigator, would interfere with 
evaluation of the investigational product or interpretation of patient safety or study 
results (criterion 27). 
At the time of the final DCO for the primary analyses of PFS and OS, study patients 
randomised to the durvalumab arm who have not progressed and who meet the above 
eligibility criteria will remain in the study.  At the time the patient progresses, and re-
treatment with durvalumab is felt to be their best treatment option, then at the time of re-
treatment they must meet the above eligibility criteria.  Patients’ eligibility should be recorded 
in their medical records.  Re-treatment will not be available within this protocol following the 
final DCO for the long-term follow-up phase of the study (CSP amendment 7).     
Study drug should be discontinued if there is confirmed PD while on treatment following a 
previous response (PR or CR) to study drug while on treatment (ie, the response and 
progression events both occurred while receiving study drug during the same treatment 
period). 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
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5. 
STUDY CONDUCT 
5.1 
Restrictions during the study 
1. 
Females of childbearing potential who are sexually active with a nonsterilised male 
partner must use 2 methods of effective contraception from screening, and must 
agree to continue using such precautions for 90 days after the final dose of study 
drug; cessation of birth control after this point should be discussed with a 
responsible physician.  Periodic abstinence, the rhythm method, and the withdrawal 
method are not acceptable methods of birth control. 
 
Females of childbearing potential are defined as those who are not surgically 
sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete 
hysterectomy) or post-menopausal (defined as 12 months with no menses 
without an alternative medical cause). 
 
Patients must use 2 acceptable methods of effective contraception as described 
in Table 4. 
2. 
Nonsterilised males who are sexually active with a female partner of childbearing 
potential must use 2 acceptable methods of effective contraception (see Table 4) 
from Day 1 and for 90 days after receipt of the final dose of study drug. 
Table 4 
Effective methods of contraception (two methods must be used) 
Barrier Methods 
Intrauterine Device Methods 
Hormonal Methods 
Male condom plus spermicide 
Copper T 
Implants 
Cap plus spermicide 
Progesterone Ta 
Hormone shot or injection 
Diaphragm plus spermicide 
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®)a 
Combined pill 
Minipill 
Patch 
a 
This is also considered a hormonal method. 
 
3. 
Patients should not donate blood whilst participating in this study. 
Restrictions relating to concomitant medications are described in Section 5.6. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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5.2 
Patient enrolment and randomisation 
At Visit 1 (Screening), the Principal Investigator, or suitably trained delegate, will: 
1. 
Obtain signed informed consent (main study) from the potential patient before any 
study specific procedures are performed.  Procedures that are part of standard of 
care may occur before informed consent is obtained. 
2. 
Assign potential patient a unique 7-digit enrolment number, beginning with ‘E#’.  
This is obtained through the Interactive Voice Response System (IVRS)/Interactive 
Web Response System (IWRS) (ECCNN08X:  CC being the country code. NN 
being the centre number, 08X being the patient enrolment code at the centre).  
Enrolment codes will start at 001 in each centre and go up sequentially (eg, at 
Centre 01, patients will be assigned E codes E0101001, E0101002, etc).  This 
number is the patient’s unique identifier and is used to identify the patient on the 
electronic case report forms (eCRFs). 
3. 
Determine patient eligibility. See Sections 4.1 and 4.2. 
At Visit 2 (Randomisation/Baseline), once the patient is confirmed to be eligible, the Principal 
Investigator, or suitably trained delegate, will: 
4. 
Call IVRS/IWRS to assign the eligible patient a unique randomisation code (patient 
number).  Randomisation codes will start at 001 and will be assigned strictly 
sequentially by IVRS/IWRS, as patients are eligible for randomisation.   
Patients may be enrolled but not randomised.  If the patient is not randomised, the 
IVRS/IWRS should be contacted to terminate the patient in the system. 
The IVRS/IWRS will also be used to track drug supply. 
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused and they cannot re-enter into the study. 
5.2.1 
Procedures for randomisation 
Patients must not be randomised unless all eligibility criteria have been met.   
At Visit 2, patients who satisfy all the entry criteria will be centrally assigned to study drug by 
the IVRS/IWRS, according to the randomisation scheme generated by the Biostatistics Group, 
AstraZeneca, or delegate.   
Patients will be randomised in a 2:1 ratio to either MEDI4736 (10 mg/kg) or placebo.  Patients 
will be stratified at randomisation based on their: age at randomisation (<65 years versus 
 years of age), sex (male versus female), and smoking history (smoker versus 
non-smoker). 


Revised Clinical Study Protocol 
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Study Code D4191C00001 
Edition Number 01.1 
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The actual study drug given to patients will be determined by the randomisation scheme in the 
IVRS/IWRS.  The randomisation scheme will be produced by a computer software program 
called GRand (AstraZeneca Global Randomisation system) that incorporates a standard 
procedure for generating randomisation numbers.  One randomisation list will be produced for 
each of the randomisation strata.  A blocked randomisation will be generated and all centres 
will use the same list in order to minimise any imbalance in the number of patients assigned to 
each treatment arm. 
Patients will be identified to the Centralised Randomisation Centre per country regulations.  
Randomisation codes will be assigned strictly sequentially, within each stratum, as patients 
become eligible for randomisation.  The IVRS/IWRS Centralised Randomisation Centre will 
inform the unblinded pharmacist of the kit identification number to be allocated to the patient 
at the randomisation visit. 
Every effort should be made to minimise the time between randomisation and starting study 
drug.  It is recommended that patients commence study drug as soon as possible after 
randomisation (ie, on the same day after randomisation in the IVRS system). 
The Investigator will call/log in to the IVRS/IWRS for each subsequent dispensing visit for 
assignment of a new kit identification number.  The kit identification number dispensed at 
each visit will correspond to the study drug to which the patient was originally randomised.  
If a patient discontinues participation in the study, then their enrolment/randomisation code 
cannot be reused. 
The IVRS/IWRS may not be available after the final DCO for the study.  In this case a manual 
process will need to be followed. 
5.3 
Procedures for handling patients incorrectly enrolled or 
randomised or initiated on study drug 
Patients who fail to meet the inclusion/exclusion criteria should not, under any 
circumstances, be enrolled or receive study medication.  There can be no exceptions to this 
rule. 
Where patients that do not meet the inclusion and/or exclusion criteria, are enrolled in error, 
are randomised in error, or are incorrectly started on study drug, or where patients 
subsequently fail to meet the study criteria post initiation, a discussion must occur between the 
IQVIA’ Physician and the Investigator regarding the patient’s safety and well-being and 
whether to continue or discontinue the patient from study drug.   
The IQVIA Physician is to ensure all such contacts are appropriately documented.  In 
situations where an agreement cannot be reached, the patient should have their study drug 
stopped, then be followed up where possible as per Section 5.8.1.  Those patients randomised 
in error should remain in the study and be followed for PFS and OS where possible. 


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Edition Number 01.1 
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5.4 
Blinding and procedures for unblinding the study  
5.4.1 
Methods for ensuring blinding 
The study will be conducted in a double-blind manner.  The reconstituted MEDI4736 solution 
and its matching placebo will be identical in colour and the iv bags used for administration 
will be identical with regards to size.  All study drug will be blinded using an opaque sleeve, 
fastened with tamper-evident tape over the iv bag prior to dispensing to other study personnel 
to maintain the double-blind conditions.   
The patient, the Investigator and study centre staff will be blinded to study drug allocation.  
The study centre pharmacist will be unblinded to study drug and will prepare MEDI4736 or 
placebo for a patient as specified by the randomisation scheme and IVRS (only the unblinded 
pharmacist will know the randomisation/treatment allocation details).  Pharmacists will be 
given specific instructions for study drug preparation and will note if the double-blind 
conditions have been compromised or the blind broken.  Lot numbers of MEDI4736 
dispensed will be recorded by the pharmacist and monitored by an unblinded monitor.  Other 
study centre staff and monitors will not be given access to lot number information.   
No member of the extended study team at AstraZeneca/MedImmune, at the investigational 
centres, or any Contract Research Organisation handling data will have access to the 
randomisation scheme until the time of the final data analysis.  Exceptions are relevant 
persons within the Pharmaceutical Development Supply Chain at AstraZeneca/MedImmune or 
their designee, where the information is needed to package study drug, the drug safety 
departments at AstraZeneca/MedImmune, and pharmacists required to dispense the study drug 
at the study site.  Investigators will only be unblinded to treatment allocation in cases of 
medical emergency.   
The treatment codes and results will be kept strictly within AstraZeneca/MedImmune to 
safeguard the integrity of the blind, and hence to minimize any possible bias in data handling. 
The IDMC will be provided with unblinded data for their review but 
AstraZeneca/MedImmune and IQVIA staff and Investigators involved in the study will remain 
blinded. 
5.4.2 
Methods for unblinding the study 
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the Investigator(s) or pharmacists at the study centre from the 
IVRS/IWRS.  Routines for this will be described in the IVRS/IWRS user manual that will be 
provided to each centre.   
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation.  The 
Investigator documents and reports the action to AstraZeneca/MedImmune, without revealing 
the treatment given to a patient to the AstraZeneca/MedImmune staff.There is no known 
antidote to MEDI4736, and IQVIA/the Medical Monitor should be contacted with any 


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concerns.  Hence, overdose will not normally be considered a reason for breaking the blind.  If 
the treatment code is broken then the Investigator(s) must document and report to 
AstraZeneca/MedImmune. 
AstraZeneca/MedImmune retains the right to break the code for SAEs that are unexpected and 
are suspected to be causally related to an investigational product and that potentially require 
expedited reporting to regulatory authorities.  Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
patient have been made and documented.  If the blind is broken, the date, time and reason will 
be recorded in IVRS, and any associated AE report.  If a patient’s study drug is unblinded by 
the Investigator, or designee, the patient will be withdrawn from study drug as described in 
Section 5.8. 
For the BICR, blinded data will be provided. 
5.5 
Treatments 
5.5.1 
Identity of investigational product(s) 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply 
MEDI4736 to the Investigator as a lyophilised powder for reconstitution.  The saline solution 
for the matching placebo will be sourced locally. 
Investigational 
product 
Dosage form and strength 
Manufacturer 
MEDI4736 
Supplied as a lyophilised powder containing 200 mg 
MEDI4736.  When reconstituted with 4.0 mL of 
water for injection, the solution contains 50 mg/mL 
MEDI4736, 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose 
dihydrate, 0.02% (weight/volume) polysorbate 80, at 
pH 6.0 
AstraZeneca/MedImmune 
Placebo 
Matching placebo for injection; saline solution 
To be sourced locally 
 
 
Product preparation of MEDI4736 
The dose of investigational product for administration must be prepared by the Investigator’s 
or site’s designated investigational product manager using aseptic technique.  Commercially 
available water for injection and 0.9% (weight/volume) saline will be supplied by each site.  
Total in-use storage time from reconstitution of MEDI4736 to the start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2 to 8°C (36 to 46°F).  If the 
in-use storage time exceeds these limits, a new dose must be prepared from new vials.  
MEDI4736 does not contain preservatives and any unused portion must be discarded.  


Revised Clinical Study Protocol 
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Edition Number 01.1 
Date 04 September 2019 
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Reconstitution of investigational product 
MEDI4736 requires reconstitution prior to use.  The reconstitution should be performed with 
4.0 mL sterile water for injection for each vial with the liquid added gently to the side of the 
vial to minimize product foaming.  The vial should be gently rotated or swirled for 5 minutes 
or until dissolution is complete.  The vial should not be shaken or vigorously agitated.  
Reconstituted MEDI4736 should stand undisturbed at room temperature for a minimum of 
5 minutes or until the solution clarifies.  The reconstituted solution should appear clear or 
slightly opalescent.  A thin layer of bubbles on the liquid surface is considered normal. 
Preparation of MEDI4736 doses for administration with an iv bag 
Doses of 10 mg/kg will be administered using an iv bag containing 0.9% (weight/volume) 
saline, with a final MEDI4736 concentration ranging from 1 to 20 mg/ml, and delivered 
through an iv administration set with a 0.2-ȝPor 0.22-ȝPin-line filter.   
Patient weight at baseline should be used for dosing calculaWLRQVXQOHVVWKHUHLVD
change in weight.  Dosing day weight can be used for dosing calculations instead of baseline 
weight per institutional standard.  An additional volume of 0.9% (weight/volume) saline equal 
to the calculated volume of MEDI4736 to be added to the iv bag must be removed from the 
bag prior to addition of MEDI4736.  The calculated volume of MEDI4736 is then added to the 
iv bag, and the bag is mixed by gentle inversion to ensure homogeneity of the dose in the bag.   
No incompatibilities between MEDI4736 and polyethylene, polypropylene, polyvinylchloride, 
or polyolefin copolymers have been observed.   
Dose calculation 
The volume of reconstituted MEDI4736 (mL) to add to the iv bag is calculated as follows: 
10 mg/kg × Patient Weight (kg) ÷ MEDI4736 concentration (nominal 50 mg/mL) 
Example: For a patient weighing 80 kg, dosed at 10 mg/kg, 16 mL [10 mg/kg × 80 kg divided 
by 50 mg/mL] of MEDI4736 is to be diluted in an iv bag containing 0.9% (weight/volume) 
saline.  First, 16 mL of saline is removed from the iv bag, and then 16 mL of MEDI4736 is 
added to the bag.  The bag is mixed by gentle inversion to ensure homogeneity of the dose in 
the bag and the diluted MEDI4736 is administered as described above. 
5.5.2 
Doses and treatment regimens 
Patients enrolled in the study will receive either MEDI4736 10 mg/kg or placebo via iv 
infusion Q2W ±3 days.  Administration of study drug will commence on Day 1 following 
randomisation to MEDI4736 or placebo after confirmation of eligibility and will continue on a 
Q2W schedule for a maximum duration of 12 months (see Table 1).  Study drug should be 
discontinued prior to 12 months if there is confirmed PD (unless the Investigator considers the 
patient continues to receive benefit from study drug), initiation of alternative cancer therapy, 
unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study drug occur.   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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Disease progression requires confirmation.  In the absence of clinically significant 
deterioration the investigational site is advised to continue the patient on study drug until 
progression has been confirmed. 
If progression is not confirmed, then the patient should continue on study drug and on 
treatment assessments. 
Patients who achieve and maintain disease control (CR, PR, NED or SD) through to the end of 
the 12-month treatment period will enter follow-up per Table 2.  Upon evidence of PD 
(according to RECIST 1.1), with or without confirmation, during follow-up after completion 
of 12 months of treatment, patients may restart study drug for as long as the Investigator 
judges that they are gaining clinical benefit with the same treatment guidelines followed 
during the initial 12-month treatment period (Table 1).  Patients will only be able to restart 
study drug once.   
Patients who have a dose interruption due to toxicity at any point in the first 12 months of 
treatment may resume and complete the 12-month treatment period. 
Patients who have confirmed PD during the 12-month initial treatment period, or after 
restarting study drug, and cannot continue to receive study drug will enter follow-up with 
assessments as shown in Table 3. 
Patients with confirmed PD that continue to receive study drug at the discretion of the 
Investigator (following consultation with the sponsor) can receive study drug for a maximum 
of 12 months in the initial treatment period but for as long as the Investigator judges that they 
are gaining clinical benefit in the re-treatment period (and will follow the assessments in 
Table 1 including tumour assessments).   
Study drug should be discontinued if there is confirmed progression of disease (PD) following 
a previous response (PR or CR) to study drug. 
For all patients who receive study drug through disease progression and patients who achieve 
disease control and restart study drug upon evidence of PD (according to RECIST 1.1) during 
follow-up, 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 meet the inclusion and exclusion criteria specified in Section 4.3.  The 
patient informed consent documents will specify that treatment beyond initial evidence of PD 
or re-treatment for progression during follow up is not the standard of care and that alternative 
treatment options, either locally licensed treatments or other clinical trials, are available for 
this patient population.  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.    


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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Study drug administration 
Following preparation of MEDI4736 (see Section 5.5.1.1) or matched placebo, the entire 
contents of the iv bag should be administered as an iv infusion over approximately 60 minutes 
(±5 minutes), using a 0.2-ȝPor 0.22-ȝP in-line filter.  The iv line will be flushed with a 
volume of normal saline equal to the priming volume of the infusion set used after the 
contents of the iv bag are fully administered, or complete the infusion according to 
institutional policy to ensure the full dose is administered and document if the line was not 
flushed.  Since the compatibility of MEDI4736 with other iv medications and solutions, other 
than normal saline (0.9% [weight/volume] sodium chloride for injection), is not known, the 
solution should not be infused through an iv line in which other solutions or medications are 
being administered.  The date, start time, interruption, and completion time of study drug 
administration must be recorded in the source documents. 
Monitoring of dose administration 
Patients will be monitored during and after the infusion with assessment of vital signs at the 
times specified in Section 6.4.8. 
,QWKHHYHQWRID*UDGH 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 
RIWKHLQLWLDOUDWHXQWLOFRPSOHWLRQRIWKHLQIXVLRQ)RUSDWLHQWVZLWKD*UDGH
infusion-related reaction, subsequent infusions may be administered at 50% of the initial rate.  
Acetaminophen and/or an antihistamine (eg, diphenhydramine) or equivalent medications per 
institutional standard may be administered at the discretion of the Investigator.  If the 
infusion-UHODWHGUHDFWLRQLV*UDGHRUKLJKHULQVHYHULW\study drug will be discontinued. 
As with any antibody, allergic reactions to dose administration are possible.  Appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study personnel must be trained to recognise and treat anaphylaxis.  The study 
site must have immediate access to emergency resuscitation teams and equipment in addition 
to the ability to admit patients to an intensive care unit if necessary. 
5.5.3 
Management of toxicity 
The following general guidance should be followed for management of toxicities. 
1. 
Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity where required). 
2. 
If the symptoms promptly resolve with supportive care, consideration should be 
given to continuing study drug along with appropriate continuing supportive care.  
If medically appropriate, dose modifications are permitted (see below). 
3. 
All dose modifications should be documented with clear reasoning and 
documentation of the approach taken. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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Guidelines for the management of immune-mediated reactions, infusion-related reactions, and 
non-immune-mediated reactions for durvalumab monotherapy are provided in the Dosing 
Modification and Toxicity Management Guidelines (TMGs).   
The most current version of the TMGs is also available through the following link: 
https://tmg.azirae.com.  In addition a version of the current TMGs is maintained within the 
Site Master File.  Please contact your clinical trial associate for information on how to gain 
access to this website.  
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the immune-mediated 
adverse event (imAE).  Serologic, immunologic, and histologic (biopsy) data, as appropriate, 
should be used to support an imAE diagnosis.  In the absence of a clear alternative etiology, 
events should be considered potentially immune related. 
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued (see Section 5.8 of this protocol and the TMGs). 
These guidelines have been prepared by the Sponsor to assist the Investigator in the exercise 
of his/her clinical judgment in treating these types of toxicities.  These guidelines apply to 
AEs considered causally related to the study drug/study regimen by the reporting Investigator 
Following the first infusion of study drug, subsequent administration of study drug can be 
modified based on toxicities observed as described in the TMGs.  All toxicities will be graded 
according to CTCAE Version 4.03.   
Dose reductions are not permitted.  In case of doubt, the Investigator should consult with 
the Study Physician. 
Dose modifications will not be required for AEs that are clearly not attributed to study drug 
(such as an accident) or for laboratory abnormalities that are not deemed to be clinically 
significant.  Dosing may continue despite concurrent vitiligo of any AE grade. 
 
MEDI4736 adverse events of special interest 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring 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 investigational product.  
Unless they meet SAE criteria, AESIs will not be recorded during the Extension Study. 
The AESIs for 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 MEDI4736 monotherapy 
and combination therapy.  An AESI is defined as an adverse event that is associated with drug 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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exposure and is consistent with an immune-mediated mechanism of action and where there is 
no clear alternate aetiology.  Serologic, immunologic, and histologic (biopsy) data, as 
appropriate, should be used to support an irAE diagnosis.  Appropriate efforts should be made 
to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the irAE.  
If the Investigator has any questions in regards to an AE being an irAE, the Investigator 
should promptly contact the Study Physician. 
AESIs observed with MEDI4736 include: 
x Diarrhoea / colitis and intestinal perforation 
x Pneumonitis / interstitial lung disease 
x hepatitis / transaminase increases 
x Endocrinopathy (ie, events of hypophysitis / hypopituitarism, adrenal insufficiency, 
hyper- and hypothyroidism and type I diabetes mellitus) 
x Rash / dermatitis 
x Nephritis / blood creatinine increases 
x Pancreatitis / serum lipase and amylase increases 
x Myocarditis 
x Myositis / polymyositis   
x Neuropathy / neuromuscular toxicity (eg, Guillain-Barré, and myasthenia gravis) 
x Other inflammatory responses that are rare / less frequent with a potential immune-
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and 
other events involving the eye, skin, haematological and rheumatological events. 
 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological aetiology are also considered AESIs. 
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the MEDI4736 IB.  More specific guidelines for their evaluation and treatment are 
described in detail in the TMGs (refer to Section 5.5.3).    
Pneumonitis 
Pneumonitis has been reported in association with use of anti-PD-L1/anti-PD-1 antibodies 
(Brahmer et al 2012).  It is also seen in 5% to 15% of patients irradiated for breast, lung, and 
mediastinal tumours.  The risk of developing radiation pneumonitis is directly related to the 
volume of irradiated lung, the amount of radiation given, and the use of concurrent 
chemotherapy.  Additional risk factors include co-morbid lung disease, poor baseline 
pulmonary function testing, and low performance status. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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Radiation pneumonitis 
Symptoms of radiation pneumonitis, including low-grade fever, congestion, dry cough, 
pleuritic chest pain, and a sensation of chest fullness, usually develop 1 to 3 months after 
completion of radiation therapy.  Diagnosis is difficult, often complicated by co-morbid 
conditions and radiation injury to adjacent structures (eg, oesophagus, pericardium).  
Prednisone, in dosages of at least 50 to 60 mg per day for 1 week followed by an extended 
taper, has been shown to abate symptoms and improve lung function.  Bronchodilators and 
supplemental oxygen may be necessary. 
More specific guidelines for the evaluation and treatment of pneumonitis are described in 
detail in the TMGs. 
5.5.4 
Additional study drug 
No additional study drug is required in this study.   
5.5.5 
Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling.  Label 
text will be translated into local language. 
The label will include the following information: 
x 
Name of sponsor (AstraZeneca) 
x 
Study drug dosage form, route of administration, and quantity of dosage units 
x 
Storage conditions 
x 
Study code 
x 
Enrolment code  
x 
Directions for use 
x 
The name of the Principal Investigator, where applicable (this may be pre-printed or 
added on the label when the study drug is dispensed) 
x 
The period of use eg, expiry date. 
x 
Product Lot Identifier 
x 
Medication Identity Number 
x 
For clinical study use only. 
Labels will be provided as either a single panel label or as multi-language booklet labels. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
80(167) 
5.5.6 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions and may 
only be dispensed by a pharmacist or a qualified designee.  The investigational product label 
on the kit specifies the appropriate storage.  MEDI4736 must be stored at 2°C to 8°C.  
5.6 
Concomitant and post-study treatment(s) 
Investigators may prescribe concomitant medications or treatments (eg, acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care 
except for those medications identified as “excluded” as listed below: 
x 
Any investigational anticancer therapy 
x 
Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic, or hormonal 
therapy for cancer treatment.  Concurrent use of hormones for non-cancer-related 
conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable.  
NOTE: Local treatment of isolated lesions, excluding target lesions, for palliative 
intent is acceptable (eg, by local surgery or radiotherapy). 
x 
Immunosuppressive medications including, but not limited to systemic 
corticosteroids at doses beyond 10 mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and tumour necrosis factor alpha blockers.  Use of 
immunosuppressive medications in patients for the management of study 
drug-related AEs or their use in patients with contrast allergies is acceptable.  In 
addition, use of inhaled and intranasal corticosteroids is permitted. 
x 
Live attenuated vaccines within 30 days of dosing.  Inactivated viruses such as 
those in the influenza vaccine are permitted. 
Other medication, which is considered necessary for the patient’s safety and well-being, may 
be given at the discretion of the Investigator and recorded in the appropriate sections of the 
eCRF. 
5.7 
Treatment compliance 
Treatment compliance will be assured by site reconciliation of medication dispensed. 
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the eCRF.  The Investigator or pharmacy must retain records of 
all study drugs administered.  The study monitor will check these records to confirm the 
compliance with the protocol administration schedule.  Administration of durvalumab as 
re-treatment following the final DCO for the study will be recorded in site documents for the 
purpose of supply management but will not otherwise be reported. 
Use of investigational product in doses in excess of that specified in the protocol is considered 
to be an overdose.  Refer to Section 13.2 for procedures in case of overdose.   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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5.7.1 
Accountability 
The study drug provided for this study will be used only as directed in the study protocol. 
The study personnel will account for all study drugs dispensed to and returned from the 
patient.   
Study site personnel will account for all study drugs received at the site, unused study drugs 
and for appropriate destruction.  Certificates of delivery and destruction should be signed. 
5.8 
Discontinuation of investigational product 
Patients may be discontinued from investigational product in the following situations: 
x 
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment. 
x 
Adverse Event, that in the opinion of the Investigator or the sponsor, 
contraindicates further dosing 
x 
Severe non-compliance to study protocol that, in the opinion of the Investigator or 
sponsor, warrants withdrawal; eg, refusal to adhere to scheduled visits 
x 
Patient is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing study drug might constitute a safety risk  
x 
Any AE that meets criteria for discontinuation, as defined in Section 5.5.3  
x 
An AE related to study drug WKDWLV*UDGHZLWKWKHH[FHSWLRQRIWR[LFLWLHVWKDt 
do not meet criteria for discontinuation as defined Section 5.5.3   
x 
*UDGHLQIXVLRQUHDFWLRQ 
x 
Initiation of alternative anticancer therapy including another investigational agent 
x 
Confirmed PD and Investigator determination that the patient is no longer 
benefiting from treatment 
x 
Pregnancy or intent to become pregnant. 
If the patient is discontinued from study drug, the scheduled study visits, data collection and 
procedures should continue according to this study protocol until study closure.  Alternatively, 
if the patient does not agree to this option, a modified follow-up through eg, regular telephone 
contacts or a contact at study closure should be arranged, if agreed to by the patient and in 
compliance with local data privacy laws/practices.  See Section 5.8.1. 
Following final DCO for the study, SAEs occurring in patients on treatment or in the 90 day 
follow up period after the last dose of durvalumab must be reported directly to AstraZeneca 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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Global Patient Safety as described in Section 6.4.4.  Other AEs should be managed according 
to the durvalumab TMGs (refer to Section 5.5.3), and will be followed up per the 
Investigators’ judgment but will not otherwise be reported or recorded for the purposes of this 
study.  Following the final DCO for the study, Investigators who intend to commence or 
continue re-treatment with durvalumab should continue to monitor patients’ safety laboratory 
assessments so as to ensure that no laboratory abnormalities or AEs that could potentially 
result in IP discontinuation are overlooked.  All data will be recorded into the patients’ charts 
but will not be otherwise documented for the purposes of this study. 
Withdrawal of consent for PGx and biological sampling is included in Section 7.5. 
5.8.1 
Procedures for discontinuation of a patient from investigational product  
Patients who are permanently discontinued from further receipt of study drug, regardless of 
the reason (withdrawal of consent, due to an AE, other), will be identified as having 
permanently discontinued study drug.   
A patient that decides to discontinue investigational product will always be asked about the 
reason(s) for discontinuation and the presence of any AEs.  If possible, they will be seen and 
assessed by an Investigator(s).  Adverse events will be followed up (See Sections 6.4.3 and 
6.4.4), and questionnaires returned by the patient. 
If a patient is withdrawn from the study, see Section 5.9. 
Assessments following withdrawal of study drug 
Patients who are permanently discontinued from receiving study drug will remain in the study 
and will be followed per the study plans in Table 2 or Table 3 including the collection of any 
protocol-specified blood specimens and completion of questionnaires and case report forms 
(CRFs) relating to PRO and hospital resource use, unless consent is withdrawn or the patient 
is lost to follow-up or enrolled in another clinical study.  All patients will be followed for 
survival up to the time of final DCO for the study, at which time, unless they remain eligible 
for re-treatment with durvalumab, they will be considered to have completed the study.  
Re-treatment will not be an available treatment option within this protocol following the final 
DCO for the long-term follow up phase of the study (CSP amendment 7).  Patients who 
decline to return to the site for evaluations will be offered follow-up by phone as specified in 
the study plans as an alternative (Table 2 [for follow-up of patients achieving disease control 
or who are discontinued due to toxicity or a reason other than confirmed PD] and Table 3 [for 
follow-up of patients discontinuing due to confirmed PD]).  However, patients who 
discontinue due to an AE will need to attend all protocol-specified visits and all assessments 
will be conducted as scheduled.   
All patients who have any Grade 3 or 4 laboratory values at the time of discontinuation must 
have further tests performed and the results recorded on the appropriate eCRF until the 
laboratory values have returned to Grade 1 or 2, unless these values are not likely to improve 
because of the underlying disease.   


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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At discontinuation, all on-going study-related toxicities and SAEs must be followed until 
resolution, unless in the Investigator’s opinion, the condition is unlikely to resolve due to the 
patient’s underlying disease. 
All new AEs occurring for up to 90 days after the last dose of study drug must be recorded in 
the eCRF and reported as SAEs, if applicable.   
Patients who have disease control following completion of 12 months of treatment or patients 
who are withdrawn from study drug for reasons other than confirmed PD will continue to have 
objective tumour assessments (see Table 2).   
Drug or study procedure related SAEs must be captured until the patient completes the 
follow-up period following discontinuation of study drug (due to confirmed PD) or is 
permanently withdrawn from the study (see Section 5.9). 
When confirmed PD has been documented, the long-term follow-up information for survival 
should be collected per Table 3 (for patients discontinuing due to confirmed PD) (by 
telephone contact with the patient, patient’s family, or by contact with the patient’s current 
physician.  An exception is any patient with confirmed PD that continues to receive study 
drug at the discretion of the Investigator (following consultation with the sponsor), who can 
receive study drug for a maximum of 12 months during the initial treatment period or for as 
long as the Investigator judges that they are gaining clinical benefit in the re-treatment period 
and will follow the assessments in Table 1 including tumour assessments until study drug is 
discontinued (the patient must re-consent to be treated through disease progression [see 
Section 8.4]). 
Study drug should be discontinued if there is confirmed progression of disease (PD) following 
a previous response (PR or CR) to study drug. 
Both the patient and the physician will be asked about the subsequent treatment the patient 
receives during the follow-up period (Table 2 [for follow-up of patients achieving disease 
control or who are discontinued due to toxicity or a reason other than confirmed PD] and 
Table 3 [for follow-up of patients discontinuing due to confirmed PD]). 
5.9 
Withdrawal from study 
Patients may be discontinued from the study in the following situations: 
x 
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment  
x 
Severe non-compliance to study protocol that, in the opinion of the Investigator or 
sponsor, warrants withdrawal; eg, refusal to adhere to scheduled visits 
x 
Patient lost to follow-up 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
84(167) 
Patients are at any time free to withdraw from study (investigational product and 
assessments), without prejudice to further treatment (withdrawal of consent).  Such patients 
will always be asked about the reason(s) and the presence of any AEs.  If possible, they will 
be seen and assessed by an Investigator.  Adverse events will be followed up (see 
Sections 6.4.3 and 6.4.4); and questionnaires and all study drugs should be returned by the 
patient. 
If consent is withdrawn, the patient will not receive any further study drug or further study 
observation.  The patient will be specifically asked if they are withdrawing consent to:  
x 
Further participation in the study including any further follow-up (eg, survival calls)  
x 
Withdrawal of consent to the use of their study generated data 
x 
Withdrawal to the use of any samples (see Section 7.5). 
Note that the patient may be offered additional tests or tapering of treatment to withdrawal for 
safety, and will be offered follow-up by phone as specified in the study plans as an alternative 
(Table 2 [for follow-up of patients achieving disease control or who are discontinued due to 
toxicity or a reason other than confirmed PD] and Table 3 [for follow-up of patients 
discontinuing due to confirmed PD]).  If a patient wishes to withdraw their consent to further 
participation in the study, including survival follow-up (by phone) this should be clearly 
documented in the patient notes and in the clinical study database.    
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed such that there is insufficient information to determine the 
patient’s status at that time. 
Note: Patients who refuse to continue participation in the study, including phone contact, 
should be documented as “withdrawal of consent” rather than “lost to follow-up.”  
Investigators should document attempts to re-establish contact with missing patients 
throughout the study period.  If contact with a missing patient is re-established, the patient 
should not be considered lost to follow-up and any evaluations should resume according to the 
protocol. 
Withdrawn patients will not be replaced.  
Vital status (ie, whether a patient is dead or alive), based on public available sources, will be 
investigated at the scheduled study end. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
85(167) 
6. 
COLLECTION OF STUDY VARIABLES 
The schedule for assessments at Screening and during the Treatment Period is presented in 
Table 1.  The schedule of study procedures during follow-up for patients who have completed 
study drug and achieved disease control (until confirmed PD) and patients who have 
discontinued study drug due to toxicity or a reason other than confirmed PD is presented in 
Table 2.  The schedule of study procedures during follow-up for patients who have 
discontinued study drug due to confirmed PD is presented in Table 3.  Following final DCO 
for the study, no further study data will be captured except for SAEs (in the AstraZeneca 
Global Patient Safety database) for patients whilst the patient is either still receiving 
durvalumab (ie, re-treatment patients) or is in the 90-day safety follow-up period after 
receiving the last dose of durvalumab.  Investigators with patients in progression follow-up 
who may become eligible for re-treatment are to conduct scans/RECIST per local practice and 
safety laboratory assessments in such a way that alignment with per-protocol re-treatment 
eligibility criteria can be properly determined.  From the date CSP amendment 7 is 
implemented, assessment schedule in Table 11 is to be followed. 
6.1 
Recording of data 
The InForm Web Based Data Capture (WBDC) system will be used for data collection and 
query handling until the point of final DCO and database lock for the study.  The Investigator 
will ensure that data are recorded on the eCRFs as specified in the study protocol and in 
accordance with the instructions provided.  Data from the paper questionnaires will be 
transcribed at the Investigator site onto the eCRF.   
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. 
6.2 
Data collection at enrolment and follow-up 
6.2.1 
Enrolment procedures  
The following assessments and procedures should be performed within 42 days prior to the 
first infusion of study drug (Table 1).  For details of the nature of the assessments, see below. 
x 
Signed informed consent for the study and assignment of a patient identification 
number 
x 
Verify eligibility criteria 
x 
Demographic details including age, sex and ethnicity and also tobacco and alcohol 
consumption history 
x 
Past medical and surgical history (including previous treatments for NSCLC) 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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x 
Physical examination to assess all conditions that are current and ongoing  
x 
Weight, height and vital signs: systolic blood pressure (BP) and diastolic BP, pulse, 
respiratory rate, body temperature and oxygen saturation 
x 
Recording of AEs from the time of consent 
x 
Concomitant medications  
x 
WHO performance status  
x 
Haematology, clinical chemistry and urinalysis 
x 
Coagulation tests: prothrombin time, activated partial thromboplastin time (APTT) 
and international normalised ratio (INR).   
x 
Hepatitis B and C testing as per local practice 
x 
HIV-1 antibody testing as per local practice 
x 
Thyroid function tests: triiodothyronine (T3; free [if available]), total thyroxine (T4 
[or T4 free]), and thyroid stimulating hormone (TSH). 
x 
Pregnancy testing for female patients, as clinically indicated (urine human chorionic 
JRQDGRWURSLQ>K&*@RUVHUXPȕK&* 
x 
12-lead ECG recording 
x 
Patient questionnaires (European Organisation for Research and Treatment of 
Cancer 30-item core quality of life questionnaire [EORTC QLQ-C30] with the 
Lung Cancer Module [LC13 and EuroQoL 5 dimension, 5 level health state utility 
index [EQ-5D-5L]) 
x 
Mandatory provision of an unstained, archived tumour tissue sample in a quantity 
sufficient to allow for analysis.  Please refer to the Laboratory Manual for details. 
x 
A recent tumour biopsy (taken following completion of the most recent therapy) is 
an optional requirement, provided that a biopsy procedure is technically feasible 
and the procedure is not associated with unacceptable clinical risk.  See Section 6.7. 
x 
Blood samples for the analysis of biomarkers (including those for circulating 
soluble factors, and messenger RNA/micro RNA, and soluble PD-L1).  See 
Section 6.7. 
x 
A sample for PGx (DNA) analysis (optional) 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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x 
Tumour assessment scans of the chest and abdomen (including liver and adrenal 
glands) for assessment of disease by CT/MRI (see Appendix F).   
The Principal Investigator/sub-Investigator should adhere to the study plan, procedures and 
perform tests/observations in accordance with the protocol. 
6.2.2 
Follow-up procedures 
Patients should be discontinued from study drug if any discontinuation criteria are fulfilled, 
see Section 5.8.  The assessments to be carried out during follow-up are detailed in Table 2 
(for patients achieving disease control or who are discontinued due to toxicity or a reason 
other than confirmed PD) and Table 3 (for patients discontinuing due to confirmed PD). 
Any serious and/or non-serious AEs ongoing at the time of study drug discontinuation or 
which have occurred during the follow-up period must be followed-up (in accordance with 
Section 6.4.3 and Section 6.4.4).  Appropriate safety evaluations should be repeated and/or 
additional tests performed at any time when clinically indicated, or at the discretion of the 
Investigator, until resolution, unless, in the Investigator’s opinion, the condition is unlikely to 
resolve due to the patient’s underlying disease.  If the patient is lost to follow-up, then this 
should be noted in the eCRF. 
 
Survival follow-up 
Assessments for survival status should be made following confirmed objective disease 
progression (per RECIST v1.1 criteria) as presented in Table 2 (for patients achieving disease 
control or who are discontinued due to toxicity or a reason other than confirmed PD) and 
Table 3 (patients discontinuing due to confirmed PD).  No OS data will be recorded in the 
study database after final DCO for the study, but such information may continue to be 
collected for operational purposes for patients who remain eligible for re-treatment with 
durvalumab.  Survival follow-up for all patients will end within this protocol with the 
completion of the long-term follow up part of the study (CSP amendment 7). 
Survival information may be obtained via telephone contact with the patient, patient’s family 
or by contact with the patient’s current physician.   
In addition, patients should be contacted in the week following the DCO, which will take 
place approximately 62 months from the start of randomisation, to provide complete survival 
data.   
The status of patients ongoing in the study, those withdrawn (from the study) and those lost to 
follow-up at the time of an OS analysis should be obtained by the site personnel, by checking 
the patient notes, hospital records, contacting the patient’s general practitioner and checking 
publicly available death registries.  In the event that the patient has actively withdrawn 
consent to the processing of their personal data, the vital status of the patient (ie, if the patient 
is dead or alive) can be obtained by site personnel from publicly available resources where it 
is possible to do so under applicable local laws.  


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Second progression 
Following confirmed progression, patients will be assessed every 12 weeks for a second 
progression (using the patient’s status at first progression as the reference for assessment of 
second progression).  A patient’s progression status is defined according to local standard 
clinical practice and may involve any of: objective radiological, symptomatic progression or 
death.  RECIST measurements will not be collected for assessment of PFS2.  The date of 
PFS2 assessment and Investigator opinion of progression status (progressed or 
non-progressed) at each assessment will be recorded in the eCRF. 
6.3 
Efficacy  
For both BICR and Investigator review, RECIST 1.1 criteria will be used to assess patient 
response to treatment and allow calculation of PFS, ORR, and DoR.  The RECIST 1.1 
guidelines for measurable, non-measurable, target and non-target lesions and the objective 
tumour response criteria (CR, PR, NED, SD or PD) are presented in Appendix F.  Localised 
post-radiation changes which affect lesion sizes may occur and there may be high levels of 
necrosis/fibrosis with little or no active tumour in recently irradiated lesions.  However, 
accepting these limitations in this patient population with prior curative radiation treatment the 
prior irradiated lesions may be considered measurable and selected as target lesions providing 
they fulfil the other criteria for measurability. 
The methods of assessment of tumour burden used at baseline CT/MRI scans of the chest and 
abdomen (including liver and adrenal glands) must be used at each subsequent follow-up 
assessment.  Additional anatomy should be imaged based on signs and symptoms of 
individual patients, including new lesions at follow-up. 
The baseline assessment is part of the screening procedures and should be performed within 
0 to 42 days after the end of chemoradiation therapy and before the start of study drug.  For 
patients who are recovering from toxicities associated with prior treatment, randomisation 
may be delayed by up to 42 days from the end of the chemoradiation therapy.  Efficacy for all 
patients will be assessed by objective tumour assessments every 8 weeks for the first 
12 months (relative to the date of randomisation; Table 1), then every 12 weeks thereafter 
(Table 2) until confirmed objective disease progression as defined by RECIST 1.1 
(irrespective of the reason for stopping study drug and/or subsequent therapy).  If an 
unscheduled assessment is performed, and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits.   
Patients who achieve and maintain disease control (ie, CR, PR, NED, or SD) through to the 
end of the 12-month treatment period may restart treatment with study drug upon evidence of 
PD (according to RECIST 1.1), with or without confirmation, during follow-up.  To restart 
study drug the patient must not have received an intervening systemic anti-cancer therapy 
post-study drug discontinuation.  Patients who restart study drug must have a baseline tumour 
assessment within 28 days of restarting study drug, all further scans should occur every 
8 weeks (relative to the date of restarting study drug).  If a patient is continuing to receive 


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re-treatment after final DCO for the study or continuing in progression-free follow-up, they 
should receive scans/RECIST and other assessments per the local standard of care. 
For patients who discontinue study drug due to toxicity or a reason other than confirmed PD, 
objective tumour assessments should be continued every 8 weeks for 12 months (relative to 
the date of randomisation) then every 12 weeks thereafter until confirmed objective disease 
progression. 
Disease progression requires confirmation, the confirmatory scan should occur preferably at 
the next scheduled visit and no earlier than 4 weeks after the initial assessment of PD in the 
absence of clinically significant deterioration.  A biopsy (optional biopsy at suspected 
progression) may assist with the differentiation of malignant tumour from post-radiation 
changes and may be of assistance at the Investigator sit in confirming the malignant origin of 
regrowth within the radiation field.  However, confirmatory radiological assessments should 
still be performed at the next schedule visit to confirm radiological progression.  
Administration of study drug will continue between the initial assessment of progression and 
confirmation for progression.  For all patients who are treated through progression and 
patients who achieve disease control and restart study drug upon evidence of PD (according to 
RECIST 1.1) during follow-up, 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 and re-treatment as specified 
in Section 4.3.  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.    
Progression would be considered confirmed if the following criteria are met: 
x 
LQFUHDVHLQWKHVXPGLDPHWHUVRI target lesions compared with the nadir at 
2 consecutive visits with an absolute increase of at least 5 mm 
7KHDVVHVVPHQWRISURJUHVVLRQRILQFUHDVHLQWKHVXPGLDPHWHUVRIWDUJHW
lesions compared with the nadir is at the first progression time point relative to the 
nadir (the smallest sum of diameters and this may be at baseline or subsequent 
follow-XSYLVLW7KHFRQILUPHGVFDQFRQILUPVWKHSHUVLVWHQFHRIWKHLQFUHDVH
relative to the nadir 
x 
and/or significant progression (worsening) of non-target lesions or  new lesions at 
the confirmatory PD time-point compared with the first time point where 
progression of non-target lesions or new lesions identified 
x 
and/or additional new unequivocal lesions at the confirmatory PD time-point 
compared with the first time point new lesions identified. 


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Edition Number 01.1 
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In the absence of clinically significant deterioration the Investigator should continue the 
patient on study drug until progression is confirmed. 
If progression is not confirmed, then the patient should continue study drug and on treatment 
assessments. 
If a patient discontinues study drug (and/or receives a subsequent cancer therapy) prior to 
progression then the patient should still continue to be followed until confirmed objective 
disease progression. 
Categorisation of objective tumour response assessment will be based on the RECIST 1.1 
criteria of response: CR, PR, SD and PD.  Patients with no evidence of disease at follow-up in 
the absence of new lesions will be assigned a response of NED.  Target lesion progression will 
be calculated in comparison to when the tumour burden was at a minimum (ie, smallest sum 
of diameters previously recorded on study).  In the absence of progression, tumour response 
(CR, PR) and SD will be calculated in comparison to the baseline tumour measurements 
obtained before starting study drug. 
If there is doubt as to whether progression has occurred, particularly with non-target lesion or 
the appearance of a new lesion, it is advisable to continue study drug until the next scheduled 
assessment or sooner if clinically indicated and reassess the patient’s status.  If repeat scans 
confirm progression, then the date of the initial scan should be declared as the date of 
progression. 
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of one or more non-target lesions 
is usually not sufficient to quality for unequivocal progression status. 
Following confirmed progression, patients should continue to be followed up for survival 
every 2 months as outlined in the study plan (Table 3).  An exception is patients with 
confirmed PD that continue to receive study drug at the discretion of the Investigator 
(following consultation with the sponsor); these patients can receive study drug for a 
maximum of 12 months and will have scans every 8 weeks (relative to the date of 
randomisation per Table 1) until study drug is stopped.   
Study drug should be discontinued if there is confirmed progression of disease (PD) following 
a previous response (PR or CR) to study drug. 
Patients with confirmed PD that discontinue study drug, should have scans conducted 
according to local standard clinical practice (see Section 6.2.2.2) and submitted for BICR until 
the patient commences a new treatment (these scans are optional; see Table 3). 
It is important to follow the assessment schedule as closely as possible.  Please refer to the 
study plans (Table 1 [Screening and the Treatment Period], Table 2 [for follow-up of patients 


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achieving disease control or who are discontinued due to toxicity or a reason other than 
confirmed PD] and Table 3 [for follow-up of patients discontinuing due to confirmed PD]) 
and Appendix F. 
6.3.1 
Central reading of scans 
The co-primary analysis for this study will be based on PFS from BICR using assessment of 
tumours using RECIST 1.1.  In addition, an exploratory analysis of PFS from BICR by 
assessment of tumours using irRECIST 1.1 (Wolchok et al 2009, Nishino et al 2013) will be 
conducted (see Section 12.2.3 for the analysis methods).  All imaging assessments including 
unscheduled visit scans will be collected on an ongoing basis and sent to an AstraZeneca 
appointed Contract Research Organisation for central analysis.  Results of these independent 
reviews will not be communicated to Investigators, and the management of patients will be 
based solely upon the results of the RECIST assessment conducted by the Investigator.   
6.4 
Safety 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section.  
Safety guidelines around SAE reporting described within the protocol remain in effect after 
the final DCO for the study.  
6.4.1 
Definition of adverse events  
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the 
abnormal results of an investigation (eg, laboratory findings, ECG).  In clinical studies, an AE 
can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered. 
The term AE is used to include both SAEs and non-serious AEs. 
For cases where it could be suspected that a tissue-derived medicine has been contaminated by 
a pathogen, information about any of the above conditions (including infection) should be 
collected.  Any deterioration of the disease targeted in the study and associated symptoms 
should not be regarded as an AE as far as the deterioration can be anticipated. 
6.4.2 
Definitions of serious adverse event 
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils one or more of the following criteria: 
x 
Results in death 
x 
Is immediately life-threatening 


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x 
Requires in-patient hospitalisation or prolongation of existing hospitalisation  
x 
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions 
x 
Is a congenital abnormality or birth defect 
x 
Is an important medical event that may jeopardise the patient or may require 
medical intervention to prevent one of the outcomes listed above. 
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol. 
6.4.3 
Recording of adverse events 
Time period for collection of adverse events 
Adverse events 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 study drug).  
Adverse events not meeting SAE criteria that occur after the final DCO for the study in 
patients still on durvalumab will be followed up as per standard clinical practice but will not 
be recorded for the purposes of this study.   
SAEs will be recorded from the time of informed consent, throughout the treatment period and 
including the follow-up period (90 days after the last dose of study drug). 
After the final DCO for the study, any SAEs occurring whilst the patient is either still 
receiving durvalumab (ie, re-treatment patients) or is in the 90-day safety follow-up period 
after receiving the last dose of durvalumab must be reported to AstraZeneca following the 
procedures outlined in Section 6.4.4.  If a patient discontinues from study drug for reasons 
other than disease progression, and therefore continues to have tumour assessments using 
RECIST, drug or procedure-related SAEs must be captured until the patient is considered to 
have confirmed PD and will have no further RECIST assessments.   
For screening failures (ie, patients who do not receive study treatment), SAEs will be 
collected from the time of signature of informed consent until the patient is withdrawn from 
study.  Any SAE related to a mandated study procedure should be reported. 
Follow-up of unresolved 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/study completion.   
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the eCRF.  
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 


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Edition Number 01.1 
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Post study events 
After the patient has been permanently withdrawn from the study, there is no obligation for 
the Investigator to actively report information on new AE or SAEs occurring in former study 
patients after the 90-day safety follow-up period.  However, if an Investigator learns of any 
SAEs, including death, at any time after the patient has been permanently withdrawn from 
study, and he/she considers there is a reasonable possibility that the event is related to the 
investigational product, the Investigator should notify AstraZeneca/MedImmune Drug Safety 
or its representative. 
Variables 
The following variables will be collected for each AE on the eCRF: 
x 
AE (verbatim) 
x 
The date and time when the AE started and stopped 
x 
The maximum CTCAE grade reported 
x 
Whether the AE is serious or not 
x 
Investigator causality rating against the investigational product (yes or no) 
x 
Action taken with regard to investigational product 
x 
Administration of treatment for the AE 
x 
AE caused patient’s withdrawal from study (yes or no) 
x 
Outcome. 
In addition, the following variables will be collected for SAEs: 
x 
Date AE met criteria for SAE 
x 
Date Investigator became aware of SAE 
x 
AE is serious due to 
x 
Date of hospitalisation 
x 
Date of discharge 
x 
Probable cause of death 
x 
Date of death 


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Edition Number 01.1 
Date 04 September 2019 
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x 
Autopsy performed 
x 
Causality assessment in relation to Study procedure(s) 
x 
Causality assessment in relation to Other medication 
x 
Description of AE. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.4.2.  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. 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. 
Causality collection 
The Investigator will assess causal relationship between investigational product 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 to the Clinical 
Study Protocol. 
Relationship to protocol procedures 
The Investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the SAE Report Form.  This includes nontreatment-emergent SAEs (ie, SAEs 
that occur prior to the administration of study drug) as well as treatment-emergent SAEs.  A 
protocol-related SAE may occur as a result of a procedure or intervention required during the 
study (eg, blood collection).  The following guidelines should be used by Investigators to 
assess the relationship of SAEs to the protocol: 
x 
Protocol related: The event occurred due to a procedure/intervention that was 
described in the protocol for which there is no alternative aetiology present in the 
patient’s medical record. 
x 
Not protocol related: The event is related to an aetiology other than the procedure/ 
intervention that was described in the protocol (the alternative aetiology must be 
documented in the study patient’s medical record). 


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Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’, or revealed by observation will be collected and recorded in the eCRF.  
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately. 
Adverse events based on examinations and tests 
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
CSR.  Deterioration as compared to baseline in protocol-mandated laboratory values and vital 
signs should therefore only be reported as AEs if they fulfil any of the SAE criteria or are the 
reason for discontinuation of treatment with the investigational product.  An abnormal 
laboratory finding (including ECG findings) that requires an action or intervention by the 
Investigator, or a finding judged by the Investigator to represent a change beyond the range of 
normal physiologic fluctuation, should also be reported as an AE. 
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 AE(s). 
Asymptomatic Grade 3 or 4 increases in amylase or lipase resulting in interruption of dosing 
(refer to Section 5.5.3) should be reported as AEs. 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
NB. Cases where a patient shows an AST or $/7[8/1or WRWDOELOLUXELQ[8/1PD\
need to be reported as SAEs.  These cases should be reported as SAEs if after evaluation they 
meet the criteria for a Hy’s Law case or if any of the individual liver test parameters fulfil any 
of the SAE criteria.  For potential Hy’s Law to be met, the elevation in transaminases must 
precede or be coincident with (ie, on the same day) the elevation in total bilirubin, but there is 
no specified timeframe within which the elevations in transaminases and total bilirubin must 
occur.  Please refer to Appendix E ‘Actions required in cases of combined increase of 
Aminotransferase and Total Bilirubin – Hy’s Law’, for further instructions in cases of 
combined increases of aminotransferase and total bilirubin. 


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Criteria for Hy’s Law (FDA Guidance 2009) 
x 
The drug causes hepatocellular injury, generally shown by a higher incidence of 
3-fold or greater elevations above the ULN of ALT or AST than the 
(non-hepatotoxic) control drug or placebo  
x 
Among trial subjects showing such aminotransferase elevations, often with 
aminotransferases much greater than 3 x ULN, one or more also show elevation of 
serum total bilirubin to >2 x ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase)  
x 
No other reason can be found to explain the combination of increased 
aminotransferases and total bilirubin, such as viral hepatitis A, B, or C; pre-existing 
or acute liver disease; or another drug capable of causing the observed injury. 
Guidelines for management of patients with hepatic function abnormality are outlined in the 
TMGs (refer to Section 5.5.3). 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease.  The 
development of new, or progression of existing metastasis to the primary cancer under study 
should be considered as disease progression and not an AE.  Events, which are unequivocally 
due to disease progression, should not be reported as an AE during the study. 
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 study drug and have been 
identified after the patient’s inclusion in this study.   
Deaths 
All deaths that occur during the study, or within the protocol-defined follow-up period after 
the administration of the last dose of study drug, must be reported as follows: 
x 
Death clearly the result of disease progression should be reported to the study 
monitor at the next monitoring visit and should be documented in the eCRF but 
should not be reported as a SAE.   
x 
Where death is not due (or not clearly due) to PD under study, the AE causing the 
death must be reported to the study monitor as a SAE within 24 hours.  The report 
should contain a comment regarding the co-involvement of PD, if appropriate, and 
should assign main and contributory causes of death.  


Revised Clinical Study Protocol 
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Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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x 
Deaths with an unknown cause should always be reported as a SAE.  A post 
mortem maybe helpful in the assessment of the cause of death, and if performed a 
copy of the post-mortem results should be forwarded to AstraZeneca/MedImmune 
Drug Safety or its representative within the usual timeframes.   
6.4.4 
Reporting of serious adverse events 
All SAEs occurring whilst the patient is either receiving study drug or in the 90 day safety 
follow up period after receiving the last dose of study drug have to be reported, whether or not 
considered causally related to the investigational product, or to the study procedure(s).  All 
SAEs occurring prior to final DCO for the study will be recorded in the eCRF. 
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
appropriate AstraZeneca/MedImmune representatives (ie, IQVIA) immediately, or no later 
than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca/MedImmune representative (ie, IQVIA) works with the 
Investigator to ensure that all the necessary information is provided to the 
AstraZeneca/MedImmune 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/MedImmune representatives of any follow-up information on a previously 
reported SAE immediately, or no later than 24 hours of when he or she becomes aware of it. 
Investigators or other site personnel send relevant eCRF modules by fax to IQVIA and any 
other relevant supporting documentation (eg, ECG, laboratory results, autopsy report). 
Please refer to the study specific Safety Handling Plan. 
The AstraZeneca/MedImmune representative will advise the Investigator/study site personnel 
how to proceed.  
The reference document for definition of expectedness/listedness is the IB for MEDI4736. 
After the final DCO for the study, any SAEs occurring whilst the patient is either still 
receiving durvalumab (ie, re-treatment patients) or in the 90 day safety follow up period after 
receiving the last dose of durvalumab are to be recorded in the CRF and reported directly to 
the AstraZeneca/MedImmune 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. 


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6.4.5 
Laboratory safety assessment 
Blood and urine samples for determination of clinical chemistry, haematology, urinalysis, 
thyroid function tests, amylase, and lipase will be taken at the times indicated in Table 1 
(Screening and the Treatment Period), Table 2 (follow-up for patients achieving disease 
control or who are discontinued due to toxicity or a reason other than confirmed PD) and 
Table 3 (follow-up for patients discontinuing due to confirmed PD).  Please also refer to the 
Laboratory Manual. 
Patients in progression-free follow up after the final DCO are to undergo sampling for local 
laboratory assessments in such a way that continued per-protocol re-treatment eligibility can 
be properly determined.  Patients receiving re-treatment after final DCO for the study are to 
undergo sampling for laboratory assessments in such a way that continued per-protocol 
re-treatment eligibility can be properly determined.  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 in order to 
manage AEs in accordance with the durvalumab TMGs (refer to Section 5.5.3); data will be 
recorded on patient charts but will not otherwise be reported for the purposes of this study. 
The laboratory variables to be measured are presented in Table 5, Table 6 and Table 7. 
Table 5 
Haematology 
Activated partial thromboplastin timea 
Mean corpuscular haemoglobin concentration 
Basophils 
Mean corpuscular volume 
Eosinophils 
Monocytes 
Haematocrit 
Neutrophils 
Haemoglobin 
Platelet count 
International normalised ratio 
Red blood cell count 
Lymphocytes 
Total white cell count 
Mean corpuscular haemoglobin 
 
a 
Activated partial thromboplastin time will be determined at Screening only unless clinically indicated. 
Haematology assessments (absolute counts, as appropriate) to be performed at each visit and when clinically 
indicated. 
 
Table 6 
Clinical chemistry (serum or plasma) 
Albumin 
Glucose 
Alkaline phosphatasea 
Lactate dehydrogenase 
Alanine aminotransferasea 
Lipaseb 
Aspartate aminotransferasea 
Magnesiumb 
Amylaseb 
Potassium 
Bicarbonate 
Sodium 


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Table 6 
Clinical chemistry (serum or plasma) 
Albumin 
Glucose 
Calcium  
Total bilirubina 
Chloride 
Total protein 
Creatinine (creatinine clearance)b 
Urea or blood urea nitrogen, depending on local practice 
Gamma glutamyltransferasec 
Uric acidb 
a 
Tests for aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin 
must be conducted concurrently and assessed concurrently. 
b 
Creatinine clearance, magnesium, amylase, lipase, and uric acid tested at Screening Day 1 (unless screening 
laboratory assessments are performed within 3 days prior to Day 1) and every 4 weeks thereafter.   
c 
Gamma glutamyltransferase tested at Screening, Day 1 and as clinically indicated.  Clinical chemistry 
assessments to be performed at each visit and when clinically indicated. 
 
NB. In case a patient shows an AST or $/7[8/1or WRWDOELOLUXELQ[8/1SOHDVH
refer to Appendix E ‘Actions required in cases of combined increase of Aminotransferase and 
Total Bilirubin – Hy’s Law’, for further instructions.  These cases should be reported as SAEs 
if after evaluation they meet the criteria for a Hy’s Law case or if any of the individual liver 
test parameters fulfil any of the SAE criteria.  All patients with an AST, ALT or bilirubin 
YDOXHWKHODWWHU[8/1DWWKHWLPHRIWKHODVWGRVHRI study drug should have a further 
liver chemistry profile (AST, ALT, bilirubin and alkaline phosphatase) performed 30 days 
(±7days) after permanent discontinuation of study drug. 
Table 7 
Urinalysis 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Colour and appearance 
a 
Microscopy should be used as appropriate to investigate white blood cells and use the high power field for 
red blood cells. 
Urinalysis to be performed at Screening, Day 1, every 4 weeks of treatment and as clinically indicated. 
 
Haematology, clinical chemistry and urinalysis tests will be performed by the hospital’s local 
laboratory.  Additional analyses may be performed if clinically indicated. 
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF.  See Section 6.4.3 for when abnormal laboratory values 
should be reported as AEs. 
All patients who have any Common Toxicity Criteria (CTC) Grade 3 or 4 laboratory values at 
the time of completion or discontinuation from study drug must have further tests performed 
until the laboratory values have returned to CTC Grade 1 or 2, unless these values are not 
likely to improve because of the underlying disease. 
For blood volumes see Section 7.1. 


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6.4.6 
Physical examination 
For timing of individual measurements refer to the study schedules (Table 1 [Screening and 
the Treatment Period], Table 2 [for follow-up of patients achieving disease control or who are 
discontinued due to toxicity or a reason other than confirmed PD] and Table 3 [for follow-up 
of patients discontinuing due to confirmed PD]).  Patients receiving re-treatment after final 
DCO for the study are to undergo physical examinations as clinically indicated at the 
discretion of the Investigator and per local standard of care; data will be recorded on patient 
charts but will not otherwise be reported for the purposes of this study. 
A complete physical examination will be performed and will include an assessment of the 
following (as clinically indicated): general appearance, respiratory, cardiovascular, abdomen, 
skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, 
musculo-skeletal (including spine and extremities), genital/rectal and neurological systems. 
Performance status will be assessed using WHO performance status at the times specified in 
Table 1, Table 2, and Table 3 based on the following: 
1. 
Fully active, able to carry out all usual activities without restrictions and without the 
aid of analgesia 
2. 
Restricted in strenuous activity, but ambulatory and able to carry out light work or 
pursue a sedentary occupation.  This group also contains patients who are fully 
active, as in Grade 0, but only with the aid of analgesics. 
3. 
Ambulatory and capable of all self-care, but unable to work.  Up and about more 
than 50% of waking hours 
4. 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
5. 
Completely disabled, unable to carry out any self-care and confined totally to bed or 
chair. 
Note: WHO performance status should also be collected at other site visits that the patient 
attends, if appropriate site staff are available to collect such information.  In addition, please 
provide World Health Organization performance status when information on subsequent 
anticancer therapy is provided, where possible. 
6.4.7 
Electrocardiogram 
Clinical interpretation and management of patients for all ECGs will be done locally.   
The same method of assessment should be used throughout.   
Electrocardiograms will be recorded at 25 mm/sec.   


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Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study.  ECGs should be obtained after the patient has been rested in a supine position for at 
least 5 minutes and recorded while the patient remains in that position.  In case of clinically 
significant ECG abnormalities, including a QTc value >470 ms, 2 additional 12-lead ECGs 
should be obtained over a brief period (eg, 30 minutes) to confirm the finding.  Patients 
receiving re-treatment after final DCO for the study are to receive ECGs as clinically 
indicated at the discretion of the Investigator and per local standard of care; data will be 
recorded on patient charts but will not otherwise be reported for the purposes of this study. 
All ECGs should be assessed by the Investigator as to whether they are clinically significantly 
abnormal / not clinically significantly abnormal.  If there is a clinically significant abnormal 
finding, the Investigator will record it as an AE on the eCRF (see Section 6.4.3). 
At Screening, mean QTc with Bazett’s correction (QTc = 47¥5PXVWEHPVHF 
6.4.8 
Vital signs 
For timings of assessments refer to the study plans in Table 1 (Screening and the Treatment 
Period), Table 2 (for follow-up of patients achieving disease control or who are discontinued 
due to toxicity or a reason other than confirmed PD) and Table 3 (for follow-up of patients 
discontinuing due to confirmed PD).  Patients receiving re-treatment after final DCO for the 
study are to undergo vital signs assessments as clinically indicated at the discretion of the 
Investigator and per local standard of care; data will be recorded on patient charts but will not 
otherwise be reported for the purposes of this study. 
Patients will be monitored with assessment of vital signs (BP, pulse, respiratory rate, 
temperature and oxygen saturation) at Screening and on the day of each infusion and in the 
follow-up period on Day 30.  On infusion days vital signs will all be taken before the infusion.  
Blood pressure and pulse will also be collected during and after the infusion (see 
Section 6.4.8.1). 
Additional monitoring with assessment of vital signs is at the discretion of the Investigator per 
standard clinical practice or as clinically indicated.  
Additional recording of vital signs may be captured on an unscheduled vital signs eCRF and 
on the eCRF for AE/SAE where applicable.  The date and time of collection and measurement 
will be recorded on the appropriate eCRF. 
Pulse and blood pressure
Blood pressure and pulse will be collected before, during and after the infusion at the 
following times (based on a 60-minute infusion): 
x 
At the beginning of the infusion (at 0 minutes) 
x 
Every 15 minutes during the infusion (at 15, 30, and 45 minutes) (all ±5 minutes) 


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x 
At the end of the infusion (at 60 minutes ±5 minutes) 
x 
In the 1-hour observation period post-infusion: 30 and 60 minutes after the infusion 
(ie, 90 and 120 minutes from the start of the infusion) (±5 minutes). 
If the infusion takes longer than 60 minutes then BP and pulse measurements should follow 
the principles as described above or more frequently if clinically indicated. 
The date and time of collection and measurement will be recorded on the appropriate eCRF. 
 
Temperature, respiratory rate and oxygen saturation 
On infusion days, temperature, respiratory rate and oxygen saturation should be collected 
before the infusion. 
6.4.9 
Other safety assessments 
Pregnancy tests on either blood (VHUXPȕ-hCG) or urine (hCG) samples will be performed for 
pre-menopausal women of childbearing potential at the times specified in Table 1.  Tests will 
be performed by the hospital’s local laboratory.  If results are positive the patient is 
ineligible/must be discontinued from the study.  In the event of a suspected pregnancy during 
the study, the test should be repeated. 
Other safety tests to be performed at Screening include:  
x 
Coagulation tests: prothrombin time, APTT and INR only performed at Screening 
and if clinically indicated 
x 
Hepatitis B and C testing as per local practice 
x 
HIV-1 antibody testing as per local practice 
x 
T3 free (if available), total T4 (or T4 free), and TSH. 
Timings for additional thyroid function tests (TSH and T3 free [if available] and total T4 [or 
T4 free]) are shown in Table 1 (Screening and the Treatment Period), Table 2 (for follow-up 
of patients achieving disease control or who are discontinued due to toxicity or a reason other 
than confirmed PD) and Table 3 (for follow-up of patients discontinuing due to confirmed 
PD).
6.5 
Patient reported outcomes  
Timings of the assessments for PRO are presented in Table 1 (Screening and the Treatment 
Period), Table 2 (for follow-up of patients achieving disease control or who are discontinued 
due to toxicity or a reason other than confirmed PD) and Table 3 (for follow-up of patients 
discontinuing due to confirmed PD).  There will be no further collection of PRO data after the 
final DCO for the study. 


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The EORTC QLQ-C30 and cancer-specific symptom modules are self-administered 
questionnaires and are to be completed by the patient without the assistance of the 
investigational site personnel.  All questionnaires should be completed before any other study 
procedures are conducted at the visit.  Patient reported outcome questionnaires need to be 
administered at the times specified in the study plans before other clinical procedures.  If 
patients have scans at an outside facility or missed a scheduled data collection, PRO 
questionnaires need to be administered at the next visit.  It takes about 20 to 40 minutes for 
patients to complete all 3 questionnaires and the patients are asked to only fill out 
questionnaires that have been validated to be relevant to their specific type of cancer; hence 
the burden to the patient is moderate.  When the patient completes the questionnaires, study 
coordinators need to review the questionnaires for missing responses and then ask the patient 
to date and sign at places specified in the questionnaires. 
6.5.1 
EORTC QLQ-C30 
The EORTC QLQ-C30 is a 30-item self-administered questionnaire (Appendix G).  There are 
9 multiple item scales: 5 scales that assess aspects of functioning (physical, role, cognitive, 
emotional, and social); 3 symptom scales (fatigue, pain, and nausea and vomiting); and a 
global health status/Quality of Life (QoL) scale.  There are 5 single-item measures assessing 
additional symptoms commonly reported by cancer patients (dyspnoea, loss of appetite, 
insomnia, constipation, and diarrhoea) and a single item concerning perceived financial 
impact of the disease.  All but 2 questions have 4-point scales: “Not at all,” “A little,” “Quite a 
bit,” and “Very much.”  The 2 questions concerning global health status and QoL have 7 point 
scales with ratings ranging from “Very poor” to “Excellent.”  For each of the 15 domains 
(9 multiple-item scales, 6 single item scales), final scores are transformed such that they range 
from 0 to 100 whereas higher scores indicate greater functioning, greater QoL, or greater level 
of symptoms (Aaronson et al 1993).  The EORTC QLQ C30 questionnaire should be 
completed before the LC13 module. 
6.5.2 
Lung Cancer Module (LC13) 
For NSCLC patients, a disease-specific 13-item self-administered questionnaire for lung 
cancer was developed (LC13; Appendix G) to be used in conjunction with the EORTC 
QLQ-C30 (Bergman et al 1994).  It comprises both multi-item and single-item measures of 
lung cancer-associated symptoms (ie, coughing, haemoptysis, dyspnoea, and pain) and side 
effects from conventional chemotherapy and radiotherapy (ie, hair loss, neuropathy, sore 
mouth and dysphagia).  The EORTC QLQ C30 questionnaire should be completed before the 
LC13 module. 
6.5.3 
EuroQoL 5-dimension, 5-level health state utility index (EQ-5D-5L) 
The EuroQoL 5-dimension utility index (EQ-5D) is a standardised measure of health status 
developed by the EuroQol Group in order to provide a simple, generic measure of health for 
clinical and economic appraisal (EuroQoL 1990).  Applicable to a wide range of health 
conditions and treatments, it provides a simple descriptive profile and a single index value for 
health status that can be used in the clinical and economic evaluation of health care as well as 
in population health surveys. 


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The questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort 
and anxiety/depression.  Each dimension has 5 response options (no problems, slight 
problems, moderate problems, severe problems, and extreme problems) that reflect increasing 
levels of difficulty (EuroQoL 2013). 
Since 2009, the EuroQol group has been developing a more sensitive version of the EQ-5D 
(the EQ-5D-5L) which expands the range of responses to each dimension from 3 to 5 levels of 
increasing severity (Herdman et al 2011).  Preliminary studies indicate that the 5L version 
improves upon the properties of the 3L measure in terms of reduced ceiling effect, increased 
reliability and an improved ability to differentiate between different levels of health  
(Janssen et al 2008a, Janssen et al 2008b, Pickard et al 2007). 
The patient will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions.  The questionnaire also includes a visual 
analogue scale, where the patient will be asked to rate current health status on a scale of 0 to 
100, with 0 being the worst imaginable health state.  
The assessment of health state utility will provide important information for payers and will 
be used within economic evaluations of MEDI4736. 
6.5.4 
Administration of patient reported outcomes questionnaires 
Each centre must allocate the responsibility for the administration of the PRO instruments to a 
specific individual (eg, a research nurse, study coordinator) and if possible, assign a back-up 
person to cover if that individual is absent.  The AstraZeneca/MedImmune Study Delivery 
Team (or delegate) will provide relevant training in the administration of the PRO 
questionnaires.  The PRO questionnaires must be administered and completed at the clinic as 
per the study plan.  The EORTC-QLQC 30, LC13, and EQ-5D will be administered on the 
days specified in the study plans (Table 1 [on-treatment], Table 2 and Table 3 [follow-up]). 
It is important that the significance and relevance of the data are explained carefully to 
participating patients so that they are motivated to comply with data collection. 
The instructions for completion of the PRO questionnaires are as follows: 
x 
It must be completed prior to any other study procedures (following informed 
consent) and before discussion of disease progress to avoid biasing the patient’s 
responses to the questions. 
x 
It must be completed in private by the patient. 
x 
The patient should be given sufficient time to complete the PRO questionnaires at 
their own speed. 
x 
The patient should not receive help from relatives, friends or clinic staff to answer 
the PRO questionnaires.  However, if the patient is unable to read the questionnaire 


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(eg, is blind, illiterate, or forgot their reading glasses), the PRO questionnaires may 
be read out by trained clinic staff and responses recorded. 
x 
On completion of the PRO questionnaires, it should be handed back to the person 
responsible for PRO questionnaires, who should check for completeness. 
x 
Only 1 answer should be recorded for each question. 
x 
Data from the paper questionnaires will be transcribed at the Investigator site onto 
the eCRF.   
6.6 
Pharmacokinetics and ADA 
6.6.1 
Collection of PK samples and determination of drug concentration 
Blood samples (3.5 mL) for determination of MEDI4736 in serum will be taken at the times 
presented in the study plans in Table 1 (Screening and the Treatment Period), Table 2 (for 
follow-up of patients achieving disease control or who are discontinued due to toxicity or a 
reason other than confirmed PD) and Table 3 (for follow-up of patients discontinuing due to 
confirmed PD).  Patients receiving re-treatment after final DCO for the study will not undergo 
drug concentration or anti-drug antibody assessments. 
Measurement of MEDI4736 concentrations in serum will be performed using a validated 
immunoassay.  Samples for determination of MEDI4736 concentrations in serum will be 
analysed by a designated third party on behalf of AstraZeneca/MedImmune, using an 
electrochemiluminescence assay.  The lower limit of quantification of MEDI4736 in serum is 
50 ng/mL; however, this is dependent on the assay used. 
Samples will be collected, labelled stored and shipped as detailed in Laboratory Manual.  For 
blood volume see Section 7.1. 
6.6.2 
Collection of samples to measure for the presence of ADA and ADA 
neutralising antibodies 
Presence of ADA will be assessed in samples taken according to the schedule presented in 
Table 1 (Screening and the Treatment Period), Table 2 (for follow-up of patients achieving 
disease control or who are discontinued due to toxicity or a reason other than confirmed PD) 
and Table 3 (for follow-up of patients discontinuing due to confirmed PD). 
Samples will be measured for the presence of ADA and ADA neutralising antibodies using 
validated assays.  Tiered analysis will be performed to include screening, confirmatory and 
titre assay components and positive-negative cut points will be employed that were 
statistically determined from drug naive validation samples.   


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6.7 
Biomarker analysis 
Mandatory tumour and blood biomarkers to be evaluated to support the exploratory objectives 
of the study are described in Section 6.7.1 through Section 6.7.4.  Alternative biomarkers may 
be evaluated as determined by additional data associated with disease progression or response 
to MEDI4736. 
Biomarker assessments that may have the potential to identify patients likely to respond to 
treatment with MEDI4736 (determined from other MEDI4736 studies) will be investigated to 
determine a patient’s biomarker status and for possible correlation with efficacy endpoints.  
Exploratory biomarker research, beyond the scope of the secondary endpoint assessments, will 
not form part of the CSR.  The results may be pooled with biomarker data from other 
MEDI4736 studies to test existing hypotheses or to generate hypotheses to be tested in future 
studies of NSCLC and MEDI4736. 
Samples will be taken at the times presented in the study plans in Table 1 (Screening and the 
Treatment Period), Table 2 (for follow-up of patients achieving disease control or who are 
discontinued due to toxicity or a reason other than confirmed PD) and Table 3 (for follow-up 
of patients discontinuing due to confirmed PD).  For blood volume see Section 7.1.  Patients 
receiving re-treatment after final DCO for the study will not undergo biomarker analyses. 
6.7.1 
Collection of patient selection biomarker data  
At Screening, an unstained, archived tumour tissue sample (formalin fixed paraffin embedded 
[FFPE]) in a quantity sufficient to allow for analysis (see the Laboratory Manual) must be 
deemed to be available.  If an archived tumour block cannot be shipped for this study, then at 
least 10 newly cut, unstained slides with tissue sections of 4 microns thick may be provided 
for analysis as described in the Laboratory Manual. 
An optional image-guided core needle (at least 18 gauge) tumour biopsy following completion 
of the most recent therapy, or upon evidence of PD after randomisation to MEDI4736 or 
placebo, should be performed according to institutional practice, provided it is not associated 
with unacceptable clinical risk.  If provided, the sample should be of a sufficient quantity to 
allow for analysis (see the Laboratory Manual).  Tumour lesions planned for biopsy must not 
be used as index lesions for assessment of disease.   
If tumour biopsies are taken and it is clinically practical, patients will undergo 4 core biopsies, 
but a minimum of at least 3 core biopsies are required.  The first and third core biopsies will 
be placed in formalin and processed for FFPE, while the second and fourth core biopsies 
(fourth biopsy, if available) will be immediately frozen in liquid nitrogen and then stored 
at -80°C (where such storage facilities exist).   
Tumour biopsies will be stored at AstraZeneca/MedImmune Research and Development 
(R&D) or an appropriate vendor selected by AstraZeneca/MedImmune.  Core biopsies may be 
used for correlative studies such as immunohistochemistry, tumour mutation analysis, RNA 


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analysis, proteomic analysis, and assessment of immunodiversity.  Samples will be collected, 
labelled, stored and shipped as detailed in the Laboratory Manual. 
The expression and spatial distribution of PD-L1 protein within the tumour microenvironment 
will be evaluated for any relationship with efficacy endpoints.   
6.7.2 
Blood borne biomarkers 
Blood or tissue samples will be analysed to evaluate protein, nucleic acid, and cellular 
biomarkers that relate to MEDI4736 treatment.  
Blood and tissue collected for analysis of immune cell gene expression profiles within the 
peripheral and tumoural compartments will be evaluated for any relationship with efficacy 
endpoints.   
Blood (plasma or serum) samples will also be collected for analysis of circulating soluble 
factors in relation to immune status at baseline and in response to treatment.  Factors to be 
analysed may include but are not limited to: the presence of IFN-ȖWXPRXUQHFURVLVIDFWRU-Į
interleukin (IL)-2, IL-6, IL-10, IL-8, IL-12, and levels of soluble PD-L1, as well as antibodies 
against tumour, self, or viral antigens. 
6.7.3 
Tumour samples (immune-related or response-related markers) 
The expression and spatial distribution of immune-related or response-related markers by 
immunohistochemistry may also include, but may not be limited to, PD-L1, CTLA-4, CD3, 
CD4, CD8, CD45RO, forkhead box P3, granzyme B, OX40, PD1, cleaved caspase 3 and 
Ki67.  Archived material (or biopsies if available), may also be analysed for the presence of 
key mutations which may include but are not limited to: EGFR, K-ras, N-ras, B-raf, 
anaplastic lymphoma kinase and the met proto oncogene to evaluate their potential relevance 
and correlations with response to MEDI4736 treatment. 
6.7.4 
Genomic analysis 
Whole blood and tumour samples will be collected for RNA and/or micro RNA/messenger 
RNA sample preparation.  Ribonucleic acid may be used in the analyses of transcript and/or 
micro RNA expression and stored for future analyses.  Ribonucleic acid analyses will be 
conducted to evaluate its utility to identify subsets of patients responsive to MEDI4736. 
6.7.5 
Management of biomarker data  
The biomarker data will have unknown clinical significance.  AstraZeneca/MedImmune will 
not provide biomarker research results to patients, their family members, any insurance 
company, an employer, clinical study Investigator, general physician or any other third party, 
unless required to do so by law.  The patient’s samples will not be used for any purpose other 
than those described in the study protocol. 
Individual patients will not be identified in any report or publication resulting from this work.  
The data and results of this research may be reviewed with collaborators and published, but 


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neither the patient’s name nor any other personal identifiers will appear in any publication or 
report.   
6.8 
Pharmacogenetics 
6.8.1 
Collection of pharmacogenetic samples 
Refer to Appendix D for details of the genetic research (optional DNA component).  For 
blood volume see Section 7.1. 
6.9 
Health economics 
For the purposes of economic evaluation it is necessary to capture healthcare resource use 
related to the treatment and the underlying disease.  Within the study the following will be 
captured: 
x 
Hospital episodes including the type of contact (hospitalisations, outpatient, day 
case), reason, length of stay by ward type (including intensive care unit) and 
concomitant medications and procedures 
x 
Treatment-related to AEs (including the method of delivery of the treatment) 
x 
Treatment not related to the study. 
The above resource use data will mainly come from the patient’s medical record and will be 
captured in the eCRF. 
The assessment of health economic resource use data will provide important information for 
payers and will be used within economic evaluations of MEDI4736. 
7. 
BIOLOGICAL SAMPLING PROCEDURES  
7.1 
Volume of blood 
The total volume of blood that will be drawn from each patient in this study depends on the 
length of time that the patient receives study drug.  Table 8 is a guide to the approximate 
volume of blood that will be drawn from each patient, based on the assumption that each 
patient remains in the study on treatment for 3 months and attends all the planned visits.  The 
sample volumes below are intended as a guide, the exact volume will be dependent on the 
collection tube sizes available from the supplier (eg, site, Contract Research Organisation). 
Blood samples taken during progression follow-up or during re-treatment following the final 
DCO for the study are to be in accordance with the Investigator’s judgment and local 
institutional practice. 
Laboratory assessments should be monitored in such a way that continued per-protocol 
re-treatment eligibility can be properly determined.  It is recommended that Investigators 


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monitor the patient’s safety laboratory assessments prior to and periodically during the 
treatment with durvalumab in order to manage AEs in accordance with the durvalumab TMGs 
(refer to Section 5.5.3). 
Table 8 
Volume of blood to be drawn from each patient in the first 3 months 
on-treatment 
Assessment 
Sample 
volume (mL) 
No. of 
samples 
Total 
volume (mL) 
Safety 
Clinical chemistry (serum chemistry) 
1.0 
8 
8.0 
Haematology 
2.0 
8 
16.0 
Hepatitis/HIV 
3.0 
1 
3.0 
Thyroid 
1.0 
7 
7.0 
Coagulation 
3.0 
1 
3.0 
Pharmacokinetic(s) 
3.5  
3 
10.5 
Biomarkers 
Soluble PD-L1(to assess target 
engagement) 
3.5 
2 
7.0 
ADA testing including ADA neutralising 
antibodies (to identify ADA responses in 
patient circulation) 
8.5 (1 x 3.5 mL 
sample and 1 x 
5.0 mL sample)  
2 
17.0 
Circulating soluble factors (to assess 
cytokines, chemokines, growth factors 
and antibodies against tumour and self 
antigens in circulation) 
5.0  
3 
15.0 
miRNA/mRNA (to examine immune cell 
gene expression profiles in circulation) 
5.0 mL sample at 
Randomisation 
2.5 mL at other 
timepoints 
2 
7.5 
Pharmacogenetic(s) 
8.5  
1 
8.5 
Total 
44 mL 
38 
102.5 mL 
ADA  Anti-drug antibody; HIV  Human immunodeficiency virus; miRNA  Micro RNA; mRNA  Messenger 
RNA; PD-L1  Programmed death ligand 1. 
 


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7.2 
Handling, storage and destruction of biological samples 
The samples will be used up or disposed of after analyses or retained for further use as 
described here. 
Biological samples for future research will be retained at AstraZeneca/MedImmune R&D or 
an appropriate vendor selected by AstraZeneca/MedImmune, on behalf of AstraZeneca/ 
MedImmune for a maximum of 15 years following the Last Patient’s Last Visit in the study.  
The results from future analysis will not be reported in the CSR but separately in a Scientific 
Publication. 
AstraZeneca/MedImmune ensures that any biological samples remaining after analysis have 
been performed may be repatriated upon request or kept until the end of the period specified 
in the informed consent.   
7.2.1 
Pharmacokinetic, immunogenicity and/or pharmacodynamic (soluble PD-L1) 
samples 
Samples will be disposed of after the CSR has been finalised.  For sample processing, 
handling and shipment refer to the Investigators Laboratory Manual. 
7.2.2 
Pharmacogenetic samples 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 
15 years, from the date of the Last Patient’s Last Visit, after which they will be destroyed.  
DNA is a finite resource that may be used up during analyses.  Samples will be stored and 
used until no further analyses are possible or the maximum storage time has been reached. 
Refer to Appendix D for details of the optional (DNA) genetic research. 
7.3 
Labelling and shipment of biohazard samples 
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix C ‘IATA 6.2 Guidance Document’. 
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca/MedImmune and 
appropriate labelling, shipment and containment provisions are approved. 


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7.4 
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, keeps full traceability of collected biological 
samples from the patients while in storage at the centre until shipment or disposal (where 
appropriate) and keeps documentation of receipt of arrival. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival. 
IQVIA keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers. 
Samples retained for further use are registered in the AstraZeneca biobank system during the 
entire life cycle. 
7.5 
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/destroyed, and the action documented.  If samples are already analysed, 
AstraZeneca/MedImmune is not obliged to destroy the results of this research. 
As collection of the biological samples is an optional part of the study, then the patient may 
continue in the study. 
The Principal Investigator: 
x 
Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca/MedImmune or its representative 
x 
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented 
x 
Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed/destroyed, the action 
documented and the signed document returned to the study site 
x 
Ensures that the patient and AstraZeneca/MedImmune or its representative are 
informed about the sample disposal. 
AstraZeneca/MedImmune or its representative ensures the central laboratory(ies) holding the 
samples is/are informed about the withdrawn consent immediately and that samples are 
disposed of/destroyed and the action documented and returned to the study site. 


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In the event that analysis/research has already been performed, AstraZeneca/MedImmune will 
retain the results and associated data for regulatory reasons but these will not be used in any 
subsequent analyses.   
AstraZeneca/MedImmune ensures that biological samples are returned to the source or 
destroyed at the end of a specified period as described in the informed consent. 
8. 
ETHICAL AND REGULATORY REQUIREMENTS 
8.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonisation 
(ICH)/Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca 
policy on Bioethics and Human Biological Samples. 
8.2 
Patient data protection 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 
AstraZeneca/MedImmune will not provide individual genotype results to patients, any 
insurance company, any employer, their family members, general physician or any other third 
party, unless required to do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient.  For example, in the case of 
a medical emergency, an AstraZeneca/MedImmune Physician (or representative or delegate) 
or an Investigator might know a patient’s identity and also have access to his or her genetic 
data.  Also Regulatory Authorities may require access to the relevant files, though the 
patient’s medical information and the genetic files would remain physically separate. 
All data protection and confidentiality principles are applicable to the biomarker research.   
8.3 
Ethics and regulatory review 
An Ethics Committee (Independent Ethics Committee or Institutional Review Board [IRB], as 
applicable) should approve the final study protocol, including the final version of the 
Informed Consent Form and any other written information and/or materials to be provided to 
the patients.  The Investigator will ensure the distribution of these documents to the applicable 
Ethics Committee, and to the study site staff. 
The opinion of the Ethics Committee should be given in writing.  The Investigator should 
submit the written approval to AstraZeneca before enrolment of any patient into the study.   


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The Ethics Committee should approve all advertising used to recruit patients for the study. 
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements. 
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually.   
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations. 
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities. 
For all countries except the US and Canada, AstraZeneca will provide Regulatory Authorities, 
Ethics Committees and Principal Investigators with safety updates/reports according to local 
requirements, including Suspected Unexpected Serious Adverse Reactions (SUSARs), where 
relevant. 
For the US and Canada, each Principal Investigator is responsible for providing the Ethics 
Committees/IRB with reports of any SUSARs from any other study conducted with the 
investigational product.  AstraZeneca will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements. 
8.4 
Informed consent 
The Principal Investigator(s) at each centre will: 
x 
Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study 
x 
Ensure each patient is notified that they are free to discontinue from the study at any 
time 
x 
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided 
x 
Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study 
x 
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File 
x 
Ensure a copy of the signed Informed Consent Form is given to the patient 


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x 
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the informed consent form that is approved by an Ethics Committee. 
The PGx component of the study (relating to DNA) is optional and will be detailed on a 
separate informed consent form.   
For all patients who are treated through progression and patients who achieve disease control 
and restart study drug upon evidence of confirmed PD (according to RECIST 1.1) during 
follow-up, 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 meet the inclusion and exclusion criteria specified in Section 4.3.  The 
informed consent documents will specify that treatment beyond initial evidence of PD or re-
treatment for progression during follow up is not the standard of care and that alternative 
treatment options, either locally licensed treatments or other clinical trials, are available for 
this patient population.  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.   
Patients who are eligible for re-treatment following final DCO for the study must sign the re-
treatment informed consent prior to receiving durvalumab.  Copies of the informed consent 
must be maintained with the patient’s medical records. 
8.5 
Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the International 
Co-ordinating Investigator and AstraZeneca. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol). 
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols. 
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to Ethics Committee see Section 8.3. 
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s Ethics Committee are to approve the revised Informed Consent Form before 
the revised form is used.  
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee. 


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8.6 
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all 
study-related activities and documents, to determine whether these activities were conducted, 
and data were recorded, analysed, and accurately reported according to the protocol, GCP, 
guidelines of the ICH, and any applicable regulatory requirements.  The Investigator will 
contact AstraZeneca immediately if contacted by a regulatory agency about an inspection at 
the centre. 
9. 
STUDY MANAGEMENT BY ASTRAZENECA 
IQVIA is responsible for the management of this study and thus throughout this section 
IQVIA is considered the representative of AstraZeneca.   
9.1 
Pre-study activities 
Before the first patient is entered into the study, it is necessary for a representative of 
AstraZeneca to visit the investigational study site to: 
x 
Determine the adequacy of the facilities 
x 
Determine availability of appropriate patients for the study 
x 
Discuss with the Investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to protocol adherence, and the responsibilities of 
AstraZeneca or its representatives.  This will be documented in a Clinical Study 
Agreement between AstraZeneca and the Investigator.  
9.2 
Training of study site personnel 
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures (including those 
listed in the Laboratory Manual) and the IVRS and WBDC system(s) utilised.   
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 


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9.3 
Monitoring of the study 
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to: 
x 
Provide information and support to the Investigator(s) 
x 
Confirm that facilities remain acceptable 
x 
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks 
are being performed 
x 
Perform source data verification (a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating patients. This 
will require direct access to all original records for each patient (eg, clinic charts). 
x 
Ensure withdrawal of informed consent to the use of the patient’s biological 
samples is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the patient. 
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct. 
9.3.1 
Source data 
Refer to the Clinical Study Agreement for location of source data.   
9.4 
Study agreements 
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail. 
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled. 
9.4.1 
Archiving of study documents 
The Investigator follows the principles outlined in the Clinical Study Agreement. 


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9.5 
Study timetable and end of study 
If the study reaches statistical significance for PFS/OS at the interim or final analyses, 
additional follow-up for that particular endpoint may occur based on the needs for long term 
follow up with more mature data in order to estimate the long-term benefit for MEDI4736.  
The study will continue until all analyses for long term PFS/OS benefit are complete and those 
patients who have been in OS and PFS follow-up for approximately 5 years will be considered 
to have completed the study.  Patients who have been progression free for approximately 
5 years are considered cured and will no longer be considered eligible for retreatment within 
this protocol.  Those patients who are still actively in retreatment, and continuing to receive 
clinical benefit, will have the option to continue on study drug on an alternate rollover or 
extension protocol.   
The roll-over or safety extension study will ensure treatment continuation with visits and 
assessments per its protocol.  Any patient that would be proposed to move to such study 
would be asked to sign a new informed consent. 
The study may be terminated at individual centres once there are no longer any patients being 
treated or followed in progression-free or overall survival follow up or once the final DCO for 
the study has occurred and all queries at that centre have been resolved.   
9.5.1 
Data collection after the primary analysis of PFS and OS 
If the study achieves statistical significance for the co-primary endpoints of PFS and/or OS at 
one of the planned interim analyses, then that will be considered the final analysis for that 
endpoint.  Further analyses for that particular endpoint may still occur depending on the need 
to have long-term follow up or more mature data; the last DCO of the study will then be the 
last assessment of long-term benefit.   
Patients who are receiving MEDI4736 due to re-treatment after both primary analyses of PFS 
and OS have been conducted may continue receiving MEDI4736 treatment, if the Investigator 
judges that they are gaining clinical benefit.  It is recommended that the patients continue the 
scheduled site visits and that Investigators monitor the patient’s safety laboratory results prior 
to and periodically during the treatment with MEDI4736 in order to manage AEs in 
accordance with the MEDI4736 TMGs (refer to Section 5.5.3).  A summary of study 
procedures to be followed for patients in long-term follow up or in re-treatment (effective at 
the time of approval of CSP Amendment 7) is presented in Table 11.   
Patients in progression-free follow up will receive tumour assessment scans in accordance 
with Table 11 (effective at the time of approval of CSP Amendment 7) up to the time of final 
DCO and are to undergo sampling for local laboratory assessments in such a way that 
continued per-protocol re treatment eligibility can be properly determined in the event of 
progression.  Scans are to be submitted for BICR in the same manner that they were during 
the treatment portion of the study.   
Patients in progression-free follow up and who are eligible for re-treatment (ie, patients who 
were randomised to the MEDI4736 arm, who completed the initial 12 months of treatment, 


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and who meet the eligibility criteria for re-treatment [see below]) remain eligible for possible 
future re treatment upon progression for up to ~5 years following their initial study 
randomisation if they still meet the re-treatment eligibility criteria and the Investigator judges 
that the patient will gain clinical benefit at that time.  Patients who progress >3 years after 
randomisation must have a biopsy to confirm that this is a true recurrence of their original 
tumour and not a new primary lesion to allow for confirmation of their eligibility for 
re-treatment. 
Eligibility criteria for re-treatment: 
 The patient must provide signed, written and dated consent through the re-treatment 
informed consent form (criterion 1).  This consent document will specify re-treatment 
upon progression during follow up is not the standard of care and that alternative treatment 
options, either locally licensed treatments or other clinical trials, are available for this 
patient population.  
 A biopsy is mandated at the time of progression if more than 3 years have passed since 
randomisation as confirmation of true recurrence of the original tumour and not a new 
primary lesion; the Investigator must consult with the Study Physician if such sampling is 
not feasible. 
 The patient must meet serum creatinine CL >40 mL/min by the Cockcroft-Gault formula 
(or by 24-hour urine collection as defined by the formula in protocol inclusion 
criterion 10) and the criterion for AST/ALT.   
The patient should not enter re-treatment if any of the following exclusion criteria are 
fulfilled: 
 Concurrent enrolment in another clinical study, unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional study 
(criterion 4) 
 Current or prior use of immunosuppressive medication within 28 days before the first dose 
of study drug, with the exceptions of intranasal and inhaled corticosteroids or systemic 
corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, 
or an equivalent corticosteroid (criterion 9) 
 Any unresolved toxicity CTCAE >Grade 2 from previous anti-cancer therapy.  Patients 
with irreversible toxicity that is not reasonably expected to be exacerbated by the 
investigational product may be included (eg, hearing loss) after consultation with the 
AstraZeneca/MedImmune study physician (criterion 11)   
 $Q\SULRU*UDGHLU$(ZKLle previously receiving study treatment, or any unresolved 
irAE >Grade 1 (criterion 13) 
 Be currently receiving, or have received in the interim period after stopping study drug, 
any chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment.  
Note: Local treatment of isolated lesions, excluding target lesions, for palliative intent is 
acceptable (eg, by local surgery or radiotherapy) (drawn from criterion 14)  


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 Recent major surgery within 4 weeks prior to dosing (excluding the placement of vascular 
access) that would prevent administration of investigational product (criterion 15) 
 Active or prior documented autoimmune disease within the past 2 years (patients with 
vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment within the past 
2 years are not excluded) (criterion 16) 
 Active or prior documented inflammatory bowel disease (eg, Crohn’s disease, ulcerative 
colitis) (criterion 17) 
 0HDQ47LQWHUYDOFRUUHFWHGIRUKHDUWUDWH47FPVFDOFXODWHGIURP
3 electrocardiograms (ECGs) using Bazett’s Correction (criterion 21) 
 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses 
including any patient known to have evidence of acute or chronic hepatitis B, hepatitis C 
or human immunodeficiency virus (HIV), or psychiatric illness/social situations that 
would limit compliance with study requirements or compromise the ability of the patient 
to give written informed consent (criterion 22) 
 Active infection of tuberculosis, as determined by clinical signs and symptoms (criterion 
23) 
 Receipt of live attenuated vaccination within 30 days prior to dosing or within 30 days of 
receiving study drug (criterion 24) 
 Female patients who are pregnant, breast-feeding or male or female patients of 
reproductive potential who are not employing an effective method of birth control 
(criterion 26) 
 Any condition that, in the opinion of the Investigator, would interfere with evaluation of 
the investigational product or interpretation of patient safety or study results (criterion 27). 
 
Data collection during long-term follow up: 
After the primary analysis of PFS and OS is conducted, all data will be recorded on patient 
charts only, and not in the WBDC system, with the exception of the following which will 
continue to be collected and recorded on the WBDC system (see Table 9):  


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Table 9 
eCRFs to be completed during long-term follow up 
Assessment to be captured 
Relevant CRF page to be completed 
RECIST assessments: tumour assessments should be 
performed relative to the date of randomisation as 
follows:  every 26 weeks (±4 weeks) until confirmed 
PD by RECIST 1.1 by investigational site review. 
Please refer to Table 11 for timings of confirmatory 
scans.   
RECIST1TLF, RECIST1NTLF, 
RECIST2NL, RECISTVR 
Survival : every 8 weeks (±1 week) 
SURVIVE 
Statement of death 
DEATH 
Subsequent anti-cancer therapy 
CAPRXPOST, CAPRXRPOST, CONPRO 
Hospitalisations and hospital resource utilisation 
HOSPAD 
Specific concomitant medications for all patients 
regardless of treatment arm and disease status 
(supportive care therapy – see Table 10) 
MED 
All SAEs experienced by patients whilst receiving 
treatment with MEDI4736 or within 90 days of 
discontinuing MEDI4736 must continue to be 
reported to the Sponsor within the usual timelines 
(ie, immediately, or no later than 24 hours of when 
the site becomes aware of the SAE; see Section 6.4.4).  
If a SAE is reported then all data relevant to the SAE 
(eg, concomitant medications, laboratory data, 
dosing data, new medical or surgical history) should 
be submitted as part of the SAE report 
SAE 
 
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and 
non-immune-mediated reactions for MEDI4736 monotherapy are provided in the TMGs.  The 
most current version of these guidelines is to be maintained within the Site Master File.  In 
addition, a version of the current TMGs is available through the following link:   
https://tmg.azirae.com  
Please contact the Clinical Research Associate for information on how to gain access to this 
website.    
Review of patient charts may be conducted periodically as needed by AstraZeneca or an 
authorised representative.    


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Table 10 
Concomitant medications/Supportive Care therapy of interest 
during safety follow up 
1 
Pain medications 
2 
Antibiotics (systemic) 
3 
Antifungals (systemic) 
4 
Antiemetics 
5 
Red blood cell transfusion 
6 
Platelet transfusion 
7 
Erythropoiesis-stimulating agents (ESAs) 
8 
Granulocyte-colony stimulating factor (GCSF) 
9 
Steroids (Dosing and duration of treatment are particularly important) 
10 
Anti-depressants 
 


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Table 11 
Schedule of study procedures: Long-term follow-up and re-
treatment period after primary PFS and OS analyses 
Assessmenta 
Frequency 
Patients in survival follow-up 
Survival assessment 
Q8w (±1w) 
Hospital resource utilisation 
As applicable but at least Q12w 
Concomitant medications (see section 9.5.1 & 
Table 10) 
As applicable but at least Q12w 
Subsequent anti-cancer therapy 
As applicable 
 
Patients in progression-free follow-up 
Survival assessment 
Q8w (±1w) 
Hospital resource utilisation 
As applicable but at least Q12w 
Concomitant medications (see section 9.5.1 & 
Table 10) 
As applicable but at least Q12w 
Tumour assessment (CT or MRI) 
Q26w (±4w)c  
 
Patients eligible for or receiving re-WUHDWPHQWXSWRGD\VSRVWODVWGRVH 
Written informed consent for re-treatment only (Note: 
Patients are required to re-consent to continue study 
drug when restarting study drug following initial 
disease control [See Section 8.4]) 
Upon determination of progression. 
Verification of eligibility criteria for re-treatment 
(including tumour biopsyd) 
Upon determination of progression. 
Survival assessment 
Q8w (±1w) 
Hospital resource utilisation 
As applicable, but at least Q12w 
MEDI4736 (Durvalumab) administration for 
re-treatmentb 
Q2w (±3d) 
Serious adverse event assessment (see sections 6.4.2, 
6.4.3 and 6.4.4) 
As applicable 
Concomitant medications (see section 9.5.1 & 
Table 10) 
As applicable, but at least Q12w 
Tumour assessment (CT or MRI) 
Q26w (±4w) c 
Vital signs, haematology, serum chemistrya 
It is recommended that for re-treatment patients 
haematology, clinical chemistry, thyroid function and 
vital signs continue to be assessed as per the initial 
12 month treatment period as detailed in Table 1. 
 
a 
Assessments are to be performed at the times stipulated and as clinically required in the management of the patient.  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 as per the schedule of study 
procedures above in order to manage AEs in accordance with the durvalumab toxicity management guidelines (refer to 


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Section 5.5.3). It is recommended that results for urea and electrolytes, full blood count and liver function tests should 
be available before commencing an infusion.  If screening laboratory assessments are performed within 3 days prior to 
Day 1, they do not need to be repeated at Day 1.  All assessments to be performed pre-infusion unless stated otherwise. 
b 
Patients with confirmed PD who continue to receive study drug at the discretion of the Investigator (following 
consultation with the sponsor) can receive study drug for as long as the Investigator judges that they are gaining clinical 
benefit.  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.  Study drug should be discontinued if there is 
confirmed progression of disease (PD) following a previous response (PR or CR) to study drug. 
c 
Q26w (±4w) relative to date of randomisation until confirmed PD by RECIST 1.1 by investigational site review. An 
additional scan should be performed following any scan indicating progression and submitted for BICR review. 
d 
The collection of tumour biopsies at the time of progression prior to re-treatment is mandated if more than 3 years have 
passed since randomisation; the Investigator must consult with the Study Physician if such sampling is not feasible. 
CT  Computed tomography; MRI  Magnetic resonance imaging; PD  Progression of disease.   
 
9.5.2 
Data collection after the final DCO for the study 
The last DCO of the study will be the last assessment of long-term benefit.  After the final 
DCO, patients in OS and PFS follow-up will be considered to have completed the study.  
Patients who are receiving treatment at time of final DCO may continue receiving 
investigational product if the Investigator judges that they are gaining clinical benefit.   
For re-treatment patients who do continue to receive study drug beyond the time of the final 
DCO, Investigators will report SAEs to AstraZeneca/Medimmune Patient Safety until 90 days 
after study drug is discontinued, in accordance with Section 6.4.4 (Reporting of Serious 
Adverse Events).  Any non-serious AE that is ongoing at the time of this DCO is to be 
followed up at the discretion of the Investigator and per local practice and in alignment with 
the TMGs (refer to Section 5.5.3) of this protocol.  Data will not be captured for the purposes 
of this study outside of being recorded in the patients’ source documents.   
Following the final DCO for the study, SAE reporting applies only to patients who are still 
receiving MEDI4736 or who are in the 90-day safety follow up period post the last dose.   
10. 
DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE 
Data management will be performed by IQVIA. 
The data collected through third party sources will be obtained and reconciled against study 
data. 
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA).  Medications 
will be classified according to the WHO Drug Dictionary.  All coding will be performed by 
IQVIA. 
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail. 


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The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
When all data have been coded, validated, signed and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked. 
Data associated with biological samples will be transferred to laboratories internal or external 
to AstraZeneca/MedImmune. 
Any genotype data generated in this study will be stored in the AstraZeneca genotyping 
Laboratory Information Management System (LIMS) database, or other appropriate secure 
system within AstraZeneca and/or third party contracted to work with 
AstraZeneca/MedImmune to analyse samples.  The results from this genetic research may be 
reported in the CSR for the main study, or in a separate report as appropriate. 
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.   
11. 
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA, OR DELEGATE 
A comprehensive Statistical Analysis Plan (SAP) will be prepared. 
11.1 
Calculation or derivation of efficacy variable(s) 
11.1.1 
RECIST 1.1 based endpoints 
 Blinded Independent Central Review of RECIST 1.1-based assessments 
The BICR of all radiological imaging data will be carried out using RECIST version 1.1.  All 
radiological scans for all patients (including those at unscheduled visits, or outside visit 
windows) will be provided to the BICR.  Prior radiotherapy reports will also be provided to 
the BICR to allow the selection of appropriate target lesions.  The imaging scans will be 
reviewed by 2 independent radiologists using RECIST 1.1 and will be adjudicated, if required.  
For each patient, the BICR will define the overall visit response data (CR, PR, SD, PD or not 
evaluable [NE]) and the relevant scan dates for each time point (ie, for visits where response 
or progression is/is not identified).  If a patient has had a tumour assessment that cannot be 
evaluated then the patient will be assigned a visit response of not evaluable (NE) (unless there 
is evidence of progression in which case the response will be assigned as PD).  Endpoints (of 
PFS, ORR, and DoR) will be derived from the overall visit response date and the scan dates. 
Further details of the BICR will be documented in the Imaging Charter.  


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 Investigator RECIST 1.1-based assessments 
All RECIST assessments, whether scheduled or unscheduled, will be included in the 
calculations.  This is also regardless of whether a patient discontinues study drug or receives 
another anti-cancer therapy.   
At each visit, patients will be programmatically assigned a RECIST 1.1 visit response of CR, 
PR, NED, SD, or PD depending on the status of their disease compared with baseline and 
previous BICR assessments.  Patients with no evidence of disease at follow-up in the absence 
of new lesions will be assigned a response of NED.  The baseline assessment is part of the 
screening procedures and should be performed within 0 to 42 days after the end of 
chemoradiation therapy and before the start of study drug.  For patients who are recovering 
from toxicities associated with prior treatment, randomisation may be delayed by up to 
42 days from the end of the chemoradiation therapy.   
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 response will be assigned as PD).   
Please refer to Appendix F for the definitions of CR, PR, NED, SD and PD.  
11.1.2 
Blinded Independent Central Review of irRC-based assessments 
The definitions of CR, PR, SD and PD according to irRECIST 1.1, as outlined by  
Wolchok et al 2009, Nishino et al 2013, will be outlined clearly in the Imaging Charter. 
11.1.3 
Co-primary endpoints
The co-primary endpoints are OS and PFS. 
 Overall survival 
OS is defined as the time from the date of randomisation until death due to any cause.  Any 
patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the patient was known to be alive.  
Note: Survival calls will be made in the week following the date of DCO for the analysis, and 
if patients are confirmed to be alive or if the death date is post the DCO date these patients 
will be censored at the date of DCO.  Death dates may be found by checking publicly 
available death registries. 
 Progression free survival 
PFS (per RECIST 1.1 as assessed by the BICR) will be defined as the time from the date of 
randomisation until the date of objective disease progression or death (by any cause in the 
absence of progression) regardless of whether the patient withdraws from randomised therapy 
or receives another anti-cancer therapy prior to progression.  Patients who have not progressed 
or died at the time of analysis will be censored at the time of the latest date of assessment from 
their last evaluable RECIST 1.1 assessment.  However, if the patient progresses or dies after 


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2 or more missed visits, the patient will be censored at the time of the latest evaluable 
RECIST 1.1 assessment prior to the 2 missed visits.  If the patient has no evaluable visits or 
does not have baseline data they will be censored at Day 1 unless they die within 2 visits of 
baseline.   
The PFS time will always be derived based on scan/assessment dates not visit dates. 
RECIST 1.1 assessments/scans contributing towards a particular visit may be performed on 
different dates.  The following rules will be applied: 
x 
The date of progression will be determined based on the earliest of the scan dates of 
the component that triggered the progression for the adjudicated reviewer selecting 
PD or of either reviewer where both select PD as a time point response and there is 
no adjudication for central review (BICR) data 
x 
For investigational assessments, the date of progression will be determined based 
on the earliest of the RECIST assessment/scan dates of the component that indicates 
progression 
x 
When censoring a patient for PFS the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment. 
Note: For target lesions, only the latest scan date is recorded in the RECIST eCRF out of all 
scans performed at that assessment for the target lesions and similarly for non-target lesions 
only the latest scan date is recorded out of all scans performed at that assessment for the non-
target lesions. 
Additionally, PFS will be obtained using the algorithm described above for the RECIST BICR 
data, but following a modification whereby any objective disease progression must be 
confirmed by the next scheduled scan.  The confirmatory scan must be no sooner than 4 weeks 
after the initial suspected progression.  If disease progression is confirmed (or disease 
progression occurs and no further scans are recorded) then the date of progression will be 
when it was originally observed.  Patients with a single disease progression and no further 
tumour assessment scans will be treated as PD in the analysis.   
In the absence of clinically significant deterioration the investigational site is advised to 
continue the patient on study drug until progression has been confirmed. 
For exploratory purposes, PFS will also be obtained using the irRC data obtained from BICR.  
Objective disease progressions also require confirmation under this approach. 
11.1.4 
Proportion of patients alive at 24 months 
The proportion of patients alive at 24 months (ie, OS24) will be defined as the Kaplan-Meier 
estimate of OS at 24 months. 


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11.1.5 
Objective response rate 
ORR (per RECIST 1.1 as assessed by BICR) is defined as the number (%) of patients with at 
least 1 visit response of CR or PR and will be based on all randomised patients who have 
measurable disease.  If the BICR finds any patients do not have measurable disease at baseline 
then the analysis of ORR for the BICR data will exclude these patients, so that the 
denominator is a subset of the Intent-to-Treat (ITT) population who have measurable disease 
at baseline per BICR.  Therefore, data obtained up until progression, or the last evaluable 
assessment in the absence of progression, will be included in the assessment of ORR.  Patients 
who go off treatment without progression, receive a subsequent therapy and then respond will 
not be included as responders in the ORR.   
ORR will also be obtained using the algorithm described above for the RECIST site 
Investigator tumour data.  The denominator is a subset of the Intent-to-Treat (ITT) population 
who have measurable disease at baseline per the site Investigator.   
Additionally, ORR will be obtained using the algorithm described above from the RECIST 
BICR data, but following a modification where any objective progression requires 
confirmation.  Therefore, data obtained up until confirmed progression, or the last evaluable 
assessment in the absence of a confirmed progression, will be included in the assessment of 
ORR.  Note that the response may be after an unconfirmed progression. 
For exploratory purposes, ORR will also be obtained for the irRC data obtained from BICR.   
11.1.6 
Duration of response 
DoR (per RECIST 1.1 as assessed by BICR) will be defined as the time from the date of first 
documented response until the first date of documented progression or death in the absence of 
disease progression.  The end of response should coincide with the date of progression or 
death from any cause used for the RECIST 1.1 PFS endpoint (Section 11.1.3.2).   
The time of the initial response will be defined as the latest of the dates contributing towards 
the first visit response of CR or PR.  Only patients with measurable or non-measurable disease 
at baseline can achieve an objective response of CR and only patients with measurable disease 
at baseline can achieve an objective response of PR. 
If a patient does not progress following a response, then their DoR will be censored at the PFS 
censoring time. 
DoR will not be defined for those patients who do not have documented response. 
11.1.7 
Proportion of patients alive and progression free at 12 months 
The proportion of patients alive and progression free at 12 months (ie, APF12) will be defined 
as the Kaplan-Meier estimate of PFS at 12 months. 


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11.1.8 
Proportion of patients alive and progression free at 18 months 
The proportion of patients alive and progression free at 18 months (ie, APF18) will be defined 
as the Kaplan-Meier estimate of PFS at 18 months. 
11.1.9 
Time from randomisation to second progression (PFS2) 
PFS2 will be defined as the time from the date of randomisation to the earliest of the 
progression event subsequent to that used for the PFS endpoint or death.  The date of 
second progression will be recorded by the Investigator and defined according to local 
standard clinical practice and may involve any of: objective radiological, symptomatic 
progression or death.  Second progression status will be reviewed every 12 weeks following 
the progression event used for the co-primary variable PFS (the first progression) and status 
recorded.  Patients alive and for whom a second disease progression has not been observed 
should be censored at the last time known to be alive and without a second disease 
progression, ie, censored at the latest of the PFS or PFS2 assessment date if the patient has not 
had a second progression or death. 
11.1.10 
Time to death or distant metastasis 
TTDM will be defined as the time from the date of randomisation until the first date of distant 
metastasis or death in the absence of distant metastasis.  Distant metastasis is defined as any 
new lesion that is outside of the radiation field according to RECIST 1.1 or proven by biopsy.  
Patients who have not developed distant metastasis or died at the time of analysis will be 
censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 
assessment.  However, if the patient has distant metastasis or dies after 2 or more missed 
visits, the patient will be censored at the time of the latest evaluable RECIST 1.1 assessment 
prior to the 2 missed visits.  If the patient has no evaluable visits or does not have baseline 
data they will be censored at Day 1 unless they die within 2 visits of baseline. 
11.2 
Calculation or derivation of safety variable(s) 
11.2.1 
Adverse events 
Data from all cycles of randomised treatment will be combined in the presentation of safety 
data.  AEs (both in terms of MedDRA preferred terms and CTCAE grade) will be listed 
individually by patient and treatment arm.   
Any AE occurring before treatment with study drug will be included in the data listings but 
will not be included in the summary tables of AEs. 
Any AE occurring within 90 days of discontinuation of investigational product (ie, the last 
dose of MEDI4736 or placebo) may be included in the AE summaries, but the majority of 
those summaries will omit those AEs observed after a patient has received further therapy for 
cancer.  Further details will be provided in the SAP.  Any events in this period that occur after 
a patient has received further therapy for cancer (following discontinuation of study drug) will 
be flagged in the data listings. 


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A separate data listing of AEs occurring more than 90 days after discontinuation of study drug 
will be produced.  These events will not be included in AE summaries.  
11.2.2 
Other significant adverse events (OAEs) 
During the evaluation of the AE data, an AstraZeneca/MedImmune medically qualified expert 
will review the list of AEs that were not reported as SAEs and AEs leading to discontinuation.  
Based on the expert’s judgement, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered OAEs and reported as 
such in the CSR.  A similar review of laboratory/vital signs/ECG data will be performed for 
identification of OAEs. 
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious) or significant 
additional treatment. 
11.2.3 
Safety assessments 
For the change from baseline summaries for vital signs, laboratory data, ECGs, and physical 
examination, the baseline value will be the latest result obtained prior to the start of study 
drug.   
The QT interval corrected for heart rate using Fridericia’s formula (QTcF) will be derived 
during creation of the reporting database using the reported ECG values (RR and QT). 
QTcF = QT/RR^ (1/3) where RR is in seconds 
Corrected calcium 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)] x 0.02) 
The denominator used in laboratory summaries will only include evaluable patients, in other 
words those who had sufficient data to have the possibility of an abnormality.   
For example: 
x 
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 
x 
If a CTCAE criterion does not consider changes from baseline, to be evaluable the 
patient need only have 1 post dose-value recorded. 
The denominator in vital signs data should include only those patients with recorded data. 
11.3 
Calculation or derivation of patient reported outcome variables 
PRO questionnaires will be assessed using the EORTC QLQ-C30 with the LC13 module 
(HRQoL with lung cancer specific additional concerns) and EQ-5D-5L.  All 


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items/questionnaires will be scored according to published scoring guidelines or the 
developer’s guidelines, if published guidelines are not available.  All PRO analyses will be 
based on the ITT study population. 
 EORTC QLQ-C30 
The EORTC QLQ-C30 consists of 30 questions that can be combined to produce 5 functional 
scales (physical, role, cognitive, emotional, social), 3 symptom scales (fatigue, pain, 
nausea/vomiting), 5 individual items (dyspnoea, insomnia, appetite loss, constipation, 
diarrhoea) and a global measure of health status.  The EORTC QLQ-C30 will be scored 
according to the EORTC QLQ-C30 scoring manual (Fayers et al 1999).  An outcome variable 
consisting of a score from 0 to 100 will be derived for each of the symptom scales/symptom 
items, the functional scales and the global health status scale in the EORTC QLQ-C30 
according to the EORTC QLQ-C30 Scoring Manual.  Higher scores on the global health status 
and functioning scales indicate better health status/function but higher scores on symptom 
scales/items represent greater symptom severity. 
The change from baseline in HRQoL will be assessed using the EORTC QLQ-C30 global 
QoL scale which includes 2 items from the EORTC QLQ-C30: “How would you rate your 
overall health during the past week? (Item 29) and “How would you rate your overall QoL 
during the past week? (Item 30).   
Definition of clinically meaningful changes 
Changes in score compared with baseline will be evaluated.  A minimum clinically 
meaningful change is defined as an absolute change in the score from baseline of 10 for 
scales/items from the EORTC QLQ-C30 (Osoba et al 1998).  For example, a clinically 
meaningful improvement in physical function (as assessed by EORTC QLQ-C30) is defined 
as an LQFUHDVHLQWKHVFRUHIURPEDVHOLQHRI, whereas a clinically meaningful deterioration 
is defined as a decrease in the score from bDVHOLQHRI.  At each post-baseline assessment, 
the change in symptoms/functioning from baseline will be categorised as improvement, no 
change or deterioration as shown in Table 12. 


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Table 12 
Mean change and visit response in health related quality of life 
Score 
Change from baseline 
Visit response 
EORTC QLQ-C30 Global quality 
of life score 
 
Improvement 
-10 
Deterioration 
Otherwise 
No change 
EORTC QLQ-C30 symptom 
scales/items 
 
Deterioration 
-10 
Improvement 
Otherwise 
No change 
EORTC QLQ-C30 functional 
scales 
 
Improvement 
-10 
Deterioration 
Otherwise 
No change 
EORTC QLQ-C30  European Organisation for Research and Treatment of Cancer 30-item core quality of life 
questionnaire. 
 
For each subscale, if <50% of the subscale items are missing, then the subscale score will be 
divided by the number of non-missing items and multiplied by the total number of items on 
the subscales (Fayers et al 1999).  If at least 50% of the items are missing, then that subscale 
will be treated as missing.  Missing single items are treated as missing.  The reason for any 
missing questionnaire will be identified and recorded.  If there is evidence that the missing 
data are systematic, missing values will be handled to ensure that any possible bias is 
minimised. 
Time to symptom deterioration 
For each of the symptoms scales/items in the EORTC QLQ-C30, time to symptom 
deterioration will be defined as the time from randomisation until the date of the first 
clinically meaningful symptom deterioration (an increase in the score from EDVHOLQHRIRU
death (by any cause) in the absence of a clinically meaningful symptom deterioration, 
regardless of whether the patient withdraws from study drug or receives another anticancer 
therapy prior to symptom deterioration.  Death will be included as an event only if the death 
occurs within 2 visits of the last PRO assessment where the symptom change could be 
evaluated.   
Patients whose symptoms (as measured by EORTC QLQ-C30) have not shown a clinically 
meaningful deterioration and who are alive at the time of the analysis will be censored at the 
time of their last PRO assessment where the symptom could be evaluated.  Also, if symptoms 
deteriorate after 2 or more missed PRO assessment visits or the patient dies after 2 or more 
missed PRO assessment visits, the patient will be censored at the time of the last PRO 


Revised Clinical Study Protocol 
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Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
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assessment where the symptom could be evaluated.  If a patient has no evaluable visits or does 
not have baseline data they will be censored at Day 1. 
The population for the analysis of time to symptom deterioration will include a subset of the 
ITT population who have baseline scores of . 
Time to QoL/Function deterioration 
For QoL, time to deterioration will be defined as the time from the date of randomisation until 
the date of the first clinically meaningful deterioration (a decrease in the function scales or the 
global health status/QoL from baseline of 10) or death (by any cause) in the absence of a 
clinically meaningful deterioration, regardless of whether the patient withdraws from study 
drug or receives another anticancer therapy prior to QoL/function deterioration.  Death will be 
included as an event only if the death occurs within 2 visits of the last PRO assessment where 
the QoL/function change could be evaluated.   
Patients whose QoL (as measured by EORTC QLQ-C30) have not shown a clinically 
meaningful deterioration and who are alive at the time of the analysis will be censored at the 
time of their last PRO assessment where the QoL/function could be evaluated.  Also, if QoL 
deteriorates after 2 or more missed PRO assessment visits or the patient dies after 2 or more 
missed PRO assessment visits, the patient will be censored at the time of the last PRO 
assessment where QoL/function could be evaluated.  If a patient has no evaluable visits or 
does not have baseline data they will be censored at Day 1. 
The population for the analysis of time to QoL/function deterioration will include a subset of 
WKH,77SRSXODWLRQZKRKDYHEDVHOLQHVFRUHVRI10. 
Symptom improvement rate 
The symptom improvement rate will be defined as the number (%) of patients with 
2 consecutive assessments at least 14 days apart that show a clinically meaningful 
improvement (a decrease from baseline score 10 for EORTC QLQ-C30 symptom 
scales/items) in that symptom from baseline. 
The denominator will consist of a subset of the ITT population who have a baseline symptom 
score of >10. 
QoL/function improvement rate 
The QoL/function improvement rate will be defined as the number (%) of patients with 
2 consecutive assessments at least 14 days apart that show a clinically meaningful 
improvement (an increase from baseline score 10 for EORTC QLQ-C30 functional scales 
and global health status/QoL) in that scale from baseline. 
The denominator will consist of a subset of the ITT population who have a baseline 
QoL/function score of . 


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Edition Number 01.1 
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 LC13  
The LC13 is a lung cancer specific module from the EORTC comprising 13 questions to 
assess lung cancer symptoms (cough, haemoptysis, dyspnoea and site-specific pain), 
treatment-related side-effects (sore mouth, dysphagia, peripheral neuropathy and alopecia) and 
pain medication.  The LC13 incorporates symptom scales including: 
x 
Dyspnoea (multi-item scale based on 3 questions: were you short of breath when 
you rested; walked; climbed stairs)
x 
Cough: 1 item (how much did you cough?) 
x 
Haemoptysis: 1 item (did you cough up blood?) 
x 
Pain: 3 individual items (Have you had pain in your chest; your arm or shoulder; 
other parts of your body?) 
The dyspnoea scale is only used if all 3 items have been scored; otherwise the items are 
treated as single-item measures.  The scoring approach for the LC13 is identical in principle to 
that for the symptom scales/single items of the EORTC QLQ-C30.   
Definition of clinically meaningful changes
Changes in score compared with baseline will be evaluated.  A minimum clinically 
meaningful change is defined as an absolute change in the score from baseline of 10 for 
scales/items from the LC13 (Osoba et al 1998).  For example, a clinically meaningful 
deterioration or worsening in chest pain (as assessed by LC13) is defined as an increase in the 
VFRUHIURPEDVHOLQHRI10, whereas a clinically meaningful improvement is defined as a 
GHFUHDVHLQWKHVFRUHIURPEDVHOLQHRI10.  At each post-baseline assessment, the change in 
symptoms from baseline will be categorised as improvement, no change or deterioration as 
shown in Table 13. 
Table 13 
Visit Response for HRQoL and disease-related symptoms 
Score 
Change from baseline 
Visit response 
LC13 symptom scales/items 
10 
Deterioration 
-10 
Improvement 
Otherwise 
No change 
HRQoL  Health Related Quality of Life; LC13  Lung Cancer Module. 
 
Time to symptom deterioration 
For each of the symptoms scales/items in LC13, time to symptom deterioration will be defined 
as the time from the date of randomisation until the date of the first clinically meaningful 
V\PSWRPGHWHULRUDWLRQDQLQFUHDVHLQWKHVFRUHIURPEDVHOLQHRI10) or death (by any cause) 
in the absence of a clinically meaningful symptom deterioration, regardless of whether the 


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Edition Number 01.1 
Date 04 September 2019 
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patient withdraws from study drug or receives another anticancer therapy prior to symptom 
deterioration.  Death will be included as an event only if the death occurs within 2 visits of the 
last PRO assessment where the symptom change could be evaluated.   
Patients whose symptoms (as measured by LC13) have not shown a clinically meaningful 
deterioration and who are alive at the time of the analysis will be censored at the time of their 
last PRO assessment where the symptom could be evaluated.  Also, if symptoms deteriorate 
after 2 or more missed PRO assessment visits or the patient dies after 2 or more missed PRO 
assessment visits, the patient will be censored at the time of the last PRO assessment where 
the symptom could be evaluated.  If a patient has no evaluable visits or does not have baseline 
data they will be censored at Day 1. 
The population for the analysis of time to symptom deterioration will include a subset of the 
ITT population who have baseline scores RI90. 
Symptom improvement rate 
The symptom improvement rate will be defined as the number (%) of patients with 
2 consecutive assessments at least 14 days apart that show a clinically meaningful 
improvement (a decrease from baseline score 10 for LC13 symptom scales/items) in that 
symptom from baseline. 
The denominator will consist of a subset of the ITT population who have a baseline symptom 
score of >10. 
 Calculation or derivation of health state utility (EQ-5D-5L) 
The EQ-5D-5L index comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression).  For each dimension, respondents select which 
statement best describes their health on that day from a possible 5 options of increasing levels 
of severity (no problems, slight problems, moderate problems, severe problems and unable 
to/extreme problems).  A unique EQ-5D health state is referred to by a 5 digit code allowing 
for a total of 3125 health states.  For example, state 11111 indicates no problems on any of the 
5 dimensions.  These data will be converted into a weighted health state index by applying 
scores from EQ-5D value sets elicited from general population samples (the base case will be 
the United Kingdom valuation set, with other country value sets applied in scenario analyses).  
Where value sets are not available, the EQ-5D-5L to EQ-5D-3L crosswalk will be applied 
(Oemar and Janseen 2013).  In addition to the descriptive system, respondents also assess their 
health on the day of assessment on a visual analogue scale, ranging from 0 (worst imaginable 
health) to 100 (best imaginable health).  This score is reported separately.  


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11.4 
Calculation or derivation of pharmacokinetic variables 
11.4.1 
PK non-compartmental analysis 
The actual sampling times will be used in the PK calculations.  MEDI4736 concentration data 
and summary statistics will be tabulated.  Individual and mean blood MEDI4736 
concentration-time profiles will be generated and included in the report.  Pharmacokinetic 
parameters will be determined using standard non-compartmental methods.  The following PK 
parameters will be determined after the first and steady-state doses: peak concentration and 
trough concentration will be reported after the first or steady-state dose, as data allow.  
Samples below the lower limit of quantification will be treated as missing in the analyses.  
11.4.2 
Population PK and exposure-response/safety analysis 
A population PK model will be developed using a non-linear mixed-effects modelling 
approach in patients with NSCLC.  The impact of physiologically-relevant patient 
characteristics (covariates) and disease on PK will be evaluated.  The relationship between 
MEDI4736 PK exposure and the effect on safety and efficacy endpoints will be evaluated.  
The results of such an analysis will be reported in a separate report.   
11.4.3 
Immunogenicity analysis 
Immunogenicity results will be reported descriptively by summarizing the number and 
percentage of patients who develop detectable anti-MEDI4736 antibodies.  The 
immunogenicity titre and presence of neutralizing ADA will be reported for samples 
confirmed positive for the presence of anti-MEDI4736 antibodies.  The effect of 
immunogenicity on PK, PDx, efficacy and safety will be evaluated if data allow. 
11.5 
Calculation or derivation of biomarker variable(s) 
Biomarker(s) will be assessed for evaluable patients according to pre-specified criteria that 
will be detailed in the SAP.  
11.6 
Calculation or derivation of pharmacogenetic variables 
In the case of genetic data, only the date the patient gave consent to participation in the 
genetic research and the date the blood sample was taken from the patient will be recorded in 
the eCRF and database.  The genetic data generated from the study will be stored in the 
AstraZeneca LIMS database or other appropriate system.  This database is a secure database, 
which is separate from the database used for the main study.  Some or all of the dataset from 
the main study may be duplicated within the AstraZeneca LIMS database for exploratory 
genetic analysis.  Data will be reported outside the CSR (please see Appendix D). 
11.7 
Calculation or derivation of health economic variables 
Frequency and estimates of resource use, including length of stay and number of hospital 
admissions, will be derived from the health resource use information. 


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12. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION BY ASTRAZENECA 
12.1 
Description of analysis sets 
A comprehensive SAP will be prepared.  The Full Analysis Set (FAS) and the Safety Analysis 
Set described below will be applied to all randomised patients. 
Table 14 gives a summary of outcome variables and analysis populations. 
Table 14 
Summary of outcome variables and analysis populations 
Outcome variable 
Populations 
Efficacy Data 
 
OS, PFS 
ITT 
OS24, ORR, DoR, APF12, APF18, PFS2, PRO endpoints, and TTDM 
ITT 
Demography 
ITT 
PK data 
PK 
Safety Data 
 
Exposure 
Safety 
Adverse events 
Safety 
Laboratory measurements 
Safety 
Vital Signs 
Safety 
APF12  Proportion of patients alive and progression free at 12 months from randomisation; APF18  Proportion of 
patients alive and progression free at 18 months from randomisation; DoR  Duration of response;  
ITT  Intent-to-Treat; ORR  Objective response rate; OS Overall survival; OS24  Proportion of patients alive at 
24  months from randomisation;  PFS  Progression free survival; PFS2  Time from randomisation to second 
progression; PK  Pharmacokinetic; PRO  Patient reported outcomes; TTDM  Time to death or distant metastasis. 
 
12.1.1 
Full analysis set  
Intent-to-treat: The primary statistical analysis of the efficacy of MEDI4736 versus placebo 
will include all randomised patients and will compare the treatment arms on the basis of 
randomised treatment, regardless of the treatment actually received.  Patients who were 
randomised but did not subsequently go on to receive study drug are included in the ITT 
population.  Note, this is also known as the FAS.  Therefore, all efficacy and HRQoL data will 
be summarised and analysed using the FAS on an ITT basis. 


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12.1.2 
Safety analysis set 
All patients who received at least one dose of randomised study drug (MEDI4736 or placebo) 
and for whom any post-dose data are available will be included in the safety population.  
Throughout the safety results sections, erroneously treated patients (eg, those randomised to 
Treatment A but actually given Treatment B) will be accounted for in the actual treatment 
arm.  
When assessing safety and tolerability, summaries will be produced based on the safety 
analysis set. 
12.1.3 
PK analysis set 
All patients who receive at least 1 dose of MEDI4736 per the protocol, for whom any 
post-dose data are available and do not violate or deviate from the protocol in ways that would 
significantly affect the PK analyses will be included in the PK analysis set.  The population 
will be defined by the Study Team Physician, Pharmacokineticist, and Statistician prior to any 
analyses being performed. 
12.2 
Methods of statistical analyses 
There will be 1 treatment comparison of interest: 
x 
MEDI4736 10 mg/kg versus placebo 
OS and PFS are co-primary endpoints and the study has been sized to characterise the OS and 
PFS benefit of MEDI4736 10 mg/kg.  
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment arm.  Continuous variables will be summarised by the number of observations, 
mean, standard deviation, median, minimum, and maximum.  Categorical variables will be 
summarised by frequency counts and percentages for each category.  Unless otherwise stated, 
percentages will be calculated out of the population total for the corresponding treatment arm.  
Baseline will be the last assessment of the variable under consideration prior to the intake of 
the first infusion of study drug, except for efficacy variables.  For efficacy variables, baseline 
is defined as the last visit prior to randomisation. 
Efficacy data will be summarised and analysed on the ITT analysis set.   
Safety data will be summarised on the safety analysis set. 
Results of all statistical analysis will be presented using a 95% confidence interval (CI) and 
p-value, unless otherwise stated. 
The following table details which endpoints are to be subjected to formal statistical analysis, 
together with pre-planned sensitivity analyses making clear which analysis is regarded as 
primary for that endpoint. 


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Table 15 
Formal statistical analyses to be conducted and pre-planned 
sensitivity analyses 
Endpoints Analysed 
Notes 
Overall Survival 
Primary analysis using a stratified log-rank test 
Sensitivity analysis using a Kaplan-Meier plot of time to 
censoring where the censoring indicator of the primary 
analysis is reversed – attrition bias 
Progression Free Survival 
Stratified log-rank test using BICR tumour data (RECIST 
1.1) 
Sensitivity analyses using BICR tumour data (RECIST 1.1) 
1) Interval censored analysis – evaluation time bias 
2) Analysis using alternative censoring rules – 
attrition bias 
Sensitivity analysis stratified log-rank test using site 
Investigator tumour data (RECIST 1.1) – ascertainment 
bias 
Sensitivity analysis stratified log-rank test using BICR 
tumour data (RECIST 1.1, modified for confirmation of 
progression) – confirmation bias 
Exploratory analysis stratified log-rank test using BICR 
tumour data (irRC)   
Proportion of patients alive at 
24 months 
Hazard ratio using the Kaplan-Meier estimates of survival 
at 24 months (following the method described by  
Klein et al 2007) 
Objective Response Rate 
Fisher’s exact test using BICR tumour data (RECIST 1.1) 
Sensitivity analysis using the Fisher’s exact test using site 
Investigator tumour data (RECIST 1.1) 
Sensitivity analysis using the Fisher’s exact test using 
BICR tumour data (RECIST 1.1, modified for confirmation 
of progression) 
Exploratory analysis using the Fisher’s exact test using 
BICR tumour data (irRC)  
Duration of Response 
Analysis following the method described by  
Ellis et al 2008 using BICR tumour data (RECIST 1.1) 
Proportion of patients alive and 
progression free at 12 and 18 months  
Hazard ratio using the Kaplan Meier estimates of 
progression free survival at 12 and 18 months (following 
method described by Klein et al 2007) 
Time from randomisation to second 
progression  
Stratified log-rank test  
Time to death or distant metastasis 
Stratified log-rank test using site BICR tumour data 
(RECIST 1.1) 


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Table 15 
Formal statistical analyses to be conducted and pre-planned 
sensitivity analyses 
Endpoints Analysed 
Notes 
Symptom improvement rate (EORTC 
QLQ-C30 and LC13 endpoints) 
Logistic regression 
QoL/Function improvement rate 
(EORTC QLQ-C30 endpoints) 
Logistic regression 
Time to QoL/Function deterioration 
(EORTC QLQ-C30 endpoints) 
Stratified log-rank test 
Sensitivity analysis using alternative censoring rules – 
attrition bias 
Time to symptom deterioration 
(EORTC QLQ-C30 and LC13 
endpoints) 
Stratified log-rank test 
Sensitivity analysis using alternative censoring rules – 
attrition bias 
Change from baseline (EQ-5D-5L 
health state utility values and Visual 
Analogue Scale) 
Mixed model repeated measures analysis 
BICR  Blinded Independent Central Review; EORTC QLQ-C30  European Organisation for Research and 
Treatment of Cancer 30-item core quality of life questionnaire; EQ-5D-5L  EuroQoL 5 dimension, 5 level health 
state utility index; irRC  Immune-related response criteria; LC13  Lung Cancer Module; QoL  Quality of Life; 
RECIST  Response Evaluation Criteria In Solid Tumours. 
 
All outputs will be summarised by treatment arm for all randomised patients (ITT).   
12.2.1 
Multiple testing strategy 
The multiple testing procedure will define which significance levels should be applied to the 
interpretation of the raw p-values for the 2 primary endpoints of PFS and OS and the key 
secondary endpoints of OS24 and ORR. 
There will be up to 4 DCO time points in the study.  The DCO for the interim PFS analysis 
(first analysis) will be done when 367 PFS events have occurred (52% maturity), 
approximately 30 months after the first patient is randomised.  The DCO for the primary PFS 
analysis (second analysis) and the first interim OS analysis will be done when at least 458 PFS 
events have occurred (65% maturity) at approximately 36 months after first patient is 
randomised (with approximately 285 OS events, 41% maturity). The third analysis DCO will 
occur at the time of the second OS interim analysis when it is expected that 393 OS events 
have occurred (56% maturity, approximately 47 months after the first patient is randomised).  
The DCO for the primary OS analysis (fourth analysis) will be done when 491 OS events have 
occurred (70% maturity) at approximately 62 months. 
The overall 5% type 1 error will be split between the co-primary endpoints OS and PFS.  An 
alpha level of 2.5% will be allocated to OS analysis and PFS analysis equally.  An interim 
PFS analysis for superiority will occur when approximately 367 PFS events have occurred and 


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the primary PFS analysis will be performed when 458 PFS events have accumulated.  The 
2.5% alpha level allocated to PFS will be controlled at the interim and primary time point by 
using the Lan DeMets (Lan and DeMets 1983) spending function that approximates an 
O’Brien Fleming approach, where the significance level applied at the interim depends upon 
the proportion of information available.  If 80% of the PFS events required at the time of the 
primary PFS analysis is available at the time of the interim (ie, 367/458 PFS events have 
occurred), the 2-sided significance level to be applied for the PFS interim analysis would be 
1.04% and the 2-sided significance level to be applied for the primary PFS analysis would be 
2.19%. 
The first interim OS analysis for superiority will occur at the time of the primary PFS analysis 
and the second interim OS analysis will occur when it is expected that 393 OS events have 
occurred.  The 2.5% alpha level allocated to OS will be controlled at the interim and primary 
time point by using the Lan DeMets (Lan and DeMets 1983) spending function that 
approximates an O’Brien Fleming approach, where the significance level applied at the 
interim depends upon the proportion of information available.  For example, if 58% and 80% 
of OS events required at the time of the primary OS analysis is available at the time of the 
interim (ie, 285/491 and 393/491 events have occurred), the 2-sided significance level to be 
applied for the OS interim analysis would be 0.21% and 0.98% respectively, and the 2-sided 
significance level to be applied for the primary OS analysis would be 2.17%. 
At the time of the primary PFS, interim OS and primary OS analyses, hypotheses will be 
tested using a multiple testing procedure with an alpha-exhaustive recycling strategy  
(Burman et al 2009).  With this approach, hypotheses will be tested in a pre-defined order.  At 
the time of the primary PFS analysis, the PFS endpoint will be tested first and at the time of 
the primary OS analysis, the OS endpoint will be tested first.  The other hypotheses will then 
be tested in the multiple testing procedure using a weighted proportion of alpha (test mass; the 
total test mass equals alpha) and test mass that becomes available after each rejected 
hypothesis is recycled to the hypotheses not yet rejected.  This testing procedure stops when 
the entire test mass is allocated to non-rejected hypotheses.  Implementation of this 
pre-defined ordered testing procedure, including recycling, will strongly control type I error at 
5% (2-sided), amongst all key hypotheses.   
At the primary PFS analysis, if significance is achieved on the primary PFS analysis, then the 
alpha will be recycled to OS primary analysis followed by the secondary endpoints, OS24 and 
ORR.   
Similarly, if OS is significant at the interim analysis, the available alpha will be recycled to 
PFS primary analysis followed by the secondary endpoints.  If OS is significant at the primary 
analysis timepoint, available alpha will be recycled to PFS primary analysis followed by the 
secondary endpoints.  Spending alpha between secondary endpoints in this way will strongly 
control type I error (Glimm et al 2009).  Figure 3 shows the multiple testing framework.  


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Figure 3 
Multiple testing procedures for controlling the type 1 error rate 
 
 
12.2.2 
Co-primary endpoints 
 Overall survival 
The primary analysis of the co-primary endpoint, OS, will occur when approximately 
491 deaths have occurred (approximately 70% maturity).  OS will be analysed using a 
stratified log-rank test adjusting for DJHDWUDQGRPLVDWLRQYHUVXV\HDUVRIDJHVH[
(male versus female), and smoking history (smoker versus non-smoker).   
The effect of treatment will be estimated by the hazard ratio (HR) together with its 
corresponding 97.5% CI and p-value for the ITT population.   
The HR and CI can be estimated from the stratified log-rank as follows (Berry et al 1991, 
Collett 2003, Selke and Siegmund 1983): 
 
 
 
 


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Where 
 is the stratified log-rank 
test statistic obtained from the SAS LIFTEST procedure, 
 
, is its 
standard deviation, k denotes the stratum and d1ki and e1ki are the observed and expected 
events in Group 1, stratum k. 
Kaplan-Meier plots of OS will be presented by treatment arm.  Summaries of the number and 
percentage of patients who have died, those still in survival follow-up, those lost to follow-up 
and those who have withdrawn consent will be provided along with the median OS for each 
treatment.  
The assumption of proportionality will be assessed.  Proportional hazards will be tested firstly 
by examining plots of complementary log-log (event times) versus log (time) and, if these 
raise concerns, by fitting a time-dependent covariate to assess the extent to which this 
represents random variation.  If a lack of proportionality is evident, the variation in treatment 
effect will be described by presenting piecewise HR calculated over distinct time-periods.  In 
such circumstances, the HR can still be meaningfully interpreted as an average HR over time 
unless there is extensive crossing of the survival curves.  If lack of proportionality is found, 
this may be is a result of treatment-by-covariate interactions, which will be investigated. 
A sensitivity analysis for OS will examine the censoring patterns to rule out attrition bias, 
achieved by a Kaplan-Meier plot of time to censoring where the censoring indicator of OS is 
reversed. 
Subgroup analyses will be conducted comparing OS between treatments in the following 
subgroups of the FAS: 
x 
Age at randomisation (<YHUVXV\HDUVRIDJH 
x 
Sex (male versus female) 
x 
Smoking status (smoker versus non-smoker).   
Other baseline variables may also be assessed if there is clinical justification or an imbalance 
is observed between the treatment arms.  The purpose of the subgroup analyses is to assess the 
consistency of treatment effect across expected prognostic factors. 
No adjustment to the significance level for testing will be made since all these analyses will be 
considered supportive of the primary analysis of OS. 
Cox proportional hazards modelling will be employed to assess the effect of covariates on the 
HR estimate.  Before embarking on more detailed modelling, an initial model will be 
constructed, containing treatment and the stratification factors alone, to ensure any output 
from the Cox modelling is likely to be consistent with the results of the stratified log-rank test. 
 


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The presence of quantitative interactions will be assessed by means of an overall global 
interaction test.  This will be performed in the overall population by comparing the fit of a 
Cox proportional hazards model including treatment, all covariates, and all covariate-by 
treatment interaction terms, with one that excludes the interaction terms and will be assessed 
at the 2-sided 10% significance level.  If the fit of the model is not significantly improved then 
it will be concluded that overall the treatment effect is consistent across the subgroups. 
If the global interaction test is found to be statistically significant, an attempt to determine the 
cause and type of interaction will be made.  Stepwise backwards selection will be performed 
on the saturated model, whereby (using a 10% level throughout) the least significant 
interaction terms are removed one-by-one and any newly significant interactions re-included 
until a final model is reached where all included interactions are significant and all excluded 
interactions are non-significant.  Throughout this process all main effects will be included in 
the model regardless of whether the corresponding interaction term is still present.  This 
approach will identify the factors that independently alter the treatment effect and prevent 
identification of multiple correlated interactions. 
Any quantitative interactions identified using this procedure will then be tested to rule out any 
qualitative interaction using the approach of Gail and Simon 1985. 
Additionally, for each subgroup, the HR (MEDI4736: placebo) and 95% CI will be calculated 
from a log-rank test within each individual subgroup.  These will be presented on a forest plot 
including the HR and 95% CI from the overall population. 
If there are too few events available for a meaningful analysis of a particular subgroup (it is 
not considered appropriate to present analyses where there are less than 20 events in a 
subgroup), the relationship between that subgroup and OS will not be formally analysed.  In 
this case, only descriptive summaries will be provided. 
 Progression free survival  
The primary analysis of the co-primary endpoint, PFS, will occur when it is expected that 
458 PFS events have occurred (65% maturity).  PFS based upon the BICR data will be 
analysed using a stratified log-rank test adjusting for the same factors as for OS.  The effect of 
treatment will be estimated by the HR together with its corresponding 97.5% CI and p-value 
for the full ITT population.  Kaplan-Meier plots of PFS will be presented by treatment arm.  
Summaries of the number and percentage of patients experiencing a PFS event, and the type 
of event (RECIST 1.1 or death) will be provided along with median PFS for each treatment. 
The assumption of proportionality will be assessed in the same way as for OS.  The analysis 
will be based on the programmatically derived PFS using BICR data.   
Sensitivity analyses will be performed to assess possible evaluation-time bias that may be 
introduced if scans are not performed at the protocol-scheduled timepoints.  The midpoint 
between the time of progression and the previous evaluable RECIST assessment will be 
analysed using a log-rank test.  For patients whose death was treated as PFS event, the date of 


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death will be used to derive the PFS time used in the analysis.  This approach has been shown 
to be robust to even highly asymmetric assessment schedules (Sun and Chen 2010).  
Attrition bias will be assessed by repeating the PFS analysis except that the actual PFS event 
times, rather than the censored times, of patients who progressed or died in the absence of 
progression immediately following 2, or more, non-evaluable tumour assessments will be 
included.  In addition, patients who take subsequent therapy prior to progression or death will 
be censored at their last evaluable assessment prior to taking the subsequent therapy.  This 
analysis will be supported by a Kaplan-Meier plot of the time to censoring where the 
censoring indicator of the PFS analysis is reversed. 
Ascertainment bias will be assessed by analysing site Investigator data.  The stratified 
log-rank test will be repeated on the programmatically derived PFS using the site Investigator 
data based upon RECIST.  The HR and CI will be presented.   
If there is an important discrepancy between the primary analysis using the BICR and this 
sensitivity analysis using site Investigator data assessments, then the proportion of patients 
with site but no central confirmation of progression will be summarised; such patients have 
the potential to introduce bias in the central review due to informative censoring.  An 
approach that imputes an event at the next visit in the central review analysis may help inform 
the most likely HR value (Fleischer et al 2011), but only if an important discrepancy exists.  
An additional analysis using the BICR tumour data will be performed to determine the effect 
of confirmation of progression.  The stratified log-rank test will be repeated on the 
programmatically derived PFS using BICR tumour data based upon RECIST modified for 
confirmation of progression.  The HR and CI will be presented. 
An exploratory analysis of PFS using the irRC data obtained from the BICR will be 
performed.  The stratified log-rank test will be repeated on PFS using the BICR based upon 
the irRC data.  The HR and CI will be presented. 
Subgroup analyses and a forest plot will be provided comparing PFS between treatments in 
the same way as previously specified for OS.  Unless there is a marked difference between the 
results of the statistical analyses of the PFS from the BICR tumour data and that of the site 
Investigator, this will only be performed upon the programmatically derived PFS endpoint 
using BICR data based upon RECIST. 
No adjustment to the significance level for testing will be made since all these subgroup and 
sensitivity analyses will be considered supportive of the primary analysis of PFS. 


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12.2.3 
Proportion of patients alive at 24 months (OS24) 
The proportion of patients alive at 24 months (ie, OS24) will be summarised (using the 
Kaplan-Meier curve) and presented by treatment arm.  It will be compared between treatments 
by using the Kaplan-Meier estimator of survival at 24 months for each treatment to obtain the 
HR.  The HR and CI will be presented. 
12.2.4 
Objective response rate 
The ORR will be based on the programmatically derived RECIST using the BICR data.  The 
ORR will be compared between MEDI4736 versus placebo using a Fisher’s exact test.  A 
binary response variable for ORR will be used for the analysis with the categories of CR and 
PR versus SD, PD and NE.  The results of the analysis will be presented in terms of the 
proportion of responders and a p-value.   
This analysis of ORR will be repeated using the results of the programmatically derived PFS 
using the site Investigator data from all scans based upon RECIST as a sensitivity analysis to 
confirm the results of the primary analysis derived from the CRFs.  An additional sensitivity 
analysis will be performed on ORR using BICR tumour data based upon RECIST modified 
for confirmation of progression to determine if there is any difference when using progression 
confirmation rules.  Finally, an exploratory analysis of ORR using the irRC data obtained 
from the BICR will be performed where the above analysis will be repeated.  
Summaries will be produced that present the number and percentage of patients with a tumour 
response (CR/PR).  Overall visit response data will be listed and summarised over time for all 
patients (ie, the FAS).  For each treatment arm, best objective response (BoR) will be 
summarised by n (%) for each category (CR, PR, NED, SD, PD, NE).  No formal statistical 
analyses are planned for BoR. 
12.2.5 
Duration of response 
In order to analyse the DoR between arms the Expected Duration of Response (EDoR) will be 
derived for each treatment arm (Ellis et al 2008) for the BICR tumour data.  The EDoR is the 
product of the proportion of patients responding to treatment and the mean DoR in responding 
patients and provides an estimate based on all randomised patients.  Treatments will be 
compared by calculating the ratio of EDoRs, using an appropriate probability distribution (to 
be specified in the SAP) for DoR in responding patients.  Additionally, descriptive data will 
be provided for the DoR in responding patients, including the associated Kaplan-Meier curves 
(without any formal comparison of treatment arms or p-value attached). 
12.2.6 
Proportion of patients alive and progression free at 12 months (APF12) 
The proportion of patients alive and progression free at 12 months will be summarised (using 
the Kaplan-Meier curve) and presented by treatment arm.  Each will be compared between 
treatments by using the Kaplan-Meier estimator of PFS at 12 months for each treatment to 
obtain the HR.  The HR and CI will be presented. 


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12.2.7 
Proportion of patients alive and progression free at 18 months (APF18) 
The proportion of patients alive and progression free at 18 months will be summarised (using 
the Kaplan-Meier curve) and presented by treatment arm.  Each will be compared between 
treatments by using the Kaplan-Meier estimator of PFS at 18 months for each treatment to 
obtain the HR.  The HR and CI will be presented. 
12.2.8 
Time from randomisation to second progression (PFS2) 
PFS2 will be analysed using identical methods as outlined for the analysis of PFS and 
adjusting for the same set of covariates, but no subgroup analysis will be performed.  Medians 
and Kaplan-Meier plots will be presented to support the analysis.  The sensitivity analysis 
outlined in Section 12.2.2.2 will not be repeated for PFS2 with the exception of a 
Kaplan-Meier plot of the time to censoring where the censoring indicator of PFS2 is reversed. 
12.2.9 
Time to death or distant metastasis 
TTDM will be analysed using identical methods as outlined for the analysis of PFS and 
adjusting for the same set of covariates, but no subgroup analysis will be performed.  Medians 
and Kaplan-Meier plots will be presented to support the analysis.  The sensitivity analysis 
outlined in Section 12.2.2.2 will not be repeated for TTDM with the exception of a 
Kaplan-Meier plot of the time to censoring where the censoring indicator of TTDM is 
reversed. 
12.2.10 
Patient reported outcomes  
The PRO endpoints that have been identified as primary are EORTC QLQ-C30 time to QoL 
deterioration of global health status and LC13 time to symptom deterioration for each of 
dyspnoea, cough, haemoptysis, and pain.  These are not part of the main multiple testing 
procedure but as supportive endpoints will need a Bonferroni adjustment to the significance 
level to aid interpretation.  Therefore, these 5 endpoints will be tested at a 1% significance 
level and 99% CIs will be produced.  
The other time to symptom deterioration endpoints will be tested at a 5% significance level 
and 95% CIs will be produced. 
 EORTC QLQ-C30 
Time to symptom deterioration will be analysed for each of the 3 symptom scales (fatigue, 
pain, nausea/vomiting) and the 5 individual symptom items (dyspnoea, insomnia, appetite 
loss, constipation, diarrhoea).  Time to QoL/function deterioration will be analysed for the 
5 function scales (physical, role, emotional, cognitive, and social) and global health 
status/QoL.  This will be achieved by comparing between treatment arms using a stratified 
log-rank test as described for the primary analysis of OS.  The sensitivity analysis to ascertain 
attrition bias will be performed as described for the primary analysis of OS for those endpoints 
identified as primary.  However, subgroup analyses and treatment interaction testing will not 
be performed.  The HR and 95% CI for each scale/item will be presented graphically on a 
forest plot. 


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A summary of the symptom improvement rate for each of the 3 symptom scales and the 
5 individual symptom items will be produced.  Similarly, a summary of QoL/function 
improvement rate for each of the 5 function scales (physical, role, emotional, cognitive, and 
social) and global health status/QoL will be produced.  Symptom improvement rate and 
QoL/function improvement rate will be analysed by comparing between treatment arms using 
a logistic regression model.  The odds ratio and 95% CI for each scale/item will be presented 
graphically on a forest plot.  If there are very few responses in one treatment arm, a Fisher’s 
exact test will be considered. 
For each of the 3 symptom scales (fatigue, pain, nausea/vomiting), 5 individual symptom 
items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea), 5 functional scales 
(physical, role, emotional, cognitive, and social), and global health status/QoL, time to 
deterioration will be presented using a Kaplan-Meier plot.  Summaries of the number and 
percentage of patients experiencing a clinically meaningful deterioration or death, and the 
median time to deterioration will also be provided for each treatment arm.   
Summaries of original and change from baseline values of each symptom scale/item, the 
global HRQoL score and each functional domain will be reported by visit for each treatment 
arm.  Graphical presentations may also be produced as appropriate.  Summaries of the number 
and percentage of patients in each response category at each visit for each ordinal item (in 
terms of the proportion of patients in the categories of improvement, no change, and 
deterioration as defined in Section 11.3.1.1) will also be produced for each treatment arm.  
 LC13 
Time to symptom deterioration for each of the 6 individual symptoms (dyspnoea, cough, 
haemoptysis, chest pain, arm/shoulder pain, other pain) will be compared between treatment 
arms using a stratified log-rank test as described for the primary analysis of OS.  The 
sensitivity analysis to ascertain attrition bias will be performed as described for the primary 
analysis of OS for those endpoints identified as primary.  However, subgroup analyses and 
treatment interaction testing will not be performed.  The HR and 95% CI for each scale/item 
will be presented graphically on a forest plot. 
For each of the 6 symptoms items in LC13, time to deterioration in symptoms will be 
presented using a Kaplan-Meier plot.  Summaries of the number and percentage of patients 
experiencing a clinically meaningful deterioration or death, and the median time to 
deterioration will also be provided for each treatment arm.   
A summary of the symptom improvement rate for each of the 6 individual symptom items will 
be produced.  The symptom improvement rate will be compared between treatment arms 
using a logistic regression model.  The odds ratio and 95% CI for each symptom will be 
presented graphically on a forest plot.  If there are very few responses in one treatment arm, a 
Fisher’s exact test will be considered. 
Summaries of original and change from baseline values of each symptom (dyspnoea, cough, 
haemoptysis, chest pain, arm/shoulder pain, other pain) and each treatment-related side effect 


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(sore mouth, dysphagia, peripheral neuropathy and alopecia) will be reported by visit for each 
treatment arm.  Graphical presentations may also be produced as appropriate.  Summaries of 
the number and percentage of patients in each response category at each visit for each ordinal 
symptom item (in terms of the proportion of patients in the categories of improvement, 
no change, and deterioration as defined in Section 11.3.1.2) will also be produced for each 
treatment arm.   
 EuroQol-5-Dimension 5-Level questionnaire 
The change from baseline in health state utility values and the visual analogue scale will be 
compared between treatment arms at each visit using a mixed model repeated measures 
analysis, which adjusts for the same factors as the primary analysis and also the baseline 
health state utility value/visual analogue scale as appropriate.  Adjusted mean differences 
between treatments and 95% CIs from these analyses will be presented, but, as this analysis is 
exploratory in nature, p-values will not be calculated. 
Descriptive statistics will be reported for the health state domain (eg, proportion in each 
domain) and the visual analogue scale by visit, as well as the change in the visual analogue 
scale value and the derived utility index value from baseline.  To support future economic 
evaluations, additional appropriate analyses may be undertaken, for example, mean health 
state utility pre- and post-treatment, and pre- and post-progression. 
12.2.11 
Healthcare resource use 
An exploratory health economic analysis of hospital episodes including type of contact 
(hospitalisation, outpatient, day case), reason, length of stay by ward type (including intensive 
care unit) and procedures and tests may be undertaken to examine the impact of disease and 
treatment on resource use to primarily support the economic evaluation of MEDI4736.  This 
would include providing descriptive statistics as appropriate, including means, median and 
ranges.
12.2.12 
Safety data 
Safety and tolerability data will be presented by treatment arm using the safety population. 
Data from all cycles of treatment will be combined in the presentation of safety data.  AEs 
(both in terms of MedDRA preferred terms and CTCAE grade) will be listed individually by 
patient.  The number of patients experiencing each AE will be summarised by treatment arm 
and CTCAE grade.  Additionally, data presentations of the rate of AEs per person-years at risk 
may be produced.  Any safety summaries examining re-treatment with MEDI4736 will be 
produced separately. 
Other safety data will be assessed in terms of physical examination, clinical chemistry, 
haematology, vital signs and ECGs.  Exposure to MEDI4736 and placebo will be summarised.  
Time on study and MEDI4736/placebo dose interruptions will also be summarised.  At the 
end of the study, appropriate summaries of all safety data will be produced, as defined in the 
SAP.  


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12.2.13 
PK data  
MEDI4736 concentration data will be listed for each patient and each dosing day, and a 
summary provided for all evaluable patients.  
Immunogenicity analysis  
Immunogenicity results will be listed by patient and a summary will be provided of the 
number and percentage of patients who develop detectable anti-MEDI4736 antibodies.  The 
immunogenicity titre and neutralising ADA data will be listed for samples confirmed positive 
for the presence of anti-MEDI4736 antibodies.   
12.2.14 
PK/PDx relationships  
If the data are suitable, the relationship between MEDI4736 PK exposure and efficacy/safety 
parameters may be investigated graphically or using appropriate data modelling approach. 
12.2.15 
Biomarker data 
The relationship of PD-L1 expression and if applicable, of exploratory biomarkers to OS, 
PFS, ORR and DoR will be presented for a subset of patients in the ITT population who are 
evaluable for each biomarker.  
This will be assessed using similar summary and graphical representations to those that are 
outlined for the efficacy outputs in Section 12.2.2 to 12.2.5.   
PD-L1 expression determined by immunohistochemistry will be reported in the CSR.  
Summaries and analyses for exploratory biomarkers will be documented in a separate analysis 
plan and will be reported outside the CSR in a separate report. 
12.2.16 
Interim analysis 
Up to 3 interim analyses will be performed, one for PFS and two for OS.  The DCO for the 
interim analysis of PFS will occur when it is expected that 367 PFS events have occurred 
(52% maturity, approximately 30 months after the first patient is randomised).  The DCO for 
the first interim analysis of OS will occur when it is expected that 458 PFS events have 
occurred (65% maturity, approximately 36 months after the first patient is randomised).  It is 
expected that approximately 285 death events (41% maturity) will be available for the interim 
OS analysis (assuming OS HR=0.73).  The second interim analysis of OS (the third interim 
analysis) will be conducted when it is expected that 393 OS events have occurred (56% 
maturity, approximately 47 months after the first patient is randomised).  The interim analyses 
will be assessed by an IDMC (further details are given in the IDMC charter).  It is expected 
that recruitment will have completed prior to the results of these interim analyses being 
available. 
 
 


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 PFS interim analysis 
Approximately 367 PFS events (52% maturity) will be available for the interim PFS analysis.   
The Lan DeMets spending function that approximates an O’Brien Fleming approach will be 
used to account for multiplicity introduced by including an interim analysis for superiority 
(Lan and DeMets 1983).   
The criterion for superiority is a statistically significant improvement in PFS at the interim 
analysis.  If 80% of the PFS events required at the time of the primary PFS analysis is 
available at the time of the interim (ie, 367/458 PFS events have occurred), the 2-sided 
significance level to be applied for the PFS interim analysis would be 1.04% and the 2-sided 
significance level to be applied for the primary PFS analysis would be 2.19%. 
If the PFS results indicate superiority, then analyses of all other endpoints may also be 
performed.  Patients would continue to be followed for PFS and survival until approximately 
458 PFS events, when the primary PFS analysis and the first interim OS analysis would be 
performed. 
If the PFS interim analysis result does not meet the criterion of stopping for superiority, then 
all patients will remain blinded and continue to be followed for PFS and OS.  
The recommendations from the IDMC will not reveal the results of the analysis but will take 
the form of “Continue/Modify/Stop”. 
OS interim analyses 
Approximately 285 and 393 death events (41% and 56% maturity) will be available for the 
first and the second interim OS analysis, respectively (assuming OS HR=0.73).   
The Lan DeMets spending function that approximates an O’Brien Fleming approach will be 
used to account for multiplicity introduced by including an interim analysis for superiority 
(Lan and DeMets 1983).   
The criterion for superiority is a statistically significant improvement in OS at the interim 
analyses.  If 58% or 80% of OS events required at the time of the primary OS analysis is 
available at the time of the interim (ie, 285/491 or 393/491 events have occurred), the 2-sided 
significance level to be applied for the OS interim analysis would be 0.21% and 0.98%, 
respectively, and the 2-sided significance level to be applied for the primary OS analysis 
would be 2.17%.  
If the PFS and/or OS results indicate superiority, then analyses of all other endpoints would be 
performed and the results of these analyses will form the basis for submissions for regulatory 
approval.  Patients would continue to be followed for survival until approximately 
491 patients have died, when an updated analysis would be performed. 


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If the PFS result is not statistically significant and/or either of the OS interim analysis result 
does not meet the criterion of stopping for superiority, then all patients will remain blinded 
and continue to be followed for survival.  
The recommendations from the IDMC will not reveal the results of the analysis but will take 
the form of “Continue/Modify/Recommend Early Submission/Stop”. 
12.3 
Determination of sample size 
The sample size for this study was selected to be consistent with the research hypothesis as 
described in Section 1.2. 
The two co-primary endpoints of this study are OS and PFS.  To control for type-I error, a 
significance level of 2.5% will be used for analysis of OS and a significance level of 2.5% will 
be used for analysis of PFS.  The study will be considered positive (a success) if either the 
PFS analysis results and/or the OS analysis results are statistically significant. 
Approximately 702 patients will be randomised 2:1 to obtain 491 death events in the ITT 
population (70% maturity).  The primary PFS analysis DCO will occur when it is expected 
that 458 PFS events have occurred (65% maturity).  If the true PFS HR is 0.67, the study will 
provide at least 95% power to demonstrate a statistically significant difference for PFS with a 
2-sided significance level of 2.5% in the ITT population; this translates to a 5-month benefit in 
median PFS over 10 months on placebo if PFS is exponentially distributed.  The smallest 
treatment difference that would be statistically significant is a HR of 0.8.  A recruitment 
period of approximately 22 months and a follow-up period of 14 months are expected for the 
PFS endpoint.  Therefore it is anticipated that this PFS analysis could be performed 
approximately 36 months after the first patient has been randomised. 
The primary OS analysis DCO will occur when it is expected that 491 OS events have 
occurred (70% maturity).  If the true OS HR is 0.73, this number of death events will provide 
at least 85% power to demonstrate a statistically significant difference for OS, assuming a 
2.5% 2-sided significance level in the ITT population; this translates to an 8-month benefit in 
median OS over 22 months on placebo if OS is exponentially distributed.  The smallest 
treatment difference that would be statistically significant is a HR of 0.81.  A recruitment 
period of approximately 22 months and a follow-up period of 40 months are expected for the 
OS endpoint.  Therefore it is anticipated that this OS analysis could be performed at 
approximately 62 months after the first patient has been randomised. 
Please refer to Appendix D for information on PGx. 
12.4 
Independent data monitoring committee  
This study will use an external IDMC to assess ongoing safety analyses as well as interim 
efficacy analyses for superiority based on PFS and OS and the primary analysis of PFS:   


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x 
The IDMC will review the safety data from approximately the first 75 patients, or 
approximately 3 months after randomisation of the first patient and then again 
3 months later 
x 
The IDMC will then meet at least every 6months thereafter up to the decision to 
unblind the study to review safety data  
x 
The IDMC will review the unblinded interim analysis summaries of efficacy data 
x 
Additional reviews of the safety data may be requested by the IDMC at additional 
points during the study. 
This committee will be composed of therapeutic area experts and biostatisticians, who are not 
employed by AstraZeneca/MedImmune and do not have any major conflict of interest. 
Following the reviews, the IDMC will recommend whether the study should continue 
unchanged, be stopped, or be modified in any way.  Once the IDMC has reached a 
recommendation, a report will be provided to AstraZeneca/MedImmune.  The report will 
include the recommendation and any potential protocol amendments, and will not contain any 
unblinding information.  The final decision to modify or stop the study will sit with the 
sponsor. 
In addition: 
x 
The IDMC will review the efficacy data when 367 progression events have 
occurred, at approximately 30 months post-randomisation, at the time of the interim 
analysis of PFS. 
x 
The IDMC will review the efficacy data when 458 progression events have 
occurred, at approximately 36 months post-randomisation at the time of the primary 
analysis of PFS and the first interim analysis of OS. 
x 
The IDMC will review the efficacy data when 393 OS events have occurred, at 
approximately 47 months post-randomisation at the time of the second interim 
analysis of OS. 
A separate IDMC charter will be developed, which will contain details of the IDMC members 
and clearly define the responsibilities of the IDMC. 
The safety of all AstraZeneca/MedImmune clinical studies is closely monitored on an ongoing 
basis by AstraZeneca/MedImmune representatives in consultation with the Patient Safety 
Department.  Issues identified will be addressed; this could involve, for instance, amendments 
to the clinical study protocol and letters to Investigators. 


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13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR 
13.1 
Medical emergencies, AstraZeneca/MedImmune and IQVIA 
contacts 
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, see Section 6.4.4 
In the case of a medical emergency the Investigator may contact the 24-hour IQVIA 
Medical Emergency Contact Centre 
 or alternative number 
.  After final DCO for the study, the Investigator should contact 
AstraZeneca/MedImmune Patient Safety using the contact information specified below: 
PPD
PPD




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If an overdose on an AstraZeneca/MedImmune study drug occurs in the course of the study 
and is associated with an SAE, then Investigators or other site personnel inform appropriate 
AstraZeneca/MedImmune representatives (ie, IQVIA) immediately, or no later than 
24 hours of when he or she becomes aware of it (see Section 6.4.4). 
The designated AstraZeneca/MedImmune representative (ie, IQVIA) works with the 
Investigator to ensure that all relevant information is provided to the 
AstraZeneca/MedImmune Patient Safety data entry site. 
For all other overdoses ie, those not associated with an SAE, reporting should be done within 
30 days. 
If an overdose on an AstraZeneca study drug occurs after the final DCO for the study, then 
Investigators or other site personnel shall inform AstraZeneca/MedImmune Patient Safety 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
13.3 
Pregnancy 
All outcomes of pregnancy should be reported to AstraZeneca/MedImmune representative (ie, 
IQVIA).   
Following the final DCO for the study, Investigators or other site personnel shall report all 
pregnancy outcomes to AstraZeneca/MedImmune Patient Safety. 
13.3.1 
Maternal exposure 
If a patient becomes pregnant during the course of the study investigational product should be 
discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication.  
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs.  Elective abortions without complications should not be handled as AEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and documented 
even if the patient was discontinued from the study. 
If any pregnancy occurs in the course of the study, then Investigators or other site personnel 
inform appropriate AstraZeneca/MedImmune representatives (ie, IQVIA) immediately, or no 
later than 24 hours of when he or she becomes aware of it. 
If any pregnancy occurs after the final DCO for the study, Investigators or other site personnel 
must inform AstraZeneca/MedImmune Patient Safety immediately, or no later than 24 
hours of when he or she becomes aware of it. 
The designated AstraZeneca/MedImmune representative works with the Investigator to ensure 
that all relevant information is provided to the AstraZeneca/MedImmune Patient Safety data 


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entry site within 1 or 5 days for SAEs, see Section 6.4.4 and within 30 days for all other 
pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT is 
used to report the outcome of the pregnancy.  Paper-based modules will be available to sites 
following final DCO for the study. 
13.3.2 
Paternal exposure 
Information on the pregnancy of a patient’s partner must be obtained directly from the 
patient’s partner.  Therefore, prior to obtaining information on the pregnancy, the Investigator 
must obtain the consent of the patient’s partner. 
Male patients should refrain from fathering a child or donating sperm during the study and for 
90 days following the last dose.   
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) should, if possible, be followed up and documented.  To 
capture information about a pregnancy from the partner of a male patient, the male patient’s 
partner consent must be obtained to collect information related to the pregnancy and outcome; 
the male patient should not be asked to provide this information.  A consent form specific to 
this situation must be used.  The outcome of any conception occurring from the date of the 
first dose until 90 days after the last dose should be followed up and documented.   


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14. 
LIST OF REFERENCES  
Aaronson et al 1993 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst 1993 Mar 3;85(5):365-76. 
Asami et al 2013 
Asami K, Okuma T, Hirashima T, Kawahara M, Atagi S, Kawaguchi T et al. Continued 
treatment with gefitinib beyond progressive disease benefits patients with activating EGFR 
mutations. Lung Cancer 2013 Mar;79(3):276-82. 
Bayman et al 2014 
Bayman N, Blackhall F, McCloskey P, Taylor P, Faivre-Finn C.  How can we optimise 
concurrent chemoradiotherapy for inoperable stage III non-small cell lung cancer? Lung 
Cancer 2014 Feb;83(2):117-25. [Epub ahead of print] 
Berger et al 2008 
Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, et al. Phase I safety 
and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in 
patients with advanced hematologic malignancies. Clin Cancer Res 2008 
May 15;14(10):3044-51. 
Bergman et al 1994 
Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M. The EORTC QLQ-LC13: a 
modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in 
lung cancer clinical trials. EORTC Study Group on Quality of Life. Eur J Cancer 
1994;30A(5):635-42. 
Berry et al 1991 
Berry G, Kitchin RM, Mock PA. A comparison of two simple hazard ratio estimators based 
on the logrank test. Stat Med 1991 May;10(5):749-55. 
Blank et al 2006 
Blank C, Kuball J, Voelkl S, Wiendl H, Becker B, Walter B, et al. Blockade of PD-L1 
(B7-H1) augments human tumor-specific T cell responses in vitro. Int J Cancer 2006 
Jul 15;119(2):317-27. 
Brahmer et al 2010 
Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study 
of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, 
clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010 
Jul 1;28(19):3167-75. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
158(167) 
Brahmer et al 2012 
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity 
of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012 
Jun 28;366(26):2455-65. 
Brahmer et al 2013 
Brahmer JR, Horn L, Antonia SJ, Spigel DR, Gandhi L, Sequist LV, et al. Survival and 
longterm follow-up of the phase 1 trial of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) 
in patients (pts) with previously treated advanced non-small cell lung cancer (NSCLC). J Clin 
Oncol. 2013;31(15_Suppl):Abstract 8030. 
Burman et al 2009 
Burman CF, Sonesson C, Guilbaud O. A recycling framework for the construction of 
Bonferroni-based multiple tests. Stat Med 2009 Feb 28;28(5):739-61.  
Butts et al 2014 
Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, et al, on behalf of 
the START trial team. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for 
stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. 
Lancet Oncol  2014;15(1):59-68.  
Cockcroft and Gault 1976 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41. 
Collett 2003 
Collett D. Modelling survival data in medical research: 2nd ed. Chapman and Hall/CRC; 2003. 
$YDLODEOHRQUHTXHVW
D’Addario et al 2010 
D’Addario G, Früh M, Reck M, Baumann P, Klepetko W, Felip E, et al; ESMO Guidelines 
Working Group. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines 
for diagnosis, treatment and follow-up. Ann Oncol 2010 May;21(Suppl 5):v116-9. 
Deng et al 2014 
Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation and 
anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 2014 
Jan 2;pii:67313. [Epub ahead of print] 
Dewan et al 2009 
Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, et al. 
Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect 
when combined with anti-CTLA-4 antibody. Clin Cancer Res 2009 Sep 1;15(17):5379-88.  


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
159(167) 
Dong et al 2003 
Dong H, Strome SE, Matteson EL, Moder KG, Flies DB, Zhu G, et al.  Costimulating aberrant 
T cell responses by B7-H1 autoantibodies in rheumatoid arthritis. J Clin Invest 2003 
Feb;111(3):363-70. 
Dong et al 2004 
Dong H, Zhu G, Tamada K, Flies DB, van Deursen JM, Chen L. B7-H1 determines 
accumulation and deletion of intrahepatic CD8(+) T lymphocytes. Immunity 2004 
Mar;20(3):327 36. 
Douillard et al 2013 
Douillard JY, Ostoros G, Cobo M, Ciuleanu T, McCormack R, Webster A, Milenkova T. 
First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, 
open-label, single-arm study. Br J Cancer. 2013 Nov 21. [Epub ahead of print] 
Drake 2012 
Drake CG. Combination immunotherapy approaches. Ann Oncol 2012 Sep;23(Suppl 
8):viii41-6. 
Ellis et al 2008 
Ellis S, Carroll KJ, Pemberton K. Analysis of duration of response in oncology trials. 
Contemp Clin Trials 2008 Jul;29(4):456-65. 
EuroQoL 1990 
EuroQol Group. EuroQol - a new facility for the measurement of health-related quality of life. 
Health Policy 1990 Dec;16(3):199-208. 
EuroQoL 2013 
EuroQol Group. EQ-5D-5L User Guide: Basic information on how to use the EQ-5D-5L 
instrument, Version 2.0, October 2013. Available from: 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/UserGuide_
EQ-5D-5L_v2.0_October_2013.pdf. Accessed 21 November 2013. 
Fayers et al 1999 
Fayers P, Aaronson NK, Bjordal K, Curran D, Groenvold M on behalf of the EORTC Quality 
of Life Study Group. EORTC QLQ-C30 Scoring Manual: 2nd Edition 1999. $YDLODEOHRQ
UHTXHVW
FDA Guidance 2009 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’.  Available from URL: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf.  Accessed 10 December 2013. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
160(167) 
FDA Guidance 2011 
FDA Guidance for Industry (issued June 2011) ‘Clinical trial endpoints for the approval of 
non-small cell lung cancer drugs and biologics’.  Available from URL: 
http://www.fda.gov/downloads/Drugs/Guidances/UCM259421.pdf. Accessed 
08 January 2014. 
Fife and Bluestone 2008 
Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the 
CTLA-4 and PD-1 pathways. Immunol Rev 2008 Aug;224:166-82. 
Fleischer et al 2011 
Fleischer F, Gaschler-Markefski B, Bluhmki E. How is retrospective independent review 
influenced by Investigator-introduced informative censoring: a quantitative approach. Stat 
Med 2011 Dec 20;30(29):3373-86. 
Forde et al 2014 
Forde PM, Kelly RJ and Brahmer JR. New strategies in lung cancer: translating 
immunotherapy into clinical practice. Clin Cancer Res 2014;20:1067-1073. 
Formenti and Demaria 2013 
Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm 
shift. J Natl Cancer Inst 2013 Feb 20;105(4):256-65.  
Gail and Simon 1985 
Gail M, Simon R. Tests for qualitative interactions between treatment effects and patient 
subsets. Biometrics 1985 Jun;41(2):361–72. 
Glimm et al 2009 
Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group-sequential 
trials. Statistics in Medicine 2009; 29:219–28. 
GLOBOCAN 2008 
GLOBOCAN 2008: Estimated cancer Incidence, Mortality, Prevalence and Disability-
adjusted life years (DALYs) Worldwide in 2008.  Available from URL: 
http://globocan.iarc.fr/factsheets/cancers/lung.asp.  Accessed 29 October 2013. 
Gordon et al 2013 
Gordon MS, Hamid O, Powderly J, Anderson M, Fine G, Mokatrin A, et al. A phase I study of 
MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic 
tumors. American Association for Cancer Research 2013 Annual Meeting; 2013 Apr 06-10; 
Washington, DC. Abstract LB-288. 
Grosso et al 2013 
Grosso J, Horak CE, Inzunza D, Cardona DM, Simon JS, Gupta AK, et al. Association of 
tumor PD-L1 expression and immune biomarkers with clinical activity in patients (pts) with 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
161(167) 
advanced solid tumors treated with nivolumab (anti-PD-1; BMS-936558; ONO-4538). J Clin 
Oncol 2013;31(Suppl):abstract 3016. 
Hamanishi et al 2007 
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed 
cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of 
human ovarian cancer. Proc Natl Acad Sci U S A 2007 Feb 27;104(9):3360-5. 
Hamid et al 2013 
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses 
with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013 Jul 11;369(2):134-44.   
Herbst et al 2013 
Herbst RS, Gordon MS, Fine GD, Sosman JA, Soria JC, Hamid O, et al. A study of 
MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic 
tumors [abstract]. J Clin Oncol 2013;31(Suppl 15):Abstract 3000. 
Herdman et al 2011 
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011 
Dec;20(10):1727-36. 
Hirano et al 2005 
Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and 
PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 2005 
Feb 1;65(3):1089-96. 
Hodi et al 2010 
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanan JB, et al. Improved 
survival with ipilimumab in patients with metastatic melanoma [published erratum appears in 
N Engl J Med 2010 Sep 23;363(13):1290]. N Engl J Med 2010 Aug 19;363(8):711-23. 
IASLC Staging Manual in Thoracic Oncology 
Staging Manual in Thoracic Oncology. Goldstraw P, Chief Executive Editor. 7th Ed. IASLC 
2010.  $YDLODEOHRQUHTXHVW 
Iwai et al 2002 
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor 
cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. 
Proc Natl Acad Sci USA 2002 Sep 17;99(19):12293-7. 
Janssen et al 2008a 
Janssen MF, Birnie E, Haagsma JA, Bonsel GJ. Comparing the standard EQ-5D three-level 
system with a five-level version. Value Health 2008 Mar-Apr;11(2):275-84. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
162(167) 
Janssen et al 2008b 
Janssen MF, Birnie E, Bonsel GJ. Quantification of the level descriptors for the standard 
EQ-5D three-level system and a five-level version according to two methods. Qual Life Res 
2008 Apr;17(3):463-73. 
Kalialis et al 2009 
Kalialis LV, Drzewiecki KT, Klyver H. Spontaneous regression of metastases from 
melanoma: review of the literature. Melanoma Res 2009 Oct;19(5):275-82. 
Keir et al 2008 
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. 
Annu Rev Immunol 2008;26:677-704. 
Kim et al 2011 
Kim DW, Lee SH, Lee JS, Lee MA, Kang JH, Kim SY et al. A multicenter phase II study to 
evaluate the efficacy and safety of gefitinib as first-line treatment for Korean patients with 
advanced pulmonary adenocarcinoma harboring EGFR mutations. Lung Cancer 2011 
Jan;71(1):65-9. 
Kirkwood et al 2010 
Kirkwood JM, Lorigan P, Hersey P, Hauschild A, Robert C, McDermott D, et al. Phase II trial 
of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. 
Clin Cancer Res 2010 Feb 1;16(3):1042-8. 
Klein et al 2007 
Klein JP, Logan B, Harhoff M, Andersen PK. Analyzing survival curves at a fixed point in 
time. Stat Med 2007 Oct 30; 26(24): 4505–19. 
Krambeck et al 2007 
Krambeck AE, Dong H, Thompson RH, Kuntz SM, Lohse CM, Leibovich BC, et al. Survivin 
and b7-h1 are collaborative predictors of survival and represent potential therapeutic targets 
for patients with renal cell carcinoma. Clin Cancer Res 2007 Mar 15;13(6):1749-56. 
Lan and DeMets 1983 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 
1983;70:659-63. 
Latchman et al 2004 
Latchman YE, Liang SC, Wu Y, Chernova T, Sobel RA, Klemm M, et al. PD-L1-deficient 
mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively 
regulates T cells. Proc Natl Acad Sci USA 2004 Jul 20;101(29):10691-6. 
Lipson and Drake 2011 
Lipson EJ, Drake CG. Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Clin 
Cancer Res 2011 Nov 15;17(22):6958-62. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
163(167) 
Loos et al 2008 
Loos M, Giese NA, Kleeff J, Giese T, Gaida MM, Bergmann F, et al. Clinical significance 
and regulation of the costimulatory molecule B7-H1 in pancreatic cancer. Cancer Lett 2008 
Sep 8;268(1):98-109. 
Maemondo et al 2010 
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H et al. Gefitinib or 
Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR. N Engl J Med 2010 
Jun;362:2380-8. 
Mitsudomi et al 2010 
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J et al. Gefitinib versus 
cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of 
the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. 
Lancet Oncol 2010 Dec;11:121-28. 
Mok et al 2009  
Mok TS, Wu Y-L, Thongprasert S, Yang C-H, Chu D-T, Saijo N et al. Gefitinib or 
carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009 Sep;361:947-57. 
Mu et al 2011 
Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer 
may contribute to poor prognosis and tumor cells immune escape through suppressing tumor 
infiltrating dendritic cells maturation. Med Oncol 2011 Sep;28(3):682-8. 
NCCN Guidelines 2014 
National Comprehensive Cancer Network. NCCN Clinical practice guidelines in oncology 
(NCCN Guidelines ): Non-Small Cell Lung Cancer. Version 1.2014. Available from URL: 
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed 
10 January 2014. 
Nishino et al 2013 
Nishino M, Biobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a 
common language for tumor response to immunotherapy: immune-related response criteria 
using unidimensional measurements. Clin Cancer Res 2013;19(14):3936-43. 
Nomi et al 2007 
Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and 
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in 
human pancreatic cancer. Clin Cancer Res 2007 Apr 1;13(7):2151-7. 
Oemar and Janseen 2013 
Oemar M, Oppe M. EQ-5D-3L User Guide: Basic information on how to use the EQ-5D-3L 
instrument V5.0 (October 2013). Available from URL: 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/EQ-5D-
3L_UserGuide_2013_v5.0_October_2013.pdf. Accessed 07 January 2014. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
164(167) 
Okudaira et al 2009 
Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, et al. Blockade of 
B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model. Int J 
Oncol 2009 Oct;35(4):741-9. 
O'Rourke et al 2010 
O'Rourke N, Roqué I, Figuls M, Farré Bernadó N, Macbeth F. Concurrent chemoradiotherapy 
in non-small cell lung cancer. Cochrane Database Syst Rev 2010 Jun;16(6):CD002140.  
Osoba et al 1998  
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998 Jan;16(1):139-44. 
Pazdur 2008 
Pazdur R.  Endpoints for assessing drug activity in clinical trials. Oncologist 
2008;13(Suppl 2):19-21. 
Pagès et al 2010 
Pagès F, Galon J, Dieu-Nosjean MC, Tartour E, Sautès-Fridman C, Fridman WH. Immune 
infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene 2010 
Feb 25;29(8):1093-102. 
Park et al 2010 
Park JJ, Omiya R, Matsumura Y, Sakoda Y, Kuramasu A, Augustine MM, et al. B7-H1/CD80 
interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood 
2010 Aug 26;116(8):1291-8. 
Pickard et al 2007 
Pickard AS, De Leon MC, Kohlmann T, Cella D, Rosenbloom S. Psychometric comparison of 
the standard EQ-5D to a 5 level version in cancer patients. Med Care 2007 Mar;45(3):259-63. 
Powderly et al 2013 
Powderly JD, Koeppen H, Hodi FS, Sosman JA, Gettinger SN, Desai R, et al.  Biomarkers 
and associations with the clinical activity of PD-L1 blockade in a MPDL3280A study. J Clin 
Oncol 2013;31(Suppl):abstract 3001. 
Rizos et al 2014 
Rizos H, Menzies AM, Pupo GM, Carlino MS, Fung C, Hyman J et al. BRAF Inhibitor 
Resistance Mechanisms in Metastatic Melanoma: Spectrum and Clinical Impact. Published 
2014 Jan. Available from URL: 
http://clincancerres.aacrjournals.org/content/early/2014/01/23/1078-0432.CCR-13-
3122.abstract Accessed 23 April 2014. 
Rizvi et al 2015 
N.A Rizvi, J.R Brahmer, S-H.I Ou, N.H Segal, S Khleif, W-J Hwu, M Gutierrez, P Schoffski, 
O Hamid, J Weiss, J Lutzky, M Maio, J.J. Nemunaitis, D Jaeger, A.S Balmanoukian, M 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
165(167) 
Rebelatto, K Steele, X Li, J.A. Blake-Haskins, S.J Antonia.  Safety and clinical activity of 
MEDI4736, an anti-PD-L1 antibody, in patients with NSCLC.  Poster presented at ASCO, J 
Clin Oncol 33, 2015 (suppl; abstr 8032). 
Robert et al 2011 
Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus 
dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011 
Jun 30;364(26):2517-26. 
Rosell et al 2011 
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E et al. Erlotinib versus 
standard chemotherapy as first-line treatment for European patients with advanced EGFR 
mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, 
randomised phase 3 trial. Lancet Oncol 2012 Jan;13:239–46. 
Saijo et al 2010 
Saijo N, Fukuoka M, Thongprasert S, Ichinose Y, Mitsudomi T, Mok TSK, et al. Lung Cancer 
Working Group Report. Jpn  J Clin. Oncol 2010;40(Suppl 1):i7-i12. 
Selke and Siegmund 1983 
Selke T, Siegmund D. Sequential analysis of the proportional hazards model. Biometrika 
1983;70:315-26. 
Shaw et al 2013 
Shaw AT, Kim D-W, Nakagawa K, Seto T, Crino L, Ahn M-J et al. Crizotinib versus 
chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013 Jun;368:2385-94. 
Sun and Chen 2010 
Sun X, Chen C. Comparison of Finkelstein's Method with the Conventional Approach for 
Interval-Censored Data Analysis. Stat Biopharm Res 2010;2(1):97-108. 
Suntharalingam et al 2006 
Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al.  
Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J 
Med 2006 Sep 7;355(10):1018-28. 
Swann and Smyth 2007 
Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest 2007 
May;117(5):1137-46. 
Thompson et al 2005 
Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, et al. 
Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. 
Cancer 2005 Nov 15;104(10):2084-91. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
166(167) 
Thompson et al 2006 
Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, et al. Tumor 
B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term 
follow-up. Cancer Res 2006 Apr 1;66(7):3381-5. 
Topalian et al 2012 
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012 
Jun 28;366(26):2443-54. 
Vanneman and Dranoff 2012 
Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer 
treatment. Nat Rev Cancer 2012 Mar 22;12(4):237-51.  
Vansteenkiste et al 2013 
Vansteenkiste J, De Ruysscher D, Eberhardt WE, Lim E, Senan S, Felip E, Peters S; ESMO 
Guidelines Working Group. Early and locally advanced non-small-cell lung cancer (NSCLC): 
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013 
Oct;24 Suppl 6:vi89-98.  
Wang et al 2010 
Wang L, Ma Q, Chen X, Guo K, Li J, Zhang M. Clinical significance of B7-H1 and B7-1 
expressions in pancreatic carcinoma. World J Surg 2010 May;34(5):1059-65. 
Wolchok et al 2009 
Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin 
Cancer Res 2009 Dec 1;15(23):7412-20. 
Wolchok et al 2010 
Wolchok JD, Weber JS, Hamid O, Lebbé C, Maio M, Schadendorf D, et al. Ipilimumab 
efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA 
subtype from four trials. Cancer Immun 2010 Oct 20;10:9. 
Yang et al 2013 
Yang JJ, Chen HJ, Yan JJ, Zhang XC, Zhou Q, Su J et al. Clinical modes of EGFR tyrosine 
kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer. 
Lung Cancer 2013 Jan;79(1):33-9. 
YERVOY™ prescribing information 
Yervoy™ [prescribing information]. Princeton, NJ, IN: Bristol-Myers Squibb Company; 2011 
[cited 2011 March]. Available from: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf. Accessed 
31 October 2013. 


Revised Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736)  
Study Code D4191C00001 
Edition Number 01.1 
Date 04 September 2019 
167(167) 
Yoshimura et al 2013 
Yoshimura N, Okishio K, Mitsuoka S, Kimura T, Kawaguchi T, Kobayashi M et al. 
Prospective Assessment of Continuation of Erlotinib or Gefitinib in Patients with Acquired 
Resistance to Erlotinib or Gefitinib Followed by the Addition of Pemetrexed. J Thorac Oncol. 
2013 Jan;8:96–101. 
Zhang et al 2008a 
Zhang C, Wu S, Xue X, Li M, Qin X, Li W, et al. Anti-tumor immunotherapy by blockade of 
the PD-1/PD-L1 pathway with recombinant human PD-1-IgV. Cytotherapy 2008;10(7):711-9. 
Zhang et al 2008b 
Zhang P, Su DM, Liang M, Fu J. Chemopreventive agents induce programmed death-1-ligand 
1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated T cell 
apoptosis. Mol Immunol 2008 Mar;45(5):1470-6. [Epub ahead of print]. 
Zou and Chen 2008 
Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev 
Immunol 2008 Jun;8(6):467-77. 


 
 
Clinical Study Protocol Amendment No 07 
Appendix A 
 
Drug Substance 
MEDI4736 
 
Study Code 
D4191C00001 
 
Edition Number 
01 
 
Date 
04 September 2019 
 
Protocol Dated 
07 December 2017 
 
 
 
 
 
 
 
 
 
Appendix A 
Signatures 










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Clinical Study Protocol Appendix B 
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Clinical Study Protocol Appendix D 
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Appendix D 
Pharmacogenetics Research 
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TABLE OF CONTENTS 
PAGE
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation or 
special term 
Explanation 
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1. 
BACKGROUND AND RATIONALE 
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2. 
GENETIC RESEARCH OBJECTIVES 
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3. 
GENETIC RESEARCH PLAN AND PROCEDURES 
3.1 
Selection of genetic research population 
3.1.1 
Study selection record 
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Inclusion criteria 
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3.1.3 
Exclusion criteria 
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3.1.4 
Discontinuation of patients from this genetic research 
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3.2 
Collection of samples for genetic research 
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3.3 
Coding and storage of DNA samples 
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4. 
ETHICAL AND REGULATORY REQUIREMENTS 
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4.1 
Informed consent 
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5. 
DATA MANAGEMENT 
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STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
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7. 
LIST OF REFERENCES 
1RQH


Revised Clinical Study Protocol Appendix E
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Appendix E
Actions Required in Cases of Combined Increase of Aminotransferase and 
Total Bilirubin - Hy’s Law


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TABLE OF CONTENTS
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1.
INTRODUCTION
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2.
DEFINITIONS
Potential Hy’s Law
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3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES
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4.
FOLLOW-UP
4.1
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5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW 
CASES
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6.
ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW
CRITERIA ARE MET BEFORE AND AFTER STARTING 
STUDY TREATMENT 
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ACTIONS REQUIRED FOR REPEAT EPISODES OF 
POTENTIAL HY’S LAW
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REFERENCES
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Revised Clinical Study Protocol Appendix F 
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Appendix F 
Guidelines for Evaluation of Objective Tumour Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumours) 
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TABLE OF CONTENTS 
PAGE
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1. 
INTRODUCTION 
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2. 
DEFINITION OF MEASURABLE, NON-MEASURABLE, 
TARGET AND NON-TARGET LESIONS 
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Special cases: 
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Target lesions: 
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Non-target lesions:
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3. 
METHODS OF ASSESSMENT 
The same method of assessment and the same technique should be used to characterize 
each identified and recorded lesion at baseline and during follow-up visits. 
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Table 1 
Summary of methods of assessment 
Target lesions  
Non-target lesions 
New lesions 
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3.1 
CT and MRI  
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3.2 
Clinical examination  
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3.3 
X-ray 
3.3.1 
Chest X-ray 
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3.3.2 
Plain X-ray  
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3.4 
Ultrasound  
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3.5 
Endoscopy and laparoscopy  
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3.6 
Tumour markers  
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3.7 
Cytology and histology  
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3.8 
Isotopic bone scan  
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3.9 
18-Fluoro-deoxyglucose positron emission tomography (FDG PET) 
scan 
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4. 
TUMOUR RESPONSE EVALUATION  
4.1 
Schedule of evaluation 
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4.2 
Target lesions 
4.2.1 
Documentation of target lesions 
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4.2.2 
Evaluation of target lesions 
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Table 2 
Evaluation of target lesions 
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4.3 
Non-target lesions 
4.3.1 
Evaluation of non-target lesions 
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Table 3 
Evaluation of non-target lesions 
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Overall visit response 
Target lesions 
Non-target lesions 
New lesions 
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Eisenhauer et al 2009 
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Appendix G 
Patient Reported Outcomes: EORTC-QLQ-C30, LC-13 and EQ-5D-5L 
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SAP_005.pdf: 
Statistical Analysis Plan
Study Code
D4191C00001
Edition Number
4.0
Date
22 March 2017
A Phase III, Randomised, Double-blind, Placebo-controlled, Multi-centre, 
International Study of MEDI4736 as Sequential Therapy in Patients with 
Locally Advanced, Unresectable Non-Small Cell Lung Cancer (Stage III) 
Who Have Not Progressed Following Definitive, Platinum-based, 
Concurrent Chemoradiation Therapy (PACIFIC)






Statistical Analysis Plan 
Study Code D4191C00001
Edition Number 4.0
Date 22 March 2017
4
TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
SIGNATURE OF STUDY STATISTICIAN ..........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN....................................3
TABLE OF CONTENTS.........................................................................................4
LIST OF ABBREVIATIONS..................................................................................8
AMENDMENT HISTORY ...................................................................................11
1.
STUDY DETAILS.................................................................................................14
1.1
Study Objectives ....................................................................................................14
1.1.1
Primary objective...................................................................................................14
1.1.2
Secondary objectives .............................................................................................14
1.1.3
Exploratory objectives ...........................................................................................15
1.2
Study Design..........................................................................................................16
1.3
Number of Subjects................................................................................................21
2.
ANALYSIS SETS .................................................................................................21
2.1
Definition of Analysis Sets ....................................................................................21
2.2
Protocol Deviations................................................................................................23
3.
PRIMARY, SECONDARY AND EXPLORATORY VARIABLES ...................25
3.1
Derivation of RECIST Visit Responses.................................................................25
3.1.1
Blinded Independent Central Review (BICR) Assessment Using RECIST 
1.1...........................................................................................................................26
3.1.2
BICR assessment using RECIST 1.1 Modified for Confirmation of 
Progression.............................................................................................................27
3.1.3
BICR assessment using irRECIST 1.1...................................................................28
3.1.4
Site investigator assessment using RECIST 1.1: target lesions.............................28
3.1.5
Site investigator assessment using RECIST 1.1: NTLs and new lesions ..............33
3.1.6
Site investigator assessment using RECIST 1.1: overall visit response ................34
3.2
Outcome Variables.................................................................................................35
3.2.1
Co-primary efficacy outcome endpoints................................................................35
3.2.1.1
Overall survival (OS).............................................................................................35
3.2.1.2
Progression free survival (PFS) .............................................................................36
3.2.2
Secondary efficacy outcome endpoints..................................................................38
3.2.2.1
Proportion of patients alive at 24 months ..............................................................38
3.2.2.2
Objective response rate..........................................................................................38


Statistical Analysis Plan 
Study Code D4191C00001
Edition Number 4.0
Date 22 March 2017
5
3.2.2.3
Duration of response..............................................................................................40
3.2.2.4
Proportion of patients alive and progression free at 12 months.............................40
3.2.2.5
Proportion of patients alive and progression free at 18 months.............................40
3.2.2.6
Time from randomisation to second progression or death (PFS2) ........................41
3.2.2.7
Time to death or distant metastasis........................................................................41
3.3
Secondary Patient Reported Outcome Variables...................................................42
3.3.1
EORTC-QLQ-C30.................................................................................................42
3.3.1.1
Time to symptom deterioration..............................................................................43
3.3.1.2
Time to HR QoL/Function deterioration ...............................................................44
3.3.1.3
Symptom Improvement Rate .................................................................................45
3.3.1.4
HR QoL/Function Improvement Rate ...................................................................45
3.3.2
EORTC-QLQ-LC-13 .............................................................................................45
3.3.2.1
Time to symptom deterioration..............................................................................46
3.3.2.2
Symptom Improvement Rate .................................................................................47
3.3.3
PRO Compliance Rates..........................................................................................47
3.4
Safety .....................................................................................................................48
3.4.1
Adverse events.......................................................................................................48
3.4.2
Laboratory data ......................................................................................................49
3.4.3
ECGs......................................................................................................................50
3.4.4
Vital signs ..............................................................................................................50
3.4.5
Time to first subsequent therapy from discontinuation of study treatment ...........51
3.4.6
Treatment exposure................................................................................................51
3.4.7
Dose intensity.........................................................................................................52
3.5
Pharmacokinetic and Immunogenicity Variables ..................................................53
3.5.1
PK non-compartmental analysis ............................................................................53
3.5.2
Population PK and exposure-response/safety analysis..........................................53
3.5.3
Immunogenicity analysis .......................................................................................53
3.6
Exploratory Variables ............................................................................................54
3.6.1
EQ-5D-5L ..............................................................................................................54
3.6.2
Health Resource Use..............................................................................................54
4.
ANALYSIS METHODS .......................................................................................55
4.1
General Principles..................................................................................................55
4.1.1
Baseline..................................................................................................................56
4.1.2
Multiplicity ............................................................................................................56
4.1.3
Visit window for safety and PRO assessments......................................................59
4.2
Analysis Methods...................................................................................................61
4.2.1
Co-primary efficacy endpoints ..............................................................................63
4.2.1.1
Overall survival......................................................................................................63
4.2.1.2
Progression free survival........................................................................................67
4.2.2
Secondary efficacy endpoints ................................................................................70
4.2.2.1
Proportion of patients alive at 24 months (OS24) .................................................70
4.2.2.2
Objective response rate..........................................................................................71


Statistical Analysis Plan 
Study Code D4191C00001
Edition Number 4.0
Date 22 March 2017
6
4.2.2.3
Duration of response..............................................................................................72
4.2.2.4
Proportion of patients alive and progression free at 12 months (APF12)..............72
4.2.2.5
Proportion of patients alive and progression free at 18 months (APF18)..............72
The proportion of patients alive and progression free at 18 months (i.e. at study day 
549) will be summarised (using the Kaplan-Meier curve) and presented by 
treatment arm.  For each treatment arm, the APF18 based on Kaplan-Meier 
method will be presented, along with its 95% confidence interval. The 
computation of the confidence interval will be based on a log(-log(.)) 
transformation........................................................................................................72
4.2.2.6
Time from randomisation to second progression (PFS2) ......................................72
4.2.2.7
Time to death or distant metastasis........................................................................73
4.2.2.8
Change in tumour size ...........................................................................................73
4.2.3
Secondary patient reported outcome endpoints .....................................................73
4.2.3.1
EORTC QLQ-C30 .................................................................................................74
4.2.3.2
EORTC-QLQ-LC13 ..............................................................................................74
4.2.3.3
Mixed models repeated measures of change from baseline in PRO 
symptoms ...............................................................................................................75
4.2.4
Safety data..............................................................................................................77
4.2.4.1
Adverse events.......................................................................................................77
4.2.4.2
Laboratory assessments .........................................................................................80
4.2.4.3
ECGs......................................................................................................................82
4.2.4.4
Vital signs ..............................................................................................................82
4.2.4.5
Physical examination .............................................................................................82
4.2.4.6
Other safety data ....................................................................................................82
4.2.5
WHO performance status.......................................................................................82
4.2.6
PK analysis.............................................................................................................82
4.2.7
Immunogenicity analysis .......................................................................................83
4.2.8
PK/PDx relationships.............................................................................................83
4.2.9
Exploratory endpoints............................................................................................83
4.2.9.1
EQ-5D-5L ..............................................................................................................83
4.2.9.2
Health resource use................................................................................................83
4.2.10
Demographic and baseline characteristics data .....................................................84
4.2.11
Treatment exposure and intensity ..........................................................................85
5.
INTERIM ANALYSES.........................................................................................85
5.1
Analysis Methods...................................................................................................85
5.1.1
PFS interim analysis ..............................................................................................86
5.1.2
OS interim analyses ...............................................................................................86
5.2
Independent Data Monitoring Committee .............................................................87
6.
CHANGES OF ANALYSIS FROM PROTOCOL ...............................................89
7.
REFERENCES ......................................................................................................90
8.
APPENDIX – DETAILS FOR TTDM..................................................................94


Statistical Analysis Plan 
Study Code D4191C00001
Edition Number 4.0
Date 22 March 2017
7
LIST OF TABLES
Table 1
Summary of outcome variables and analysis populations........................22
Table 2
TL Visit Responses...................................................................................29
Table 3
NTL Visit Responses................................................................................33
Table 4
Overall Visit Responses ...........................................................................34
Table 5
Visit response for EORTC-QLQ-C30......................................................43
Table 6
Visit response for L13 ..............................................................................46
Table 7 
Dose intensity scenarios ...........................................................................52
Table 8
Formal statistical analyses to be conducted and pre-planned 
sensitivity analyses ...................................................................................61
Table 9
Changes from the planned analysis ..........................................................89
LIST OF FIGURES
Figure 1
Study flow chart .......................................................................................19
Figure 2
Multiple testing procedures for controlling the type 1 error rate .............59


Statistical Analysis Plan 
Study Code D4191C00001
Edition Number 4.0
Date 22 March 2017
8
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
APF12
Proportion of patients alive and progression free at 12 months from 
randomisation
APF18
Proportion of patients alive and progression free at 18 months from 
randomisation 
AST
Aspartate aminotransferase
AZDD
AZ drug dictionary
Baseline
Refers to the most recent assessment of any variable prior to dosing with
study treatment/randomisation (as appropriate)
BICR
Blinded independent central review
BoR
Best overall RECIST response
CI
Confidence interval 
CR
Complete response
CRF / eCRF 
Case Report Form (electronic)
CRO
Contract Research Organisation
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
DAE
Discontinuation of investigational product due to adverse event
DBL
Data base lock
DBP
Diastolic blood pressure
DCO
Data cut-off
DoR
Duration of response
ECG
Electrocardiogram 
EDoR
Expected Duration of Response
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer 30-item core 
quality of life questionnaire


Statistical Analysis Plan 
Study Code D4191C00001
Edition Number 4.0
Date 22 March 2017
9
Abbreviation or 
special term
Explanation
EQ-5D
EuroQoL 5 dimension utility index
EQ-5D-5L
EuroQoL 5 dimension, 5 level health state utility index 
FAS
Full analysis set
FWER
Family wise error rate
GSHf
Group sequential Holm fixed
HR
Hazard ratio
HRQoL
Health-related quality of life
ICU
Intensive care unit
IDMC
Independent Data Monitoring Committee
irRC
Immune-related response criteria
irRECIST 1.1
Immune-related response criteria based on RECIST 1.1
ITT
Intention to treat
iv
Intraveneous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
KM
Kaplan-Meier
LC13
Lung Cancer Module; 13-item self-administered questionnaire from the
EORTC for lung cancer
LD
Longest diameter
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MRI
Magnetic resonance imaging
NA
Not applicable
NCI
National Cancer Institute
ND
No disease, by BICR
NE
Not evaluable
NED
No evidence of disease, by Investigator assessment
NN
Non-CR/Non-PD
NSCLC
Non-small cell lung cancer
NTL
Non-target lesions
OAE
Other significant adverse event (see definition in Section 3.4.1)
ORR
Objective response rate


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Abbreviation or 
special term
Explanation
OS
Overall survival
OS24
Proportion of patients alive at 24 months from randomisation
PD
Progressive disease
PD-L1
Programmed death ligand 1
PDx
Pharmacodynamic(s)
PFS
Progression free survival
PFS2
Time from randomisation to second progression
PGx
Pharmacogenetic(s)
PID 
Percentage intended dose
PID2
Percentage intended dose (treatment through progression)
PK
Pharmacokinetic(s)
PR
Partial response
PRO
Patient reported outcome
PT
Preferred term
Q2W
Every 2 weeks
QoL
Quality of life
QTcF
QT interval (corrected for heart rate using Fridericia's correction)
RDI
Relative dose intensity
RDI2
Relative dose intensity (treatment through progression)
RECIST
Response Evaluation Criteria In Solid Tumours.  
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Stable disease
SBP
Systolic blood pressure
SOC
System organ class
TFST
Time to first subsequent therapy or death
TL
Target lesions
TSST
Time to second subsequent therapy or death 
TTDM
Time to death or distant metastasis
ULN
Upper limit of normal
WHO
World Health Organization


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Edition Number 4.0
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AMENDMENT HISTORY
Date
Brief Description of Change
N/A
7 April 2016
Updated based on protocol amendment 4 
Abbreviations Added FWER. GSHf. irRECIST, ND, NN and TTDM 
Section 1.1 Changed primary RECIST 1.1 assessments to be BICR, secondary to 
be site investigator 
Added TTDM to objectives, Table 1, section 3.2.2.7 and 12.2.9 as had not been 
previously included
Section 1.2 changed specification that radiation must be completed within 42 
days (from 14 days) and randomisation may be delayed by up to 42 days (from 
14).
Sections 1.2, 4.1.2, 5.1 and 5.2 Updated the number of events and timelines for 
the interim analyses 
Sections 1.3 and 4.1.2 Change to alpha allocation. The alpha allocation between 
PFS and OS has been to (2.5%, 2.5%) from (0.5%, 4.5%) 
Updated Figure 1 to match revised protocol
Section 2.1 Safety analysis set updated to remove criteria that post-dose 
data should be available
Section 2.2 Violation and deviations updated based on changes to the SAP 
template
Section 3.1 updated days the baseline tumour assessment should be taken 
to match the protocol. Added details about BICR assessment
Sections 3.1.1, 3.1.2 and 3.1.3 Added sections on BICR RECIST 1.1, 
RECIST 1.1 modified for confirmation of progression and irRECIST 1.1
Section 3.2 Added information on efficacy outcomes for BICR
Section 3.2.1.1 Updated to add details about how survival data will be 
obtained
Section 3.2.1.2 Changed to BICR as primary, added details about how 
missing assessments will be determined 
Section 3.2.2.2 Changed to BICR as primary. For change in tumour size, 
change to BICR.
Section 3.2.2.7 Time to death of distant metastasis, new endpoint added to 
match protocol.
Section 3.3.1.2  Remove sensitivity anlaysis for HRQoL deterioration 
where PFS is considered an event of HRQoL deterioration
Section 3.3.2 LC-13 clinically meaningful change updated to be 10 (from 
than 5)
Section 3.3.2.1 Time to symptom deterioration.  Clinically meaning 
symptom deterioration updated to be 10 (from 5).  Sensitivity analysis 
where progression is considered an event removed
Section 3.3.2.2 Symptom improvement rate.  Clinically meaning symptom 


Statistical Analysis Plan 
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deterioration updated to be 10 (from 5)
Section 3.4.1 Adverse Events.  Changed date of collection of AEs to 
informed consent (from first dose) to match protocol.  Added a definition 
of treatment emergent adverse event.
AEs of special interest.  Removed list of AESI
Section 3.4.6 Updated definition of total exposure and calculation of 
duration of dose delays.
Sections 3.4.7 and 4.2.1 Removed PID, RID and RID2
Section 4.1.1 Baseline. Added more detail for definition of baseline
Section 4.1.2 Multiplicity. Updated as per protocol amendment.  Added 
details of multiple testing procedure.
Section 4.2 Table 8 Updated to reflect changes to protocol – BICR 
primary, site investigator assessment secondary.  For EORTC QLQ-C30 
and LC13 removed sensitivity analysis for attrition.
Section 4.2.1.1 changed CI to 97.5%, from 95.5%, to match change in 
alpha.  Added subgroup analysis for time from last dose of radiation, 
remove PD-L1 subgroup and added general biomarker subgroup.  
Clarified language for analyses of subgroups. 
Section 4.2.1.2 Changed to have BICR primary, site investigator 
secondary, including updating sensitivity analyses.
Section 4.2.2.2 Changed to have BICR primary, site investigator 
secondary
Section 4.2.2.7 new section for endpoint Time to death or distant 
metastasis
Section 4.2.3 updated key endpoints as per protocol amendment 
Section 4.2.3.1 and 4.2.3.2 removed sensitivity analyses
Section 4.2.4.1 Clarified that first subsequent cancer therapy doesn’t 
include palliative radiotherapy.  Removed some presentations of AEs.  
Removed section on long term tolerability.
Section 4.2.4.2 Clarified that first subsequent cancer therapy doesn’t 
include palliative radiotherapy.  Updated tables and figures that will be 
presented.
Section 4.2.4.4 Updated tables and figures that will be presented.
5 Dec 2016
Section 3.2.2.1 Added text to state proportion of patients alive at 12 
months will be presented
Section 3.2.2.6 Clarified title to include death for PFS2
Section 3.2.2.7 Clarified definition of Time to death or distant metastasis, 
including adding table to the Appendix
Section 3.3.1 Clarified PRO baseline should be last value prior to 
randomisation 
Section 3.4.2 Added formula for creatinine clearance
Table 8 and Section 4.2.1.1 Removed global interaction test for subgroup 
analyses, subgroups will be tested using model only including treatment


Statistical Analysis Plan 
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4.2.1.1/4.2.1.2 Clarified that the confidence intervals will be 1-alpha 
adjusted.
Section 4.2.1.1 Add details for subgroups PD-L1 and EGFR.  
Section 4.2.2.1 Remove HR and added p-value to the presentation of OS12
Section 4.2.2.3 Removed analysis of Duration of Response
Section 4.2.2.4/5 Removed HR for APF12 and APF18 and added CI for 
each treatment
Section 4.2.3.3 Added mixed models repeated measures for analyses of 
PRO endpoints
Section 4.2.4.1 Updated description of death table
22 March 2017
Sections 3.2.1.2, 3.2.2.2, 3.2.2.7 Clarify criteria for censoring in the setting 
of no progression or death from last evaluable RECIST 1.1 assessment to 
last RECIST 1.1 assessment
Section 4.2.1.1 removed text to state IVRS data will be used for the 
subgroup analyses for the stratification factors.  CRF data will be used.


Statistical Analysis Plan 
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1.
STUDY DETAILS
1.1
Study Objectives
1.1.1
Primary objective
Primary Objective:
Outcome Measure:
To assess the efficacy of MEDI4736 treatment 
compared with placebo in terms of OS and PFS
OS
PFS using BICR assessments according to RECIST 1.1
OS  Overall survival; PFS  Progression free survival; RECIST  Response Evaluation Criteria In Solid Tumours. BICR
Blinded Independent Central Review
1.1.2
Secondary objectives
Secondary Objective:
Outcome Measure:
To further assess the efficacy of MEDI4736 compared 
with placebo in terms of: OS24, ORR, DoR, APF12, 
APF18, PFS2, and TTDM.
OS24
ORR using BICR assessments according to RECIST 
1.1
DoR using BICR assessments according to RECIST 
1.1
APF12 and APF18 using BICR assessment according 
to RECIST 1.1
PFS2 as defined by local standard clinical practice
TTDM using BICR assessments according to RECIST 
1.1
To assess the safety and tolerability profile of 
MEDI4736 compared with placebo
AEs, physical examinations, vital signs, pulse, 
electrocardiograms, and laboratory findings including 
clinical chemistry, haematology and urinalysis
To assess the PK of MEDI4736 
Concentration of MEDI4736 in blood and 
non-compartmental PK parameters (such as peak 
concentration and trough, as data allow) (sparse 
sampling)
To investigate the immunogenicity of MEDI4736 
ADA (confirmatory results: positive or negative; titres 
[ADA neutralising antibodies will also be assessed]) 


Statistical Analysis Plan 
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Secondary Objective:
Outcome Measure:
To assess symptoms and health-related quality of life 
in patients treated with MEDI4736 compared with 
placebo using EORTC QLQ-C30 v3 and LC13
EORTC QLQ-C30: Time to symptom deterioration 
(fatigue, pain, nausea/vomiting, dyspnoea, loss of 
appetite, insomnia, constipation, and diarrhoea).  Time 
to QoL/function deterioration (physical function; role 
function; emotional function; cognitive function; social 
function and global health status/QoL)
LC13: Time to symptom deterioration (dyspnoea, 
cough, haemoptysis, chest pain, arm/shoulder pain, 
other pain)
Changes in World Health Organization Performance 
Status will also be assessed
ADA  Anti-drug antibody; AE  Adverse event; APF12  Proportion of patients alive and progression free at 12 months from 
randomisation; APF18  Proportion of patients alive and progression free at 18 months from randomisation; BICR Blinded 
Independent Central Review; DoR  Duration of response; EORTC QLQ-C30  European Organisation for Research and 
Treatment of Cancer 30-item core quality of life questionnaire; LC13  Lung Cancer Module; ORR Objective response rate; 
OS24  Proportion of patients alive at 24 months from randomisation; PFS2  Time from randomisation to second progression; 
PK  Pharmacokinetic(s); QoL  Quality of Life; RECIST  Response Evaluation Criteria In Solid Tumours; TTDM  Time to 
death or distant metastasis.
1.1.3
Exploratory objectives
Exploratory Objective:
Outcome Measure:
To explore irRC (irRECIST 1.1) criteria as an 
assessment methodology for clinical benefit of 
MEDI4736 compared with placebo by BICR
PFS, and ORR using BICR assessments according to 
irRC (irRECIST 1.1)
To investigate the relationship between MEDI4736 PK 
exposure and clinical outcomes, efficacy, AEs and/or 
safety parameters, if deemed appropriate 
A graphical and/or a data modelling approach will be 
used to analyse MEDI4736 PK exposure and the 
relationship with clinical outcomes, efficacy, AEs 
and/or safety parameters, as deemed appropriate
To describe and evaluate resource use associated with 
MEDI4736 treatment and underlying disease
Health resource utilisation measures including 
hospitalization, outpatient visits, or emergency 
department visits
To explore the impact of treatment and disease state on 
health state utility using the EQ-5D-5L
The EQ-5D-5L health state utility index will be used to 
derive health state utility based on patient reported data
To investigate the relationship between a patient’s 
PD-L1 expression and spatial distribution within the 
tumour microenvironment and efficacy outcomes with 
MEDI4736 
Tumoural expression of PD-L1 and spatial distribution 
within the tumour microenvironment relative to 
efficacy outcomes (OS, PFS and ORR)
To collect blood and tissue samples for analysis of 
peripheral and tumoural biomarkers
Biomarker analysis of blood and tissue to assess 
exploratory markers which may include but is not 
limited to: immune cell gene expression profiles within 
the peripheral and tumoural compartments, the 
presence of IFN-γ tumour necrosis factor-α, IL-2, IL-6, 
IL-10, IL-8, and IL-12 as well as antibodies against 
tumour, self, or viral antigens, expression of PD-L1 
and the number and phenotype of immune cells such as 
T-cells


Statistical Analysis Plan 
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Exploratory Objective:
Outcome Measure:
To explore the relationship(s) between a patient’s 
biomarker status and MEDI4736 PK exposure and 
clinical outcomes before and after treatment
Biomarker status before and after treatment and 
MEDI4736 PK exposure and relationship with clinical 
outcomes, efficacy, AEs and/or safety parameters, as 
deemed appropriate
To explore potential biomarkers in residual biological 
samples (eg, tumour, plasma and/or serum), which may 
influence the progression of cancer (and associated 
clinical characteristics) and/or prospectively identify 
patients likely to respond to MEDI4736 treatment
Correlation of biomarkers with response to MEDI4736 
treatment and/or the progression of cancer
To collect and store DNA according to each country’s 
local and ethical procedures for future exploratory 
research into genes/genetic variation that may 
influence response (i.e., distribution, safety, tolerability 
and efficacy) to study drugs and/or susceptibility to 
disease (optional)
Correlation of polymorphisms with variation in PK, 
PDx, safety or response parameters observed in 
patients treated with MEDI4736 and/or susceptibility 
to disease
AE  Adverse event; BICR  Blinded Independent Central Review; DoR  Duration of response; EQ-5D-5L  EuroQoL 5 
dimension, 5 level health state utility index; IFN  Interferon; IL  Interleukin; irRC  Immune-related response criteria; ORR 
Objective response rate; PD-L1  Programmed death ligand 1; PDx  Pharmacodynamic(s); PFS  Progression free survival; PK  
Pharmacokinetic(s); T-cell  T lymphocyte. 
With regards to biomarkers, Programmed death ligand 1 (PD-L1) expression determined by 
immunohistochemistry will be reported in the Clinical Study Report (CSR).  Other 
exploratory biomarker and Pharmacogenetic (PGx) research will be reported outside the CSR.  
Data relating to the exploratory objectives of patient reported outcome (PRO) and Health 
Related Quality of Life (HRQoL) will be reported in the CSR.
1.2
Study Design
This study is a Phase III, randomised, double-blind, placebo-controlled, multi-centre study 
assessing the efficacy and safety of MEDI4736 compared with placebo as sequential therapy 
in male and female patients with locally advanced, unresectable non-small cell lung cancer 
(NSCLC) (Stage III) who have not progressed following definitive, platinum-based, 
concurrent chemoradiation therapy.
Approximately 880 patients with locally advanced, unresectable NSCLC (Stage III) will be 
recruited and 702 patients randomised at 260 to 330 sites in Australia, Asia, Europe, North 
and South America and South Africa.  These patients will be in complete response (CR), 
partial response (PR), or have stable disease (SD) following definitive, platinum-based, 
concurrent chemoradiation therapy.
Patients will be randomised in a 2:1 ratio (MEDI4736 to placebo) to 1 of 2 arms:
!
MEDI4736 (10 mg/kg Q2W iv for up to 12 months).  
!
Placebo (matching placebo for infusion Q2W iv for up to 12 months).    


Statistical Analysis Plan 
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Randomisation will be stratified by: age at randomisation (<65 vs ≥65 years of age), sex (male 
vs female), and smoking history (smoker vs non-smoker).  Patients must not have progressed 
following definitive, platinum-based, concurrent chemoradiation therapy; radiation therapy 
must be completed within 1 to 42 days prior to randomisation in the study (the last dose of 
radiation therapy is defined as the day of the last radiation treatment session).  For patients 
who are recovering from toxicities associated with prior treatment, randomisation may be 
delayed by up to 42days from the end of the chemoradiation therapy.  For those patients 
randomised to the placebo arm no cross-in to the MEDI4736 arm is permitted and similarly 
those patients randomised to the MEDI4736 arm no cross-in to the placebo arm is permitted.
Administration of study drug will commence on Day 1 following randomisation to MEDI4736 
or placebo after confirmation of eligibility and will continue on a Q2W schedule for a 
maximum duration of 12 months.  Study drug should be discontinued prior to 12 months if 
there is confirmed PD (unless the investigator considers the patient continues to receive 
benefit from the study drug), initiation of alternative cancer therapy, unacceptable toxicity, 
withdrawal of consent, or other reasons to discontinue study drug occur.  
Tumour assessments using computed tomography (CT)/magnetic resonance imaging (MRI) 
will be performed at the times specified in Table 1, Table 2 and Table 3 of the Clinical Study 
Protocol (CSP).  Response Evaluation Criteria In Solid Tumours 1.1 (RECIST 1.1) 
measurements (using Blinded Independent Central Review [BICR] data) will be used to 
derive the co-primary variable of PFS and secondary variables of objective response rate 
(ORR), duration of response (DoR), proportion of patients alive and progression free at 12 
months (APF12), and proportion of patients alive and progression free at 18 months (APF18).  
Categorisation of objective tumour response assessment will be based on RECIST 1.1: 
complete response (CR), partial response (PR), stable disease (SD) and progressive disease 
(PD).  Patients with no evidence of disease at follow-up in the absence of new lesions will be 
assigned a response of no evidence of disease (ND).  Once a patient has had objective 
progression recorded and has discontinued study drug, the patient will be followed up for 
survival status every 2 months until death, withdrawal of consent or the end of the study.  
Patients will also be assessed every 12 weeks for a second progression defined according to 
local standard clinical practice and may involve any of: objective radiological progression, 
symptomatic progression or death.
There will be 4 data cut-off (DCO) time points in the study.  The first analysis DCO will occur 
when it is expected that 367 PFS events have occurred (52% maturity, approximately 30 
months after the first patient is randomised) and be conducted on the PFS endpoint.  The 
second analysis DCO will occur at the time of the primary PFS analysis when it is expected 
that 458 PFS events have occurred (65% maturity, approximately 36 months after the first 
patient is randomised) and the first OS interim analysis will be conducted at the same time 
(with approximately 285 events, 41% maturity).  The third analysis DCO will occur at the 
time of the second OS interim analysis when it is expected that 393 OS events have occurred 
(56% maturity, approximately 47 months after the first patient is randomised).  The fourth 
analysis DCO will occur at the time of the primary OS analysis when it is expected that 491 


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OS events have occurred (70% maturity, at approximately 62 months).  See Section 5 for 
further details.
Sensitivity analyses will be performed on PFS and ORR based on data from site investigator 
assessment based upon RECIST 1.1 and BICR data per RECIST 1.1 modified for 
confirmation of progression.  Exploratory analysis of PFS and ORR will also be performed for 
data obtained from the BICR using immune-related response criteria (irRECIST 1.1).  See 
Section 6.3 and Appendix F of the CSP for further information regarding RECIST 1.1 tumour 
assessments in this study.  
The study flow chart is presented in Figure 1.  
The schedule of study procedures at Screening and during the Treatment Period is presented 
in Table 1 of the CSP.  The schedule of study procedures during follow-up for patients who 
have completed the Treatment Period and achieved disease control (until confirmed PD) and 
patients who have discontinued study drug due to toxicity or a reason other than confirmed PD 
is presented in Table 2 of the CSP.  The schedule of study procedures during follow-up for 
patients who have discontinued study drug due to confirmed PD is presented in Table 3 of the 
CSP.  
Guidelines for the management of toxicities are described in Section 5.5.3 and Appendix H of 
the CSP.  
Details of the PGx component of the study (relating to DNA) are provided in Appendix D of 
the CSP.
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will be convened and will meet 
approximately 3 months after the study has started, or once 75 patients have been randomised 
whichever occurs first, to review safety assessments and make recommendations to continue, 
amend, or stop the study based on safety findings.    The committee will then meet again 3 
months later and then at least every 6 months thereafter.  All patients who receive a dose of 
study drug will be evaluated for safety and tolerability.  Enrolment will continue unless there 
is an unexpected safety concern.  The study may be adjusted or suspended depending on the 
IDMC review outcome. The first three efficacy analyses will also be assessed by the IDMC.
Details on the IDMC are provided in Section 12.4 of the CSP and full details of the IDMC 
procedures and processes can be found in the IDMC Charter.


Statistical Analysis Plan 
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Edition Number 4.0
Date 22 March 2017
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Figure 1
Study flow chart
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 0 to 42 days after the end of chemoradiation therapy and before 
the start of study drug.  For patients who are recovering from toxicities associated with prior treatment, randomisation 
may be delayed by up to 42 days from the end of the chemoradiation therapy.
b
Disease progression needs to be confirmed, the confirmatory scan should occur preferably at the next scheduled visit 
and no earlier than 4 weeks after the initial assessment of PD in the absence of clinically significant deterioration.  
Administration of study drug will continue between the initial assessment of progression and confirmation for 
progression.  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 and retreatment as specified in Section 4.3 of the CSP.  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 who achieve and maintain disease control (ie, CR, PR, no evidence of disease, or SD) through to the end of the 
12-month treatment period, may restart study drug upon evidence of PD (according to RECIST 1.1), with or without 
confirmation, during follow-up.  Before restarting study drug, the Investigator should ensure patients still meet all of the 
inclusion criteria and none of the exclusion criteria for this study including re-consenting to treatment.  To restart study 
drug the patient must not have received an intervening systemic anti-cancer therapy post study drug discontinuation.  
Patients should have a baseline tumour assessment within 28 days of restarting study drug, all further scans should 
occur every 8 weeks (relative to the date of restarting study drug) (maximum of 12 months of further treatment). 
Visit 1Screening Assessments
(Day -42 to -1)a
Visit 2 Day 1 Randomisation/Baseline
Patients randomised 2:1 MEDI4736:Placebo
Continue tumour assessment using RECIST 1.1.  Follow-up assessments 
per Table 2 until confirmed progression of disease
Disease control at the end of 
12 months of treatment
Treatment Period (assessments per Table 1):
Tumour assessments using RECIST 1.1 performed at Screening
and then every 8 weeks thereafter (relative to the date of randomisation) b
Discontinuation of 
treatment
Follow-up assessments and survival contact
per Table 3e
Confirmed progression of 
diseased
Due to toxicity or other 
reasons
Due to confirmed progression 
of diseased
Potential for retreatment of patients 
who have experienced disease 
control. A patient is only allowed to 
restart treatment ONCEc


Statistical Analysis Plan 
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d
Patients with confirmed PD that continue to receive study drug at the discretion of the Investigator (following 
consultation with the sponsor) can receive study drug for a maximum of 12 months.  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 and retreatment as specified in 
Section 4.3 of the protocol.  The same exceptions as noted in footnote b apply.  Patients will follow the assessments in 
Table 1 of the CSP including tumour assessments every 8 weeks (relative to the date of randomisation) until study drug 
is stopped.  Study drug should be discontinued if there is confirmed progression of disease (PD) following a previous 
response (PR or CR) to study drug.
e
Patients with confirmed PD that discontinue study drug, should have scans conducted according to local standard 
clinical practice (see Section 6.2.2.2 of the CSP) that are submitted for BICR until the patient commences a new 
treatment (these scans are optional).
Note: The DCO for the analysis of overall survival will take place once 491 death events have occurred (estimated to be 
approximately 62 months after randomisation).  At this time point, patients who are receiving study drug can either choose to 
discontinue from the study or where the Investigator believes patients are gaining clinical benefit, patients may continue to 
receive study drug.  For patients who do continue to receive study drug beyond the time of the final DCO, Investigators will 
only continue to report all SAEs to Quintiles Patient Safety until 90 days after study drug is discontinued and any SAE or 
non-serious AE that is ongoing at the time of this DCO must be followed up to resolution unless the event is considered by 
the Investigator to be unlikely to resolve, or the patient is lost to follow-up.
AE  Adverse event; BICR  Blinded Independent Central Review; CR  Complete response; DCO  Data cut-off; PD  
Progression of disease; PR  Partial response; RECIST  Response Evaluation Criteria In Solid Tumours; SAE  Serious adverse 
event; SD  Stable disease.  


Statistical Analysis Plan 
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1.3
Number of Subjects
The sample size for this study was selected to be consistent with the research hypothesis as 
described in Section 1.2 of the CSP.
The two co-primary endpoints of this study are OS and PFS.  To control for type-I error, a 
significance level of 2.5% will be used for analysis of OS and a significance level of 2.5% will 
be used for analysis of PFS.  The study will be considered positive (a success) if either the 
PFS analysis results and/or the OS analysis results are statistically significant.
Approximately 702 patients will be randomised 2:1 to obtain 491 death events in the ITT 
population (70% maturity).  The primary PFS analysis DCO will occur when it is expected 
that 458 PFS events have occurred (65% maturity).  If the true PFS HR is 0.67, the study will 
provide at least 95% power to demonstrate a statistically significant difference for PFS with a 
2-sided significance level of 2.5% in the ITT population; this translates to a 5-month benefit in 
median PFS over 10 months on placebo if PFS is exponentially distributed.  The smallest 
treatment difference that would be statistically significant is a HR of 0.8.  A recruitment 
period of approximately 22 months and a follow-up period of 14 months are expected for the 
PFS endpoint.  Therefore it is anticipated that this PFS analysis could be performed 
approximately 36 months after the first patient has been randomised.
The primary OS analysis DCO will occur when it is expected that 491 OS events have 
occurred (70% maturity).  If the true OS HR is 0.73, this number of death events will provide 
at least 85% power to demonstrate a statistically significant difference for OS, assuming a 
2.5% 2-sided significance level in the ITT population; this translates to an 8-month benefit in 
median OS over 22 months on placebo if OS is exponentially distributed (Butts et al 2014).  
The smallest treatment difference that would be statistically significant is a HR of 0.81.  A 
recruitment period of approximately 22 months and a follow-up period of 40 months are 
expected for the OS endpoint.  Therefore it is anticipated that this OS analysis could be 
performed at approximately 62 months after the first patient has been randomised.
2.
ANALYSIS SETS
2.1
Definition of Analysis Sets
Four main analysis sets are defined for this study.
Full analysis set (FAS) (Intention to treat (ITT)):
The primary statistical analysis of the efficacy of MEDI4736 vs placebo will include all 
randomised patients and will compare the treatment arms on the basis of randomised 
treatment, regardless of the treatment actually received.  Patients who were randomised but 
did not subsequently go on to receive study drug are included in the ITT population.  Note, 
this is also known as the FAS.  Therefore, all efficacy and HRQoL data will be analysed using 
the FAS on an ITT basis.


Statistical Analysis Plan 
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Safety analysis set:
All patients who received at least one dose of randomised study medication, MEDI4736 or 
placebo, (regardless of whether that was the randomised therapy intended or indeed whether, 
in rare cases, they received therapy without being randomised) will be included in the safety 
population. Throughout the safety sections, erroneously treated patients (e.g., those 
randomised to Treatment A but actually given Treatment B) will be accounted for by the 
actual treatment administered. As long as a patient received any dose of MEDI4736, the 
patient would be counted under MEDI4736 treatment group.
When assessing safety and tolerability, summaries will be produced based on the safety 
analysis set.  
PK analysis set:
All patients who receive at least 1 dose of MEDI4736 per the protocol, for whom any 
post-dose data are available and do not violate or deviate from the protocol in ways that would 
significantly affect the PK analyses will be included in the PK analysis set.  The population 
will be defined by the Study Team Physician, Pharmacokineticist and Statistician prior to any 
analyses being performed.
Table 1 gives a summary of outcome variables and analysis populations.
Table 1
Summary of outcome variables and analysis populations
Outcome variable
Populations
Efficacy Data
OS (co-primary)
FAS (ITT)
PFS (co-primary)
FAS (ITT)
OS24, APF12, APF18, PFS2, DoR, TTDM, TFST, PRO endpoints, World 
Health Organisation performance status
FAS (ITT)
ORR
FAS (ITT)
Study Population/Demography Data
Demography characteristics (e.g. age, sex etc.)
FAS (ITT)
Baseline, disease characteristics 
FAS (ITT)
Analysis populations
FAS (ITT)
Important deviations
FAS (ITT)
Medical/Surgical history
FAS (ITT)
Previous anti-cancer therapy 
FAS (ITT)
Concomitant medications/procedures
FAS (ITT) 
Subsequent anti-cancer therapy
FAS (ITT)
World Health Organization  performance status
FAS (ITT)


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Table 1
Summary of outcome variables and analysis populations
Outcome variable
Populations
PK Data
PK data
PK
Immunogenicity
Immunogenicity data
Safety
Safety Data
Exposure
Safety
Adverse events
Safety
Laboratory measurements
Safety
Vital Signs
Safety
ECGs
Safety
APF12  Proportion of patients alive and progression free at 12 months from randomisation; APF18  Proportion of 
patients alive and progression free at 18 months from randomisation; DoR  Duration of response;; ITT  Intent-to-
Treat; ORR  Objective response rate; OS Overall survival; OS24  Proportion of patients alive at 24 months from 
randomisation;  PFS  Progression free survival; PFS2  Time from randomisation to second progression; PK  
Pharmacokinetic; PRO  Patient reported outcomes; TTDM Time to death or distant metastasis, TFST Time to 
first subsequent therapy or death.
2.2
Protocol Deviations
The important protocol deviations will be listed and summarised by randomised treatment 
group. Deviation 1 below will lead to exclusion from the Safety analysis set. This means that 
this will not be shown on the relevant summary but can still be identified on the listings.  
None of the other deviations will lead to any patient being excluded from any of the analysis 
sets described in Section 2.1 (with the exception of the PK analysis set, if the deviation is 
considered to impact upon PK). If the deviations are serious enough to have the potential to 
impact the primary analysis, sensitivity analyses may be performed. The need for such a 
sensitivity analysis will be determined following review of the protocol deviations ahead of 
database lock (DBL) and will be documented prior to the primary analysis being conducted.  
Eligibility criteria deviations are deviations from the protocol inclusion and exclusion criteria.  
Post-entry deviations are deviations from the protocol that occurred after the patient was 
assigned to the study treatment.
The following general categories will be considered important deviations and be listed and 
discussed in the CSR as appropriate for the study: 
!
Deviation 1: Patients randomised but who did not receive MEDI4736/matching placebo
!
Deviation 2: Patients who deviate from the following key entry criteria in CSP 
Amendment:
a) Inclusion criteria: 3, 4, 5, 8 


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b) Exclusion criteria: 5, 6, 7, 8, 10, 12, 13, 14, 17
!
Deviation 3: Baseline RECIST scan > 42 days before randomisation.
!
Deviation 4: No baseline RECIST 1.1 assessment on or before date of randomisation.
!
Deviation 5: Received prohibited concomitant systemic anti-cancer agents. 
Refer to the CSP section 5.6 for those medications that are detailed as being ‘excluded’ 
from permitted use during the study. This will be used as a guiding principle for the 
physician review of all medications prior to DBL.
!
Deviation 6: Patients randomised who received treatment other than that to which they 
were randomised to.
The categorisation of these as important deviations is not automatic and will depend on 
duration and the perceived effect on efficacy.
In addition to the programmatic determination of the deviations above, monitoring notes or 
summaries will be reviewed to determine any important post entry deviations that are not 
identifiable via programming, and to check that those identified via programming are correctly 
classified. The final classification will be made at the blind data review meeting (BDRM) 
prior to DBL or DCO.  Decisions made at the BDRM will be documented and approved by 
AstraZeneca prior to analysis. 
Errors in treatment dispensing, in addition to incorrect stratifications, will also be investigated 
more closely.  This may occur when a patient is not randomised or treated according to the 
randomisation schedule on at least one occasion.  It is envisaged that there will be 3 sub 
categories of this within the important deviations summary:
!
Patients who receive no treatment whatsoever for a period of time due to errors in 
dispensing of medication. Note, this is not due to tolerability issues where patients may 
stop taking drug.
!
The patient receives a treatment pack with a different code to their randomisation code and 
the treatment differs from the randomized treatment.
!
The patient receives a treatment pack with a different code to their randomisation code. 
However, the actual treatment may still match the randomised treatment. For example, a 
patient is given randomisation code 0001, which according to the randomisation schedule 
is MEDI4736.  However, at the randomisation visit they are given treatment pack 0003, 
but this still contains MEDI4736.
Patients who receive the wrong treatment at any time will be included in the safety analysis 
set as described in Section 2.1.  During the study, decisions on how to handle errors in 
treatment dispensing (with regards to continuation/discontinuation of study treatment or, if 


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applicable, analytically) will be made on an individual basis with written instruction from the 
study team leader and/or statistician.
3.
PRIMARY, SECONDARY AND EXPLORATORY VARIABLES
3.1
Derivation of RECIST Visit Responses
For all patients, the RECIST version 1.1 (see further Appendix F of the CSP and Independent 
Review Charter) tumour response data will be used to determine each patient’s visit response.  
It will also be used to determine if and when a patient has progressed and also their best 
objective response.
The baseline tumour assessment is part of the screening procedures and should be performed 
within 0 to 42 days after the end of chemoradiation therapy and no more than 28 days before 
the start of study drug. For patients who are recovering from toxicities associated with prior 
treatment, randomisation may be delayed by up to 42 days from the end of the chemoradiation 
therapy.
Efficacy for all patients will be assessed by objective tumour assessments every 8 weeks 
(relative to the date of randomisation) for the first 12 months, then every 12 weeks thereafter, 
until confirmed objective disease progression as defined by RECIST 1.1 (irrespective of the 
reason for stopping study drug and/or subsequent therapy). For patients who discontinue study 
drug due to toxicity or a reason other than confirmed PD, objective tumour assessments 
should be continued every 8 weeks for 48 weeks (relative to the date of randomisation) then 
every 12 weeks thereafter until confirmed objective disease progression. 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. 
Disease progression requires confirmation, the confirmatory scan should occur preferably at 
the next scheduled visit and no earlier than 4 weeks after the initial assessment of PD in the 
absence of clinically significant deterioration.  Study treatment will continue between the 
initial assessment of progression and confirmation for progression.  For all patients who are 
treated through progression and patients who achieve disease control (i.e., CR, PR or SD)
through to the end of the 12 month treatment period and restart study treatment upon evidence 
of PD (according to RECIST 1.1), with or without confirmation, during follow-up, the 
investigator should ensure patients do not have any significant, unacceptable or irreversible 
toxicities that indicate continuing treatment will not further benefit the patient, and that the 
patient still meets all of the inclusion criteria and none of the exclusion criteria for this study 
including re-consenting to continue or restart treatment.  To restart study treatment the patient 
must not have received an intervening systemic anti-cancer therapy post study drug 
discontinuation. Study drug should be discontinued if there is confirmed PD following a 
previous response (PR or CR) to study drug.


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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.
Progression would be considered confirmed if the following criteria are met:
!
≥20% increase in the sum diameters of target lesions (TLs) compared with the nadir 
at 2 consecutive visits with an absolute increase of at least 5 mm 
The assessment of progression of ≥20% increase in the sum diameters of TLs 
compared with the nadir is at the first progression time point relative to the nadir 
(the smallest sum of diameters and this may be at baseline or subsequent follow-up 
visit).  The confirmed scan confirms the persistence of the ≥20% increase relative to 
the nadir. 
!
and/or significant progression (worsening) of non target lesions (NTLs) or new 
lesions at the confirmatory PD time point compared with the first time point where 
progression of NTLs or new lesions identified
!
and/or additional new unequivocal lesions at the confirmatory PD time point 
compared with the first time point new lesions identified.
BICR according to RECIST 1.1 will be regarded as primary in terms of the efficacy analyses. 
Sensitivity analyses will be performed using investigator assessment data and BICR using 
RECIST 1.1 modified for confirmation of progression. Additionally, the BICR will also be 
performed using irRECIST 1.1(Wolchok et al 2009, Nishino et al 2013)Nishino et al 2013, see 
also Section 3.1.3) for exploratory purposes.
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 response will be assigned as PD).
RECIST outcomes (i.e., PFS and ORR etc) will be calculated programmatically for the BICR 
and site investigator data from the overall visit responses.
3.1.1
Blinded Independent Central Review (BICR) Assessment Using RECIST 1.1 
A planned BICR will be carried out using RECIST version 1.1.  All radiological scans for all
patients (including those at unscheduled visits, or outside visit windows) will be collected on 
an ongoing basis and sent to an AstraZeneca appointed Contract Research Organisation 
(CRO) for central analysis. Information prior radiotherapy from the CRF will also be 


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provided to the BICR to delineate the anatomical region of previous definitive radiotherapy, to 
confirm that there are no lesions at baseline outside the prior radiotherapy region, to allow the 
selection of appropriate target lesions, if any at baseline, and to designate new lesions at 
follow-up that are outside the region of prior radiotherapy as ‘distant’ metastases for 
derivation of TTDM. The imaging scans will be reviewed by 2 independent radiologists using 
RECIST 1.1 and will be adjudicated, if required (i.e. two primary reviewers review the scans 
and adjudication is performed by a separate reviewer in case of a disagreement). The 
adjudicator must choose the assessments of one of the two primary reviewers. For each 
patient, the BICR will define the overall visit response (ie, the response obtained overall at 
each visit by assessing TLs, NTLs and new lesions) data and no programmatic derivation of 
visit response is necessary. Possible overall visit responses include: for patients with TLs at 
baseline: CR, PR, SD, PD, not evaluable [NE]; for patients with NTLs at baseline only: CR, 
non-CR/non-PD (NN), PD or NE; for patients with no disease identified at baseline: PD, no 
evidence of disease [ND], NE. If a patient has had a tumour assessment that cannot be 
evaluated then the patient will be assigned a visit response of NE (unless there is evidence of 
progression in which case the response will be assigned as PD). RECIST assessments/scans 
contributing towards a particular visit may be performed on different dates and for the central 
review the date of progression for each reviewer will be provided based on the earliest of the 
scan dates of the component that triggered the progression. 
If adjudication is performed, the records from the primary reviewer with which the adjudicator 
agreed will be used for data analysis (note in the case of more than one review period, the 
latest adjudicator decision will be used).  In the absence of adjudication, the records for all 
visits for a single reviewer will be used.  The reviewer selected in the absence of adjudication 
will be the reviewer who read the baseline scan first.  The records from the single selected 
reviewer will be used to derive all BICR RECIST information including dates of progression, 
visit response, censoring and changes in target lesion dimensions.  Endpoints (of PFS, ORR 
and DoR) will be derived programmatically from this information. 
Results of this independent review will not be communicated to Investigators and the 
management of patients will be based solely upon the results of the RECIST 1.1 assessment 
conducted by the Investigator.
The BICR of all patients up to each DCO will be completed before the data-base lock for the
interim analysis. Additionally the BICR of all patients will be performed for the final database 
lock for PFS which will cover all of the scans up to that point. 
Further details of the BICR will be documented in the Independent Review Charter.
3.1.2
BICR assessment using RECIST 1.1 Modified for Confirmation of 
Progression
The BICR of all scans used in the assessment of tumours will be assessed using RECIST 1.1 
modified for confirmation of progression as detailed in Sections 3.1 and 3.1.1. This means that 
the visit response of PD must be confirmed by another visit response of PD at the next 


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scheduled visit and no earlier than 4 weeks after the initial assessment of PD in the absence of 
clinical deterioration. Confirmation of progression needs to be programmatically derived.
3.1.3
BICR assessment using irRECIST 1.1
The criteria that built the foundation for irRC were the WHO criteria which existed before the 
publication of RECIST 1.1.  The irRC are, therefore, like WHO criteria, based on 
bi-dimensional measurements (Wolchok et al 2009).  More recently, RECIST 1.1 has become 
the gold standard for disease status determination for study subjects with solid tumours.  To be 
more in line with RECIST 1.1 criteria, irRC has been adjusted so that uni-dimensional 
measurements are used (referred to as irRECIST 1.1).  This modification of irRC 2009 criteria 
(irRECIST 1.1) is suggested based on the results of Nishino et al 2013, who found that irRC 
using the unidimensional measurements provide highly concordant response assessment 
compared with the bi-dimensional irRC, with less measurement variability.  Furthermore, this 
enables a consistency with RECIST 1.1 which enables a clearer contrast of the results from 
the two methods than would otherwise be possible.
The definitions of CR, PR, SD and PD according to irRECIST 1.1 are outlined clearly in the 
Independent Review Charter (referred to as irCR, irPR, irSD/irNN and irPD in that
document), but a brief description of the methodology is given here. 
In irRECIST 1.1 the presence of new lesions will not automatically trigger a declaration of 
Progressive Disease, but instead new lesions can be measured and these measurements will be 
added to the sum of diameters of the target lesions. Based on the sum of these measurements 
and % calculations thereof, the target lesion + new measured lesion response assessment will 
be derived. The overall response assessment (irCR, irPR, irSD/irNN, irPD, irNE or irND) will 
be obtained at the BICR and confirmation of PD is required. The imaging scans will be 
reviewed by 2 independent radiologists and will be adjudicated, if required. 
Where stated, the endpoints in Section 3.2 will also be derived using these assessment 
methods for supportive purposes.
3.1.4
Site investigator assessment using RECIST 1.1: target lesions
Measurable disease is defined as having at least one measurable lesion which is ≥ 10 mm in 
the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with CT or 
MRI and which is suitable for accurate repeated measurements. 
A patient can have a maximum of 5 measurable lesions recorded at baseline with a maximum 
of 2 lesions per organ (representative of all lesions involved suitable for accurate repeated 
measurement) and these are referred to as TLs.  If more than one baseline scan is recorded 
then measurements from the one that is closest to randomisation will be used to define the 
baseline sum of TLs.  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.


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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.
Note: For patients who do not have measurable disease at entry (i.e. no TLs) but have non-
measurable disease, evaluation of overall visit response at each visit will be based on the 
overall NTL assessment and the absence/presence of new lesions (see Section 3.1.6 for further 
details).  If a patient does not have measurable disease at baseline then the TL visit response 
will be not applicable (NA).  
For patients with NED at baseline (i.e. no TLs and no NTLs), evaluation of overall visit 
response at each visit will be based on absence/presence of new lesions.  If no TLs and no 
NTLs are recorded at a visit, both the TL and NTL visit response will be recorded as NA and 
the overall visit response will be NED if there is no new lesion.
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 response will be assigned as PD).  
Table 2
TL Visit Responses
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 diameters of TL, taking 
as reference the baseline sum of diameters as long as criteria 
for PD are not met.
Progressive Disease (PD)
At least a 20% increase in the sum of diameters of TLs taking 
as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also indicate an 
absolute increase of at least 5 mm
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD
Not Evaluable (NE)
Only relevant if any of the TLs were not assessed or not 
evaluable or had a lesion intervention at this visit. Note: If the 
sum of diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a TL response
Not Applicable (NA)
No TLs are recorded at baseline


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Rounding of TL data
For calculation of PD and PR for TLs, percentage changes from baseline and previous 
minimum should be rounded to 1 decimal place before assigning a TL 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, all TL 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 lesion diameter 
recorded.
Lymph nodes
For lymph nodes, if the size reduces to < 10 mm 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 < 10 mm and all other TLs 
are 0 mm then although the sum may be >0 mm the calculation of TL response should be 
over-written as a CR. 
TL visit responses subsequent to CR
A CR 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 (i.e. 0 mm or < 10 mm for lymph nodes) then 
response will be set to CR irrespective of whether the criteria for PD of TL is also met i.e. 
if a lymph node longest diameter (LD) increases by 20% but remains < 10 mm. 
!
Step 2:  If some lesion measurements are missing but all other lesions meet the CR criteria 
(i.e. 0 mm or < 10 mm 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


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TL too big to measure
If a TL 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 TL response would not give an overall visit response of PD, then this will be 
flagged and reviewed by the study team blinded to treatment assignment.  It is expected that a 
visit response of PD will remain in the vast majority of cases.  
TL too small to measure
If a TL becomes too small to measure a value of 5 mm will be entered into the database and 
used in TL calculations, unless the radiologist has indicated and 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 blinded to treatment assignment.
Irradiated lesions/lesion intervention during the study
According to the study design, it is possible that patients have some residual disease that has 
been irradiated prior to their study entry. For this reason, previously irradiated lesions may be 
selected as TLs.
Any TL (including lymph nodes), which has had intervention during the study (for example, 
irradiation / palliative surgery / embolisation), should be handled in the 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 scale up as described below, as long as 
there remain ∀1/3 of the TLs with interventions.  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, a scaled sum of 
diameters will be calculated (as long as ∀1/3 of the TLs with interventions), 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 subjected to intervention also has a value of 0 recorded.  
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 where appropriate (as per step 2 above).


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Scaling (applicable only for irradiated lesions/lesion intervention during the study)
If > 1/3 of TL measurements are treated as missing (because of intervention) then TL response 
will be NE, unless the sum of diameters of non-missing TL would result in PD (i.e. 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 TLs has increased by 5mm from nadir).
If ≤ 1/3 of the TL measurements are treated as missing (because of intervention) then the 
results will be scaled up (based on the sizes at the nadir visit to give an estimated sum of 
diameters and this will be used in calculations; this is equivalent to comparing the visit sum of 
diameters of the non- missing lesions to the nadir sum of diameters excluding the lesions with 
missing measurements).
Example of scaling
Lesion
Longest diameter 
at nadir visit
Longest diameter 
at follow-up visit
1
7.2
7.1
2
6.7
6.4
3
4.3
4.0
4
8.6
8.5
5
2.5
Intervention
Sum
29.3
26
Lesion 5 has had an intervention at the follow-up visit. 
The sum of lesions 1-4 at the follow-up is 26 mm. The sum of the corresponding lesions at 
baseline visit is 26.8 mm.
Scale up as follows to give an estimated TL sum of 28.4mm:          
Lesions that split in two
If a TL splits in two, 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 TLs merge, then the LD of the merged lesion should be recorded for one of the TL 
sizes and the other TL size should be recorded as 0 mm.
mm
4.
28
3.
29
8.
26
26
#
∃


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Change in method of assessment of TLs
CT and MRI are the only methods of assessment that can be used within the trial. If a change 
in method of assessment occurs between CT and MRI, this will be considered acceptable and 
no adjustment within the programming is needed.  
If a change in method involves clinical examination (e.g. CT changes to clinical examination 
or vice versa), any affected lesions should be treated as missing.    
3.1.5
Site investigator assessment using RECIST 1.1: NTLs 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.
NTL response will be derived based on the investigator’s overall assessment of NTLs as 
follows:  
Table 3
NTL Visit Responses 
Visit Responses
Description
Complete Response (CR)
Disappearance of all NTLs present at baseline with all 
lymph nodes non-pathological in size (<10 mm short 
axis).
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.
Non-CR/Non-PD
Persistence of one or more NTLs with no evidence of 
progression.
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
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 the presence of SD or PR in 
TLs, the overall tumour burden has increased sufficiently to merit a discontinuation of 


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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: i.e. 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.
If the question ‘Any new lesions since baseline’ has not been answered with Yes or No and 
the new lesion details are blank this is not evidence that no new lesions are present and should 
be treated as NE in the derivation of overall visit 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 
assessments where possible until objective disease progression is observed.
3.1.6
Site investigator assessment using RECIST 1.1: 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 Lesions
Non-target lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non CR/Non PD
No
PR
CR
NE
No
PR
PR
Non PD or NE
No
PR


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Table 4
Overall Visit Responses
Target Lesions
Non-target lesions
New Lesions
Overall Response
SD
Non PD or NE
No
SD
NA
Non CR/Non PD
No
SD (Non CR/Non PD)
NE
Non PD or NE
No
NE
NA
NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
NA
NA
No
NED
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not evaluable, NED = 
no evidence of disease, NA = not applicable (only relevant if there were no TL/NTL at baseline).
3.2
Outcome Variables
All RECIST assessments, whether scheduled or unscheduled, will be included in the 
calculations.  This is also regardless of whether a patient discontinues investigational product.  
RECIST 1.1 outcomes (ie PFS, ORR etc.) will be derived using the overall visit responses and 
relevant dates from the BICR.  This will be repeated using the programmatically derived 
overall visit responses from investigator RECIST 1.1 assessments.
3.2.1
Co-primary efficacy outcome endpoints
The co-primary endpoints are OS and PFS.
3.2.1.1
Overall survival (OS)
OS is defined as the time from the date of randomisation until death due to any cause (i.e., 
date of death or censoring – date of randomisation + 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 (SUR_DAT, recorded within the SURVIVE module of the eCRF). 
Note: Survival calls will be made in the week following the date of DCO for the analysis, and 
if patients are confirmed to be alive or if the death date is post the DCO date these patients 
will be censored at the date of DCO.  The status of ongoing, withdrawn (from the study) and 
“lost to follow-up” patients at the time of the final OS analysis should be obtained by the site 
personnel by checking the patient’s notes, hospital records, contacting the patient’s general 
practitioner and checking publicly-available death registries.  In the event that the patient has 
actively withdrawn consent to the processing of their personal data, the vital status of the 
patient can be obtained by site personnel from publicly-available resources where it is possible 
to do so under applicable local laws.


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Note that for any OS analysis performed prior to the final OS analysis, in the absence of 
survival calls being made, it may be necessary to use all relevant CRF fields to determine the 
last recorded date on which the patient was known to be alive for those patients still on 
treatment (since the SURVIVE module is only completed for patients off treatment if a 
survival sweep is not performed). The last date for each individual subject is defined as the 
latest among the following dates recorded on the CRFs:
• AE start and stop dates
• Admission and discharge dates of hospitalization
• Study treatment date
• End of treatment date
• Laboratory test dates
• Date of vital signs
• Disease assessment dates on RECIST CRF
• Start and stop dates of alternative anticancer treatment
• Date last known alive on survival status CRF
• End of study date
3.2.1.2
Progression free survival (PFS)
PFS (per RECIST 1.1 as assessed by BICR) will be defined as the time from the date of 
randomisation until the date of the first objective disease progression or death (by any cause in 
the absence of progression) regardless of whether the patient withdraws from randomised 
therapy or receives another anti-cancer therapy prior to progression (i.e., date of PFS event or 
censoring – date of randomisation + 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 RECIST 
1.1 assessment.  However, if the patient progresses or dies after 2 or more missed visits, the 
patient will be censored at the time of the latest RECIST 1.1 assessment prior to the two 
missed visits. 
Given the scheduled visit assessment scheme (ie eight-weekly for the first 48 weeks then 
twelve-weekly thereafter)  the definition of 2 missed visits will change.  If the previous 
RECIST assessment is less than study day 274 (ie week 39) then two missing visits will 
equate to 18 weeks since the previous RECIST assessment, allowing for early and late visits
(ie, 2 x 8 weeks + 1 week for an early assessment + 1 week for a late assessment = 18 weeks).  
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 (ie, 


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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 (ie 
week 39 to week 49). From week 49 onwards (when the scheduling changes to twelve-weekly 
assessments), two missing visits will equate to 26 weeks (ie 2 x 12 weeks + 1 week for an 
early assessment + 1 week for a late assessment = 26 weeks). If the patient has no visits or 
does not have baseline data they will be censored at study day 1 unless they die within 2 visits 
of baseline (16 weeks plus 1 week allowing for a late assessment within the visit window).  
The PFS time will always be derived based on scan/assessment dates not visit dates.
PFS will also be obtained using the algorithm described above for the RECIST site 
investigator tumour data.  
RECIST 1.1 assessments/scans contributing towards a particular visit may be performed on 
different dates.  The following rules will be applied:
!
The date of progression will be determined based on the earliest of the scan dates of the 
component that triggered the progression for the adjudicated reviewer selecting PD or of 
first reviewer where both select PD as a time point response and there is no adjudication 
for central review (BICR) data.
!
For investigational assessments, the date of progression will be determined based on the 
earliest of the RECIST assessment/scan dates of the component that indicates progression
!
When censoring a patient for PFS the patient will be censored at the latest of the dates 
contributing to a particular overall visit assessment.
Note: For TLs, only the latest scan date is recorded out of all scans performed at that 
assessment for the TLs and similarly for NTLs only the latest scan date is recorded out of all 
scans performed at that assessment for the NTLs. Additionally, PFS will be obtained using the 
algorithm described above for the RECIST BICR data, but following a modification whereby 
any objective disease progression must be confirmed by the next scheduled scan.  The 
confirmatory scan must be no sooner than 4 weeks after the initial suspected progression.  If 
disease progression is confirmed (or disease progression occurs and no further scans are 
recorded) then the date of progression will be when it was originally observed.  Patients with a 
single disease progression and no further tumour assessment scans will be treated as PD in the 
analysis.  
In the absence of clinically significant deterioration the investigational site is advised to 
continue the patient on study drug until progression has been confirmed.
For exploratory purposes, PFS will also be obtained using the irRECIST 1.1 data provided by
BICR.  Objective disease progressions also require confirmation under this approach.
Time to first subsequent therapy or death (TFST)


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As a supportive summary to PFS, time to start of first subsequent therapy or death (TFST) will 
be derived. TFST is defined as the time from randomisation to the start date of the first 
subsequent therapy after discontinuation of treatment, or death, whichever is earlier (i.e. date 
of first subsequent anti-cancer therapy/death or censoring – date of randomisation + 1).  Any 
patient not known to have had a first subsequent therapy will be censored at the last date that 
the patient was known not to have received a first subsequent therapy (obtained from the 
TTSCAPRX form).  If a patient terminated the study for reason other than death before first 
subsequent therapy, these patients will be censored at the earliest of their known to be alive 
and termination dates. Patients not receiving randomised treatment would have TFST 
calculated in the same way, i.e. time from date of randomisation to the subsequent therapy or 
death. Note that the censoring for those patients without a subsequent therapy will align with 
their OS.
3.2.2
Secondary efficacy outcome endpoints
3.2.2.1
Proportion of patients alive at 24 months
The proportion of patients alive at 24 months (i.e., OS24) will be defined as the Kaplan-Meier 
estimate of OS at 24 months.  In addition the proportion of patients alive at 12 months (i.e., 
OS12) will be presented.  This will be defined as the Kaplan-Meier estimate of OS at 12
months. 
3.2.2.2
Objective response rate
ORR (per RECIST 1.1 as assessed by the BICR) is defined as the number (%) of patients with 
at least 1 visit response of CR or PR and will be based on a subset of all randomised patients 
who have measurable disease at baseline per BICR.  If the selected reviewer did not consider 
that a patient has measurable disease then this patient should not contribute to the 
denominator.
Data obtained up until progression, or the last assessment in the absence of progression, will 
be included in the assessment of ORR. Patients who go off treatment without progression, 
receive a subsequent therapy and then respond will not be included as responders in the ORR.  
ORR will also be obtained using the algorithm described above for the RECIST site 
investigator data.  The denominator for ORR will be all randomised patients with measurable 
disease at baseline per the site investigator (ie, the ITT population).
Additionally, ORR will be obtained using the algorithm described above from the RECIST 
BICR data, but following a modification where any objective progression requires 
confirmation.  Therefore, data obtained up until confirmed progression (ie first progression 
date that is subsequently confirmed), or the last assessment in the absence of a confirmed 
progression, will be included in the assessment of ORR.  Note that the response may be after 
an unconfirmed progression.
For exploratory purposes, ORR will also be obtained for the irRECIST 1.1 data provided by
BICR.  


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Best objective response 
Best objective response (BoR) is calculated based on the overall visit response from each 
RECIST assessment.  It is the best response a patient has had following randomisation but 
prior to starting any subsequent cancer therapy and prior to RECIST progression or the last 
assessment in the absence of RECIST progression and subsequent cancer therapy. 
Categorisation of BoR will be based on RECIST using the following response categories: CR, 
PR, SD, PD and NE.
BoR will be determined programmatically based on RECIST from the overall visit response at 
each visit using BICR data including all data up until the first progression, the start of any 
subsequent cancer therapy or the last assessment in the absence of progression.  
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 +/- 1 
week, i.e. at least 49 days (to allow for the assessment window), after randomisation (i.e. 
study day 50). For CR/PR, the initial overall visit assessment which showed a response will 
use the latest of the dates contributing towards a particular overall visit assessment.
The denominator will be consistent with that used in the ORR analysis.
For patients whose PFS event is death, BoR will be calculated based upon all RECIST 
assessments prior to death.
For patients who die with no RECIST assessments, if the death occurs ≤17 weeks (i.e., 16 
weeks + 1 week to allow for a late assessment within the assessment window) after 
randomisation, then BoR will be assigned to the progression (PD) category.  For patients who 
die with no RECIST assessments, if the death occurs >17 weeks (i.e., 16 weeks + 1 week) 
after the date of first dose then BoR will be assigned to the NE category.
Progression events that have been censored due to them being more than two missed visits 
after the last assessment will not contribute to the BoR derivation.
Change in tumour size
For supportive purposes percentage change from baseline in tumour size will be derived at 
each scheduled tumour assessment visit (i.e., week 8, week 16 etc hereafter referred to as 
week X for convenience) using BICR data. Best percentage change from baseline in tumour 
size will also be derived as the biggest decrease or the smallest increase in tumour size from 
baseline.
This is based on RECIST TL measurements taken at baseline and at the timepoint of interest. 
Tumour size is defined as the sum of the longest diameters of the TLs based upon RECIST 
assessments.  TLs are measurable tumour lesions.  Baseline for RECIST is defined to be the 
last evaluable assessment prior to randomization. The change in TL tumour size at week X 


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will be obtained for each patient by taking the difference between the sum of the TLs at week 
X and the sum of the TLs at baseline. To obtain the percentage change in TL tumour size at 
week X the change in TL tumour size is divided by the sum of the TLs at baseline and 
multiplied by 100 (i.e. (week X - baseline) / baseline * 100).
Apply a window around the week X visit: Whenever tumour size data for the week X visit 
(Note: or visit at which progression was documented if before week X) is available then this 
should be used in the analysis. A windowing rule will be applied and will follow the protocol 
allowed visit window; therefore any RECIST scan performed within ± 1 week of the protocol 
scheduled visit will be used for that visit.
The above derivations will be programmed for the BICR based upon RECIST 1.1 
assessments. 
Measurements from the reviewer selected by the adjudicator will be used when adjudication 
for overall visit response has occurred, but in the case where no adjudication was required the 
measurements from the reviewer who reviewed the baseline scan first will be used for this 
analysis.
3.2.2.3
Duration of response
DoR (per RECIST 1.1 as assessed by the BICR) will be defined as the time from the date of 
first documented response until the first date of documented progression or death in the 
absence of disease progression, whichever is earlier (i.e., date of PFS event or censoring –
date of first response + 1).  The end of response should coincide with the date of progression 
or death from any cause used for the RECIST 1.1 PFS endpoint (Section 3.2.1.2).  The 
denominator for DoR related analysis will be defined as described for ORR (see Section 
3.2.2.2).
The time of the initial response will be defined as the latest of the dates contributing towards 
the first visit response of CR or PR.  
If a patient does not progress following a response, then the corresponding DoR will be 
censored at the PFS censoring time.
DoR will not be defined for those patients who do not have documented response.
3.2.2.4
Proportion of patients alive and progression free at 12 months
The proportion of patients alive and progression free at 12 months (i.e., APF12) will be 
defined as the Kaplan-Meier estimate of PFS at 12 months.
3.2.2.5
Proportion of patients alive and progression free at 18 months
The proportion of patients alive and progression free at 18 months (i.e., APF18) will be 
defined as the Kaplan-Meier estimate of PFS at 18 months.


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3.2.2.6
Time from randomisation to second progression or death (PFS2)
PFS2 will be defined as the time from the date of randomisation to the earlier of the 
progression event subsequent to that used for the PFS endpoint or death (i.e. date of 
progression event subsequent to that used for the PFS endpoint or date of death or censoring
date whichever is earliest – date of randomisation + 1). The date of the first progression will 
be programmatically determined from investigator assessed data (See Section 3.1 for details.) 
The date of second progression will be recorded by the investigator and defined according to 
local standard clinical practice and may involve any of: objective radiological, symptomatic 
progression or death.  RECIST assessments will not be collected for assessment of PFS2.  The 
date of the PFS2 assessment and investigator opinion of progression status (progressed or non-
progressed) at each assessment will be recorded in the electronic case report form (eCRF). 
Second progression status will be reviewed every 12 weeks following the progression used for 
the co-primary variable PFS (the first progression) and status recorded.  Patients alive and for 
whom a second disease progression has not been observed should be censored at the last time 
known to be alive and without a second disease progression, i.e., censored at the latest of the 
PFS or PFS2 assessment date if the patient has not had a second progression or death.
Time to second subsequent therapy or death (TSST)
As a supportive summary to PFS2, time to start of second subsequent therapy or death (TSST) 
will be derived. TSST is defined as the time from randomisation to the earlier of the second 
subsequent cancer therapy start date following study treatment discontinuation, or death (i.e. 
date of second subsequent cancer therapy/death or censoring – date of randomisation + 1).  
Any patient not known to have had a second subsequent therapy will be censored at the last 
date that the patient was known not to have received a second subsequent anti-cancer therapy
(obtained from the TTSCAPRX form).  If a patient terminated the study for reason other than 
death before second subsequent therapy, these patients will be censored at the earliest of their 
last known to be alive and termination dates. Note that the censoring for those patients 
without a second subsequent therapy will align with their OS.
3.2.2.7
Time to death or distant metastasis
TTDM will be defined as the time from the date of randomisation until the first date of distant
metastasis or death in the absence of distant metastasis. Distant metastasis is defined as any
new lesion that is outside of the radiation field according to RECIST 1.1 or proven by biopsy.
This definition is further refined as patients who enrol in the study have baseline scans 
performed only after completion of definitive chemoradiation.  All known disease must have 
received a therapeutic dose of radiation prior to protocol entry.  For this reason the TTDM 
endpoint will be determined from recurrent disease that occurs outside of the structures 
contained within the thorax, including lymph nodes, pulmonary, pleural, and mediastinal
metastatic sites and excluding the heart.  For the locations of distant metastases, see the 
Appendix. Patients who have not developed distant metastasis or died at the time of analysis 
will be censored at the time of the latest date of assessment from their last RECIST 1.1
assessment. However, if the patient has distant metastasis or dies after 2 or more missed
visits, the patient will be censored at the time of the latest RECIST 1.1 assessment prior to the 


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2 missed visits. If the patient has no visits or does not have baseline data they will be censored 
at Day 1 unless they die within 2 visits of baseline.
3.3
Secondary Patient Reported Outcome Variables
PRO questionnaires will be assessed using the EORTC-QLQ-C30 with the EORTC-QLQ-LC-
13 module (HRQoL with lung cancer specific additional concerns) and EQ-5D-5L.  All 
items/questionnaires will be scored according to published scoring guidelines or the 
developer’s guidelines, if published guidelines are not available.  All PRO analyses will be 
based on the Intent-to-Treat (ITT) population, unless stated otherwise.
3.3.1
EORTC-QLQ-C30
The EORTC-QLQ-C30 consists of 30 questions which can be combined to produce 5 
functional scales (physical, role, cognitive, emotional, social), 3 symptom scales (fatigue, 
pain, nausea/vomiting), 5 individual symptom items (dyspnoea, insomnia, appetite loss, 
constipation, diarrhoea) and a global measure of health status.  The EORTC-QLQ-C30 will be 
scored according to the EORTC scoring manual (Fayers et al 1999).  An outcome variable 
consisting of a score from 0 to 100 will be derived for each of the symptom scales/items, the 
functional scales and the global health status scale in the EORTC-QLQ-C30 according to the 
EORTC-QLQ-C30 Scoring Manual.  Higher scores on the global health status and 
functioning scales indicate better health status/function but higher scores on symptom 
scales/items represent greater symptom severity.
Baseline will be defined as the last non-missing assessment prior to randomisation for 
symptoms and summaries.
The global health status/HRQoL will be assessed using the EORTC-QLQ-C30 global QoL 
scale which includes 2 items from the QLQ-C30: “How would you rate your overall health 
during the past week? (Item 29) and “How would you rate your overall QoL during the past 
week? (Item 30).
Definition of clinically meaningful changes
Changes in score compared with baseline will be evaluated.  A minimum clinically 
meaningful change is defined as a change in the score from baseline of ≥10 for the EORTC-
QLQ-C30 (Osoba et al 1998).  For example, a clinically meaningful improvement in physical 
function (as assessed by EORTC-QLQ-C30) is defined as an increase in the score from 
baseline of ≥10, whereas a clinically meaningful deterioration is defined as a decrease in the 
score from baseline of ≥10.  At each post-baseline assessment, the change in 
symptoms/functioning from baseline will be categorised as improvement, no change or 
deterioration as shown in Table 5.


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Table 5
Visit response for EORTC-QLQ-C30
Score
Change from baseline
Visit response
Global health status/HRQoL
≥+10
Improvement
≤-10
Deterioration
Otherwise
No change
Symptom scales/items
≥+10
Deterioration
≤-10
Improvement
Otherwise
No change
Functional scales
≥+10
Improvement
≤-10
Deterioration
Otherwise
No change
EORTC-QLQ-C30  European Organization for Research and Treatment of Cancer 30-item core quality of life 
questionnaire.
For each subscale, if <50% of the subscale items are missing, then the subscale score will be 
divided by the number of non-missing items and multiplied by the total number of items on 
the subscales (Fayers et al 1999). If at least 50% of the items are missing, then that subscale 
will be treated as missing. Missing single items are treated as missing. The reason for any 
missing questionnaire will be identified and recorded. If there is evidence that the missing 
data are systematic, missing values will be handled to ensure that any possible bias is 
minimised.
For the visit level summaries of Improvement/Deterioration/No change then all patients with a 
baseline and post-baseline score will be included thus the denominator may differ from the 
time to deterioration and improvement rate endpoints derived below.  
3.3.1.1
Time to symptom deterioration
For each of the symptoms scales/items in the EORTC-QLQ-C30, time to symptom 
deterioration will be defined as the time from randomisation until the date of the first 
clinically meaningful symptom deterioration (an increase in the score from baseline of ≥10) or 
death (by any cause) in the absence of a clinically meaningful symptom deterioration, 
regardless of whether the patient withdraws from study treatment or receives another 
anticancer therapy prior to symptom deterioration (i.e. date of symptom deterioration event or 
censoring whichever is earlier – date of randomisation + 1).  Death will be included as an 
event only if the death occurs within 2 visits of the last PRO assessment where the symptom 
change could be evaluated.  
Patients whose symptoms (as measured by EORTC-QLQ-C30) have not shown a clinically 
meaningful deterioration and who are alive at the time of the analysis will be censored at the 
time of their last PRO assessment where the symptom could be evaluated.  Also, if symptoms 
deteriorate after 2 or more missed PRO assessment visits or the patient dies after 2 or more 


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missed PRO assessment visits, the patient will be censored at the time of the last PRO 
assessment where the symptom could be evaluated (prior to the two missed assessment visits). 
Given the scheduled visit assessment scheme (ie eight-weekly for the first 48 weeks then 
twelve-weekly thereafter)  the definition of 2 missed visits will change.  If the previous PRO 
assessment is less than study day 274 (ie week 39) then two missing visits will equate to 18 
weeks since the previous PRO assessment, allowing for early and late visits.  If the two 
missed visits occur over the period when the scheduled frequency of PRO assessments 
changes from eight-weekly to twelve-weekly this will equate to 22 weeks. The time period for 
the previous PRO assessment will be from study days 274 to 344 (ie week 39 to week 49). 
From week 49 onwards, two missing visits will equate to 26 weeks. If the patient has no 
evaluable visits or does not have baseline data they will be censored at day 1 unless they die 
within 2 visits of baseline (16 weeks plus 1 week allowing for a late assessment within the 
visit window). 
The population for analysis of time to symptom deterioration will include a subset of the ITT 
population who have baseline scores ≤ 90.
3.3.1.2
Time to HR QoL/Function deterioration
For HR QoL/function, time to deterioration will be defined as the time from the date of 
randomisation until the date of the first clinically meaningful deterioration (a decrease in the 
function scales or the global health status/HR QoL from baseline of ≥10) or death (by any 
cause) in the absence of a clinically meaningful deterioration, regardless of whether the 
patient withdraws from study treatment or receives another anticancer therapy prior to HR 
QoL/function deterioration (i.e. date of HRQoL/function deterioration event or censoring
whichever is earlier – date of randomisation + 1).  Death will be included as an event only if 
the death occurs within 2 visits of the last PRO assessment where the HR QoL/function 
change could be evaluated.  
Patients whose HR QoL/function (as measured by EORTC-QLQ-C30) have not shown a 
clinically meaningful deterioration and who are alive at the time of the analysis will be 
censored at the time of their last PRO assessment where the HR QoL/function could be 
evaluated.  Also, if HR QoL/function deteriorates after 2 or more missed PRO assessment 
visits (using the same definitions for two missed visits as used in the ‘Time to Symptom 
deterioration’ derivation above) or the patient dies after 2 or more missed PRO assessment 
visits, the patient will be censored at the time of the last PRO assessment where the symptom 
could be evaluated. If the patient has no evaluable visits or does not have baseline data they 
will be censored at day 1 unless they die within 2 visits of baseline (16 weeks plus 1 week 
allowing for a late assessment within the visit window). 
The population for analysis of time to HR QoL/function deterioration will include a subset of 
the ITT population who have baseline scores ≥10.  
In the analysis, RECIST 1.1 progression will not be considered as HRQoL/function 
deterioration and data will not be affected by RECIST progression.


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3.3.1.3
Symptom Improvement Rate
The symptom improvement rate will be defined as the number (%) of patients with 
2 consecutive assessments at least 14 days apart that show a clinically meaningful 
improvement (a decrease from baseline score ≥10 for EORTC-QLQ-C30 symptom 
scales/items) in that symptom from baseline. The denominator will consist of a subset of the 
ITT population who have a baseline symptom score >10.
3.3.1.4
HR QoL/Function Improvement Rate
The HR QoL/function improvement rate will be defined as the number (%) of patients with 
2 consecutive assessments at least 14 days apart that show a clinically meaningful 
improvement (an increase from baseline score ≥10 for EORTC-QLQ-C30 functional scales 
and global health status/HR QoL) in that scale from baseline. The denominator will consist of 
a subset of the ITT population who have a baseline HR QoL/function score ≤90.
3.3.2
EORTC-QLQ-LC-13
The EORTC-QLQ-LC-13 is a lung cancer specific module from the EORTC comprising 
13 questions to assess lung cancer symptoms (cough, haemoptysis, dyspnoea, chest pain, 
arm/shoulder pain, and other pain), treatment related side-effects (sore mouth, dysphagia, 
peripheral neuropathy and alopecia) and pain medication.  The LC-13 incorporates symptom 
scales including:
!
Dyspnoea (multi-item scale based on 3 questions: were you short of breath when 
you rested; walked; climbed stairs)
!
Cough: 1 item (how much did you cough?)
!
Haemoptysis: 1 item (did you cough up blood?)
!
Pain: 3 individual items (Have you had pain in your chest; your arm or shoulder; 
other parts of your body?)
The dyspnoea scale is only used if all 3 items have been scored; otherwise the items are 
treated as single-item measures.  The scoring approach for the EORTC-QLQ-LC-13 is 
identical in principle to that for the symptom scales/single items of the EORTC-QLQ-C30.  
Definition of clinically meaningful changes
Changes in score compared with baseline will be evaluated.  A minimum clinically 
meaningful change is defined as an absolute change in the score from baseline of ≥10 for 
scales/items from the LC-13 (Osoba et al 1998).  For example, a clinically meaningful 
deterioration or worsening in chest pain (as assessed by EORTC-QLQ-LC-13) is defined as an 
increase in the score from baseline of ≥10, whereas a clinically meaningful improvement is 
defined as a decrease in the score from baseline of ≥10.  At each post-baseline assessment, the 
change in symptoms from baseline will be categorised as improvement, no change or 
deterioration as shown in Table 6.


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Table 6
Visit response for L13 
Score
Change from baseline
Visit response
Symptom scales/items
≥+10
Deterioration
≤-10
Improvement
Otherwise
No change
LC13  Lung Cancer Module.
For the visit level summaries of Improvement/Deterioration/No change then all patients with a 
baseline and post-baseline score will be included thus the denominator may differ from the 
time to deterioration and improvement rate endpoints  derived below.  
3.3.2.1
Time to symptom deterioration
For each of the symptoms scales/items in EORTC-QLQ-LC-13, time to symptom 
deterioration will be defined as the time from the date of randomisation until the date of the 
first clinically meaningful symptom deterioration (an increase in the score from baseline of 
≥10) or death (by any cause) in the absence of a clinically meaningful symptom deterioration, 
regardless of whether the patient withdraws from study treatment or receives another 
anticancer therapy prior to symptom deterioration (i.e. date of symptom deterioration event or 
censoring – date of randomisation + 1).  Death will be included as an event only if the death 
occurs within 2 visits of the last PRO assessment where the symptom change could be 
evaluated.  
Patients whose symptoms (as measured by EORTC-QLQ-LC-13) have not shown a clinically 
meaningful deterioration and who are alive at the time of the analysis will be censored at the 
time of their last PRO assessment where the symptom could be evaluated.  Also, if symptoms 
progress after 2 or more missed PRO assessment visits (using the same definitions for two 
missed visits as used in the ‘Time to symptom deterioration’ derivation in Section 3.3.1) or the 
patient dies after 2 or more missed PRO assessment visits, the patient will be censored at the 
time of the last PRO assessment where the symptom could be evaluated.  If the patient has no 
evaluable visits or does not have baseline data they will be censored at day 1 unless they die 
within 2 visits of baseline (16 weeks plus 1 week allowing for a late assessment within the 
visit window).  
The population for analysis of time to symptom deterioration will include a subset of the ITT 
population who have baseline scores ≤ 90 as a worsening of 10 points is not possible with a 
baseline value of >90.
In the analysis, RECIST 1.1 progression will not be considered as symptom deterioration and 
data will not be affected by RECIST progression. 


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3.3.2.2
Symptom Improvement Rate
The symptom improvement rate will be defined as the number (%) of patients with 
2 consecutive assessments at least 14 days apart that show a clinically meaningful 
improvement (a decrease from baseline score ≥10 for LC-13 symptom scales/items) in that 
symptom from baseline. The denominator will consist of a subset of the ITT population who 
have a baseline symptom score >10 as a lessening of 10 points is not possible at a baseline 
score of <10.
3.3.3
PRO Compliance Rates 
Summary measures of overall compliance and compliance over time will be derived for the 
EORTC-QLQ-C30 and EORTC-QLQ-LC13 respectively. These will be based upon:
!
Received questionnaire = a questionnaire that has been received and has a completion date 
and at least one individual item completed.
!
Expected questionnaire =  a questionnaire that is expected to be completed at a scheduled 
assessment time e.g. a questionnaire from a patient who has not withdrawn from the study 
at the scheduled assessment time but excluding patients in countries with no available 
translation. For patients that have progressed, the latest of progression and safety follow-
up will be used to assess whether the patient is still under HR QoL follow-up at the 
specified assessment time.  Date of study discontinuation will be mapped to the nearest 
visit date to define the number of expected forms.
!
Evaluable questionnaire = a questionnaire with a completion date and at least one subscale 
that is non-missing.
!
Overall PRO compliance rate is defined as: Total number of evaluable questionnaires 
across all time points, divided by total number of questionnaires expected to be received 
across all time points multiplied by 100.
!
Overall patient compliance rate is defined for each randomised treatment group as: Total 
number of patients with an evaluable baseline and at least one evaluable follow-up 
questionnaire (as defined above), divided by the total number of patients expected to have 
completed at least a baseline questionnaire multiplied by100.
Compliance over time will be calculated separately for each visit, including baseline, as the 
number of patients with an evaluable questionnaire at the time point (as defined above), 
divided by number of patients still expected to complete questionnaires. Similarly the 
evaluability rate over time will be calculated separately for each visit, including baseline, as 
the number of evaluable questionnaires (per definition above), divided by the number of 
received questionnaires.


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3.4
Safety
Safety and tolerability will be assessed in terms of adverse events (AEs) (including serious 
adverse events [SAEs]), deaths, laboratory data, vital signs, electrocardiograms (ECGs) and 
exposure.  These will be collected for all patients.
Data from the initial treatment period (i.e., the initial 12 months of treatment) on MEDI4736 
will be compared against placebo in the main presentations of safety data and safety data from 
the re-treatment period may also be summarised separately (see Section 4.1). ‘On treatment’ 
will be defined as assessments between date of the first dose and 90 days following last dose 
of the study treatment (MEDI4736/Placebo) unless otherwise specified. Note that for one 
version of the safety outputs the period of time after the administration of subsequent therapy 
will not be considered ‘on treatment’ (see further Section 0).
The Safety analysis set will be used for reporting of safety data.
3.4.1
Adverse events 
AEs and SAEs will be collected throughout the study, from date of informed consent to 90 
days after the last dose of MEDI4736 or placebo. The Medical Dictionary for Regulatory 
Activities (MedDRA) will be used to code the AEs. AEs will be graded according to the 
National Cancer Institute Common Terminology Criteria for AEs (CTCAE Version 4.03).  A 
treatment emergent adverse event (TEAE) is an AE with an onset date or a pre-existing AE 
worsening following the first dose of study treatment through to 90 days after the last dose of 
MEDI4736 or placebo.
Adverse events that have missing causality (after data querying) will be assumed to be related 
to study drug. 
Other significant adverse events 
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and ‘Discontinuation of Investigational Product 
due to Adverse Events’ (DAEs).  Based on the expert’s judgment, significant adverse events 
of particular clinical importance may, after consultation with the Global Patient Safety 
Physician, be considered other significant adverse events (OAEs) and reported as such in the 
CSR.  A similar review of laboratory/vital signs/ECG data will be performed for identification 
of OAEs.
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious) or significant 
additional treatment.
AEs of special interest
Some clinical concepts (including some selected individual preferred terms [PTs] and higher 
level terms [HLTs]) have been considered “AEs of special interest” (AESI) to the MEDI4736 


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program. AESIs represent pre-specified risks which are considered to be of importance to a 
clinical development program.
These AESIs identified as a list of categories provided by the clinical team.  Other categories 
may be added as necessary or existing terms may be merged. An AstraZeneca medically 
qualified expert, after consultation with the Global Patient Safety Physician, has reviewed the 
AEs of interest and identified which preferred terms 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.
3.4.2
Laboratory data 
Laboratory data will be collected throughout the study, from screening to follow-up visit as 
described in the CSP.  Blood and urine samples for determination of haematology, clinical 
chemistry, and urinalysis will be collected as described in Section 6.4.5 of the CSP.  For the 
definition of baseline and the derivation of post baseline visit values considering visit window 
and how to handle multiple records, derivation rules as described in Section 4.1.3 below will 
be used.
Change from baseline in haematology and clinical chemistry variables will be calculated for 
each post-dose visit on treatment. CTCAE grades will be defined at each visit according to the
CTCAE grade criteria using local or project ranges as required, after conversion of lab result 
to corresponding preferred units. The following parameters have CTCAE grades defined for 
both high and low values: Potassium, Sodium, Magnesium, Glucose and Corrected calcium so 
high and low CTCAE grades will be calculated. 
Corrected calcium will be derived during creation of the reporting database using the 
following formula:
Corrected calcium (mmol/L) = Total Calcium (mmol/L) + ([40 – Albumin (G/L)] x 0.02)
Creatinine clearance will be derived according to the Cockroft-Gault formula (Cockcroft and
Gault 1976).
Males:
Creatinine CL = 
(mg/dL)
creatinine
serum
x 
72
Age)
-
(140
x 
(kg)
Weight 
Females:
Creatinine CL = 
(mg/dL)
creatinine
serum
x 
72
Age)
-
(140
x 
(kg)
Weight 
x 0.85


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Absolute values will be compared to the project reference range and classified as low (below 
range), normal (within range or on limits of range) and high (above range).
The maximum or minimum on-treatment value (depending on the direction of an adverse 
effect) will be defined for each laboratory parameter as the maximum (or minimum) post-
baseline value at any time.
Local reference ranges will be used for the primary interpretation of laboratory data at the 
local laboratory. Project reference ranges will be used throughout for reporting purposes. The 
denominator used in laboratory summaries of CTCAE grades will only include evaluable 
patients, in other words those who had sufficient data to have the possibility of an 
abnormality.  
For example:
!
If a CTCAE criterion involves a change from baseline, evaluable patients would 
have both a baseline and at least 1 post-dose value recorded.
!
If a CTCAE criterion does not consider changes from baseline, to be evaluable the 
patient need only have 1 post-baseline value recorded.
3.4.3
ECGs
ECG data obtained up until the 30 days from date of last dose of study treatment will be used 
for reporting. For derivation of post baseline visit values considering visit window and to 
handle multiple records present in any visit window, derivation rules as described in Section
4.1.3 below will be used. The denominator in ECGs data should include only those patients 
with recorded data.
At each time point the Investigator’s assessment of the ECG will be collected locally. Heart 
rate, duration of QRS complex, RR, PR and QT intervals will be collected centrally via a 
digital read. This digital copy of all ECGs will be held centrally by a central ECG provider, 
and the data from this review will be stored for analysis if necessary at the end of the study. If 
it is necessary to analyse this data then QTcF (Fridericia) will be calculated programmatically 
using the reported ECG values (RR and QT).
QTcF (msec) = QT (msec)
RR (sec)

For triplicate ECGs, the mean of the three ECG assessments will be used to determine the 
value at that time point.
3.4.4
Vital signs
Vital signs data obtained up until the 30 days from date of last dose of study treatment will be 
used for reporting. Change from baseline in vital signs variables will be calculated for each 


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post-dose visit on treatment. For derivation of post baseline visit values considering visit 
window and to handle multiple records, derivation rules as described in Section 4.1.3 below 
will be used. The denominator in vital signs data should include only those patients with 
recorded data.
3.4.5
Time to first subsequent therapy from discontinuation of study treatment
Time to subsequent therapy from date of last dose is defined as the time from the date of 
discontinuation of study treatment to the start date of the first subsequent therapy after 
treatment discontinuation.  Any patient not known to have had a first subsequent therapy will 
not have this calculation performed.
3.4.6
Treatment exposure
Exposure will be defined as follows for the initial treatment period and for the re-treatment 
period:
Total (or intended) exposure of study medication, 
!
Total (or intended) exposure = min(last dose date where dose>0mg+13 days, date of 
death, date of DCO)  – first dose date +1 
Actual exposure of MEDI4736/placebo
!
Actual exposure = intended exposure – total duration of dose delays, where intended 
exposure will be calculated as above.
Dose reductions are not permitted per the CSP. The actual exposure calculation makes no 
adjustment for any dose reductions that may have occurred.
Calculation of duration of dose delays (for actual exposure):
!
Since patients will receive 10 mg/kg via IV infusion q2w for up to 12 months (up to 26 
doses), the duration of dose delays will be calculated as follows:
For all dosing dates:
Total duration of dose delays= Sum of (Date of the dose - Date of previous dose – 14 
days)
Thus, if no delays were encountered, the duration would sum up to 0, since infusions 
were done every two weeks.


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3.4.7
Dose intensity 
Dose intensity will be derived separately for the initial treatment period and the re-treatment 
period. Relative dose intensity (RDI) is the percentage of the actual dose intensity delivered 
relative to the intended dose intensity through to treatment discontinuation. 
RDI will be defined as follows:
!
RDI = 100% * d/D, where d is the actual cumulative dose delivered up the actual last day 
of dosing and D is the intended cumulative dose up to the actual last day of dosing.  D is 
the total dose that would be delivered, if there were no modification to dose or schedule.  
When accounting for the calculation of intended cumulative dose 3 days should be added 
to the date of last dose to reflect the protocol allowed window for dosing for all treatments    
When deriving actual dose administered the volume before and after infusion will also be 
considered.
For the Study medication treatment, where the last dose is on the week 50 visit and if there are 
scans post week 50, the censoring of progression should occur at week 50 for the purposes of 
RDI.
Example of dose intensity for MEDI4736
Table 7
Dose intensity scenarios
Study Day
RDI
Patient
1
15
29
43
57
71
85
99
113
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 10mg/kg taken; O: Dose missed; [D]: Dose discontinued; PD: Progressive Disease
Patients 1-4 progressed on Day 115, so the intended dose through to progression was 9 * 
10mg/kg of MEDI4736 = 90mg/kg.
Patient 1 received a total of 90 mg/kg of MEDI4736, whereas other patients received less 
treatment due to: 
!
Early stopping prior to PD (Patient 2) 


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!
Dosing delays (Patient 3) 
!
Missed doses (Patient 4) 
The examples of Patients 2 and 4 illustrate that for RDI, the end of actual dosing period is 
calculated based on the smallest recovery period after the last non-zero dose. 
Patient 1:
RDI = (9 * 10 mg/kg)/ 90 mg/kg = 100%
Patient 2:
RDI = (8 * 10 mg/kg)/ 80 mg/kg = 100% 
Patient 3:
RDI = (5 * 10 mg/kg)/ 90 mg/kg = 56% 
Patient 4: 
RDI = (6 * 10 mg/kg)/ 90 mg/m2 = 67%
3.5
Pharmacokinetic and Immunogenicity Variables
Analyses to evaluate the pharmacokinetics and immunogenicity of MEDI4736 will be 
performed by AstraZeneca/MedImmune Clinical Pharmacology group or designee.
3.5.1
PK non-compartmental analysis
The actual sampling times will be used in the PK calculations. Pharmacokinetic concentration 
data and summary statistics will be tabulated.  Individual and mean blood MEDI4736 
concentration-time profiles will be generated. PK parameters will be determined using 
standard non-compartmental methods.  The PK parameters will be determined after the first 
and steady state doses: peak and trough concentration (as data allow).  Samples below the 
lower limit of quantification will be treated as missing in the analyses.
3.5.2
Population PK and exposure-response/safety analysis
A population PK model will be developed using a non-linear mixed-effects modelling 
approach in patients with NSCLC where possible.  The impact of physiologically-relevant 
patient characteristics (covariates) and disease on PK will be evaluated.  The relationship 
between PK exposure and the effect on safety and efficacy will be evaluated, if appropriate. 
The results of such an analysis will be reported in a separate report.
3.5.3
Immunogenicity analysis
Immunogenicity results will be analysed descriptively by summarizing the number and 
percentage of patients who develop detectable anti-MEDI4736 antibodies.  The 
immunogenicity titre will be reported for samples confirmed positive for the presence of 
anti-MEDI4736 antibodies. Summaries will be based upon all patients from the safety 
population. The effect of immunogenicity on PK, PDx, efficacy and safety will be evaluated, 
but such analyses, if applicable, will be reported in a separate report.


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3.6
Exploratory Variables
The following exploratory variables will be included in the CSR.
3.6.1
EQ-5D-5L
As one of the exploratory objectives, the EQ-5D-5L health state utility index will be used to 
explore the impact of treatment and disease state on health state utility.
The EQ-5D is a standardised measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal. 
Applicable to a wide range of health conditions and treatments, it provides a simple 
descriptive profile and a single index value for health status that can be used in the clinical and 
economic evaluation of health care. 
The EQ-5D-5L index comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression).  For each dimension, respondents select which 
statement best describes their health on that day from a possible 5 options of increasing levels 
of severity (no problems, slight problems, moderate problems, severe problems and unable 
to/extreme problems).  A unique EQ-5D health state is referred to by a 5 digit code allowing 
for a total of 3125 health states.  For example, state 11111 indicates no problems on any of the 
5 dimensions.  These data will be converted into a weighted health state index by applying 
scores from EQ-5D value sets elicited from general population samples (the base case will be 
the United Kingdom valuation set, with other country value sets applied in scenario analyses).  
Where values sets are not available, the EQ-5D-5L to EQ-5D-3L crosswalk (Oemar and 
Janseen 2013) will be applied.  In addition to the descriptive system, respondents also assess 
their health on the day of assessment on a visual analogue scale, ranging from 0 (worst 
imaginable health) to 100 (best imaginable health).  This score is reported separately.  
The evaluable population will comprise a subset of the ITT analysis set who have a baseline 
EQ-5D-5L assessment.
Compliance rate of EQ-5D-5L will be analysed similarly using the method stated in Section 
3.3.3.
3.6.2
Health Resource Use 
Health resource use outcome variables include the following:
!
Length of hospital stay
!
Reasons for hospitalisation
!
Length of any time spent in an intensive care unit (ICU) 
The length of hospital stay will be calculated as the difference between the date of hospital 
discharge (or death date) and the start date of hospitalisation or start of study drug if the start 


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of study drug is after start date of hospitalisation (length of hospital stay = end date of 
hospitalisation – start date of hospitalisation or start date of study drug whichever is later + 1).  
For patients with missing discharge date, the last day with available data will be used as the 
end date of hospitalisation.
For patients who were hospitalised more than one time during the study period, the length of 
hospital stay will be the sum of all durations of hospital stays.
The length of ICU stay will be calculated using the same method as detailed above for the 
length of hospital stay.
4.
ANALYSIS METHODS
There will be 1 treatment comparison of interest:
!
MEDI4736 10 mg/kg vs placebo
The co-primary endpoints are OS and PFS using RECIST 1.1. The study has been sized to 
characterise the OS and PFS benefit of MEDI4736 relative to placebo.
Results of all statistical analysis will be presented using a 95% CI and 2-sided p-value, unless 
otherwise stated.
4.1
General Principles
Efficacy and HRQoL data will be summarised and analysed on the ITT analysis set. Safety 
and treatment exposure data will be summarised based upon the safety analysis set. Study 
population and demography data will be summarised based upon the ITT analysis set. 
Efficacy from the re-treatment period may be summarised separately for the site investigator 
data. For the site investigator data, any derivations relative to baseline (e.g. day, RECIST 
derivations) in the re-treatment period will be relative to the baseline scan prior to the re-
treatment. To avoid biasing the blinded central reviewers (i.e., when determining progression) 
the baseline scans prior to re-treatment will not be identified (see further the BICR charter) 
thus no efficacy data will be summarised from the re-treatment period based upon BICR.
Safety data will be summarised from the initial treatment period. Safety data from the re-
treatment period may also be summarised via a small set of headline summaries should there 
be sufficient number of patients re-treated to warrant this. Any safety summaries representing 
the re-treatment period will be based upon a subset of the safety analysis set representing 
patients who have had at least one dose of study treatment in the re-treatment period.
The below mentioned general principles will be followed throughout the study:
!
Descriptive statistics will be used for all variables, as appropriate.  Continuous variables 
will be summarised by the number of observations, mean, standard deviation, median, 


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minimum, and maximum. For log transformed data it is more appropriate to present 
geometric mean, coefficient of variation (CV), median, minimum and maximum. 
Categorical variables will be summarised by frequency counts and percentages for each 
category.  
!
Unless otherwise stated, percentages will be calculated out of the population total and for 
each treatment group. 
!
For continuous data the mean and median will be rounded to 1 additional decimal place
compared to the original data. The standard deviation will be rounded to 2 additional 
decimal places compared to the original data. Minimum and maximum will be displayed 
with the same accuracy as the original data. 
!
For categorical data, percentages will be rounded to 1 decimal place. 
!
SAS® version 9.2 will be used for all analyses.
4.1.1
Baseline
In general, for efficacy and PRO endpoints the last observed measurement prior to
randomization will be considered the baseline measurement. However, if an evaluable
assessment is only available after randomization but before the first dose of randomized
treatment then this assessment will be used as baseline. For safety endpoints the last
observation before the first dose of study treatment will be considered the baseline
measurement unless otherwise specified.  For assessments on the day of first dose where time
is not captured, a nominal pre-dose indicator, if available, will serve as sufficient evidence that
the assessment occurred prior to first dose.
Assessments on the day of the first dose where neither time nor a nominal pre-dose indicator
are captured will be considered prior to the first dose if such procedures are required by the
protocol to be conducted before the first dose.
In all summaries change from baseline variables will be calculated as the post-treatment value
minus the value at baseline. The % change from baseline will be calculated as (post-baseline
value - baseline value) / baseline value x 100.
4.1.2
Multiplicity
The multiple testing procedure will define which significance levels should be applied to the 
interpretation of the raw p-values for the 2 primary endpoints of PFS and OS and the key 
secondary endpoints of OS24 and ORR.
There will be 4 DCO time points in the study.  The DCO for the interim PFS analysis (first 
analysis) will be done when 367 PFS events have occurred (52% maturity), approximately 30
months after the first patient is randomised.  The DCO for the primary PFS analysis (second 
analysis) and interim OS analysis will be done when at least 458 PFS events have occurred 


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(65% maturity) at approximately 36 months after first patient is randomised.  It is expected 
that approximately 285 death events (41% maturity) will be available for the interim OS 
analysis.  The third analysis data cut-off will occur at the time of the second OS interim
analysis when it is expected that 393 OS events have occurred (56% maturity, approximately
47 months after the first patient is randomised).  The DCO for the primary OS analysis (fourth 
analysis) will be done when 491 OS events have occurred (70% maturity) at approximately 62 
months.
The overall 5% type 1 error will be split between the co-primary endpoints OS and PFS.  An 
alpha level of 2.5% will be allocated to OS analysis and an alpha level of 2.5% will be 
allocated to the PFS analysis.  An interim PFS analysis for superiority will occur when 
approximately 367 PFS events have occurred and the primary PFS analysis will be performed 
when 458 PFS events have accumulated.  The 2.5% alpha level allocated to PFS will be 
controlled at the interim and primary time point by using the Lan DeMets (Lan and DeMets 
1983) spending function that approximates an O’Brien Fleming approach, where the 
significance level applied at the interim depends upon the proportion of information available.  
If 80% of the PFS events required at the time of the primary PFS analysis is available at the 
time of the interim (i.e., 367/458 PFS events have occurred), the 2-sided significance level to 
be applied for the PFS interim analysis would be 1.04% and the 2-sided significance level to 
be applied for the primary PFS analysis would be 2.19%.
An interim OS analysis for superiority will occur at the time of the primary PFS analysis.  The 
2.5% alpha level allocated to OS will be controlled at the 2 interim and primary time point by 
using the Lan DeMets (Lan and DeMets 1983) spending function that approximates an 
O’Brien Fleming approach, where the significance level applied at the interim depends upon 
the proportion of information available.  For example, if 58% or 80% of OS events required at 
the time of the primary OS analysis is available at the time of the interim (i.e., 285/491 or 
393/491 events have occurred), the 2-sided significance level to be applied for the OS interim 
analysis would be 0.21% and 0.98% and the 2-sided significance level to be applied for the 
primary OS analysis would be 2.17%.
The family wise error rate (FWER) will be strongly controlled for the testing of PFS, OS, 
OS24, and ORR including interim analyses by applying the testing procedure illustrated in the 
Figure 2 below.
The PFS and OS will be tested according to the group sequential Holm fixed (GSHf) 
procedure described in Ye et al 2012. In this procedure, the testing will start from PFS, if the 
testing for PFS is significant at the alpha level specified in Figure 2 at either interim or 
primary analysis the full 2.5% alpha level for PFS can be propagated to the testing of OS, 
which means that the OS will be tested at an overall alpha level of 5%. Following the GSHf 
procedure the alpha level for the interim analyses of OS will not be changed but the alpha 
level for the primary analysis of OS will be recalculated based on 5% alpha level overall with 
interim alpha levels as specified in Figure 2. For example, if the information fraction for the 
interim analyses is as specified (80% for PFS interim and 58%/80% for OS interims) the alpha 
level for the primary OS analysis will be 4.85% so that the FWER for OS is 5% accounting 


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for interim analyses, given testing of PFS is significant at interim (alpha=1.04%) or at primary 
analysis (alpha=2.19%).  The alpha level for the interim OS analyses will remain at 0.21% and 
0.98%.
If the testing for PFS is not significant at either the interim (alpha=1.04%) or at the primary 
analysis (alpha=2.19%), the OS will be tested at the levels specified in Figure 2.  In this case if 
the testing for OS is significant at any interim analysis or primary analysis the full 2.5% alpha 
level for OS can be propagated to the testing of PFS, which means that the PFS will be tested 
at an overall alpha level of 5%. Following GSHf, the alpha level for the interim analysis of 
PFS will not be changed but the alpha level for the primary analysis of PFS will be 
recalculated based on 5% alpha level overall with interim alpha levels as specified in Figure 2. 
For example, if the information fraction for the interim analyses is as specified (80% for PFS 
interim and 58%/80% for OS interim) the alpha level for the primary PFS analysis will be 
4.88%, given testing of OS is significant at interim (alpha=0.21% and 0.98%) or at primary 
analysis (alpha=2.17%). The alpha level for the interim PFS analysis will remain at 1.04%. 
OS24 and ORR will not be tested unless the null hypotheses for both PFS and OS are rejected 
according to the GSHf procedure described above. After both PFS and OS are rejected the 
OS24 will be tested with 5% alpha level controlled at the interim and primary time point. The 
interim analyses of OS24 will use the same interim alpha level for OS at the same analysis 
point. The alpha for primary analysis of OS24 will be calculated based on interim alpha levels 
and information fractions at the interim so that the alpha level for OS24 is controlled at 5% 
overall.  ORR will only be tested after the null hypothesis of PFS, OS, and OS24 are all 
rejected and ORR will be tested at a 5% level.
The FWER is strongly controlled at 5% for PFS and OS according to Ye et al 2012. The 
FWER for PFS, OS, and OS24 is also strongly controlled at 5% due to the fix-sequence 
testing nature and according to Glimm et al 2009. Finally the FWER is still strongly 
controlled after adding the fix-sequence testing of ORR. So the FWER is strongly controlled 
at 5% for the testing of all four endpoints. Figure 2  shows the multiple testing framework.


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Figure 2
Multiple testing procedures for controlling the type 1 error rate
4.1.3
Visit window for safety and PRO assessments
Time windows will need defining for any presentations that summarise values by visit. The 
following conventions should also apply:
!
The time windows should be exhaustive so that data recorded at any time point has the 
potential to be summarised. Inclusion within the time window should be based on the 
actual date and not the intended date of the visit.
!
All unscheduled visit data should 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:
%
Day 15, visit window 2 - 21
%
Day 29, visit window 22 – 35
%
Day 43, visit window 36 - 49
%
Day 57, visit window 50 – 63


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%
Day 71, visit window 64 – 77
%
Day 85, visit window 78 – 91
!
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 gradeable then 
the record with the highest toxicity grade should be used. Alternatively, if there 
are two records recorded on the same day and the toxicity grade is the same (or 
is not calculated for the parameter) then the average of the two records should 
be used. The listings 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.  
%
To prevent very large tables or plots being produced that contain many cells 
with meaningless data, for each treatment group visit data should only be 
summarised if the number of observations is greater than the minimum of 20 
and > 1/3 of patients dosed.
!
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. 
!
Baseline will be defined as the last non-missing measurement prior to the first dose of 
study treatment. For the re-treatment period baseline is similarly defined as the last non-
missing measurement prior to the first dose on the re-treatment period. For laboratory data, 
any assessments made on day 1 will be considered pre-dose. If there are two visits equally 
eligible to assess patient status at baseline (e.g., screening and baseline assessments both 
on the same date prior to first dose with no washout or other intervention in the screening 
period) with assessment time missing, the average can be taken as a baseline value. For 
non-numeric laboratory tests (ie some of the urinalysis parameters) where taking an 
average is not possible then the best value would be taken as baseline as this is the most 
conservative. In the scenario where there are two assessments on day 1, one with time 
recorded and the other without time recorded, the one with time recorded would be 
selected as baseline.


Statistical Analysis Plan 
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Edition Number 4.0
Date 22 March 2017
61
!
Where safety data are summarised over time, study day will be calculated in relation to 
date of first treatment.
Missing safety data will generally not be imputed. However, safety assessment values of the 
form of “< x” (i.e., below the lower limit of quantification) or > x (i.e., above the upper limit 
of quantification) will be imputed as “x” in the calculation of summary statistics but displayed 
as “< x” or “> x” in the listings.  Additionally, adverse events that have missing causality 
(after data querying) will be assumed to be related to study drug.
4.2
Analysis Methods
Table 8 details which endpoints are to be subject to formal statistical analysis, together with 
pre-planned sensitivity analyses making clear which analysis is regarded as primary for that 
endpoint.
Table 8
Formal statistical analyses to be conducted and pre-planned sensitivity 
analyses
Endpoints Analysed
Notes
Overall Survival
!
Co-primary analysis using a stratified log-rank test
!
Sensitivity analysis using a Kaplan-Meier plot of time to 
censoring where the censoring indicator of the primary 
analysis is reversed – attrition bias
!
Additional analysis using Cox proportional hazards models 
to determine the effect of covariates on the HR estimate
!
Additional analysis using Cox proportional hazards models 
to determine the consistency of treatment effect between 
subgroups via the approach of Gail and Simon 1985.
!
Subgroup analysis using Cox proportional hazards model 


Statistical Analysis Plan 
Study Code D4191C00001
Edition Number 4.0
Date 22 March 2017
62
Table 8
Formal statistical analyses to be conducted and pre-planned sensitivity 
analyses
Endpoints Analysed
Notes
Progression Free Survival
!
Co-primary analysis using stratified log-rank test using 
BICR data (RECIST 1.1)
!
Sensitivity analyses using BICR data (RECIST 1.1)
-
Interval censored analysis – evaluation time bias
-
Analysis using alternative censoring rules –
attrition bias
!
Sensitivity analysis stratified log-rank test using site 
investigator tumour data (RECIST 1.1) – ascertainment 
bias
!
Sensitivity analysis stratified log-rank test using BICR data 
(RECIST 1.1, modified for confirmation of progression) –
confirmation bias
!
Additional analysis using Cox proportional hazards models 
to determine the effect of covariates on the HR estimate
!
Additional analysis using Cox proportional hazards models 
to determine the consistency of treatment effect between 
subgroups via the approach of Gail and Simon 1985.
!
Subgroup analysis using Cox proportional hazards model 
!
Exploratory analysis stratified log-rank test using BICR 
tumour data (irRECIST)  
Proportion of patients alive at 
24 months
Kaplan-Meier estimates of survival at 24 months and p-value 
(following the method described by Klein et al 2007)
Objective Response Rate
Fisher’s exact test using BICR data (RECIST 1.1)
Sensitivity analysis using the Fisher’s exact test using site 
investigator tumour data (RECIST 1.1)
Sensitivity analysis using the Fisher’s exact test using BICR 
tumour data (RECIST 1.1, modified for confirmation of 
progression)
Exploratory analysis using the Fisher’s exact test using BICR 
tumour data (irRECIST) 
Duration of Response
Analysis following the method described by Ellis et al 2008
using BICR tumour data (RECIST 1.1)
Proportion of patients alive and 
progression free at 12 and18 months 
Kaplan Meier estimates of progression free survival at 12 and 
18 months 
Time from randomisation to second 
progression 
Stratified log-rank test 
Time to death or distant metastasis
Stratified log-rank test using site BICR tumour data
(RECIST 1.1)


Statistical Analysis Plan 
Study Code D4191C00001
Edition Number 4.0
Date 22 March 2017
63
Table 8
Formal statistical analyses to be conducted and pre-planned sensitivity 
analyses
Endpoints Analysed
Notes
Symptom improvement rate (EORTC 
QLQ-C30 and LC13 endpoints)
Logistic regression
HR QoL/Function improvement rate 
(EORTC QLQ-C30 endpoints)
Logistic regression
Time to HR QoL/Function 
deterioration (EORTC QLQ-C30 
endpoints)
Stratified log-rank test
Time to symptom deterioration 
(EORTC QLQ-C30 and LC13 
endpoints)
Stratified log-rank test
Change from baseline (EORTC QLQ 
C30 and LC13; EQ-5D-5L health 
state utility values and Visual 
Analogue Scale)
Mixed model repeated measures analysis
BICR  Blinded Independent Central Review; EORTC QLQ-C30  European Organisation for Research and Treatment of 
Cancer 30-item core quality of life questionnaire; EQ-5D-5L  EuroQoL 5 dimension, 5 level health state utility index; irRC  
Immune-related response criteria; LC13  Lung Cancer Module; HR QoL  Quality of Life; RECIST  Response Evaluation 
Criteria In Solid Tumours.
All outputs will be summarised by treatment arm as randomised for all ITT patients.  
4.2.1
Co-primary efficacy endpoints
4.2.1.1
Overall survival
The primary analysis of the co-primary endpoint, OS, will occur when approximately 491 
deaths have occurred (approximately 70% maturity).  OS will be analysed using a stratified 
log-rank test adjusting for age at randomisation (<65 vs ≥65 years of age), sex (male vs
female), and smoking history (smoker vs non-smoker) for generation of the p-value and using 
the Breslow approach for handling ties (Breslow, 1974).  
The effect of treatment will be estimated by the hazard ratio (HR) together with its 
corresponding (1-alpha adjusted)% CI and p-value for the ITT population.  
The covariates in the statistical modelling will be based on the values entered into IVRS at 
randomisation, even if it is subsequently discovered that these values were incorrect.  In 
addition a sensitivity analysis will be produced which use the covariates recorded in the CRF.
The HR and CI can be estimated from the stratified log-rank as follows (Berry et al 1991, 
Collett 2003, Sellke and Siegmund 1983):


Statistical Analysis Plan 
Study Code D4191C00001
Edition Number 4.0
Date 22 March 2017
64
Where 
is the stratified log-rank test statistic obtained from the 
SAS LIFTEST procedure,
, is its standard deviation, k denotes the stratum and 
d1ki and e1ki are the observed and expected events in Group 1, stratum k.
Kaplan-Meier plots of OS will be presented by treatment arm.  Summaries of the number and 
percentage of patients who have died, those still in survival follow-up, those lost to follow-up 
and those who have withdrawn consent will be provided along with the median OS for each 
treatment. The assumption of proportionality will be assessed.  
Proportional hazards will be tested firstly by examining plots of complementary log-log (event 
times) vs log (time) and, if these raise concerns, by fitting a time-dependent covariate to assess 
the extent to which this represents random variation.  If a lack of proportionality is evident, 
the variation in treatment effect will be described by presenting piecewise HR calculated over 
distinct time-periods.  In such circumstances, the HR can still be meaningfully interpreted as 
an average HR over time unless there is extensive crossing of the survival curves.  If lack of 
proportionality is found, this may be is a result of treatment-by-covariate interactions, which 
will be investigated.
Sensitivity analyses
A sensitivity analysis for OS will examine the censoring patterns to rule out attrition bias, 
achieved by a Kaplan-Meier plot of time to censoring where the censoring indicator of OS is 
reversed.
The number of patients prematurely censored will be summarised by treatment arm. A patient 
would be defined as prematurely censored if their survival status was not defined at the DCO.
In addition, duration of follow-up will be summarised using medians:
!
In censored patients who are alive at DCO only: Time from randomisation to date of 
censoring (date last known to be alive) for each arm.
!
In all patients: Time from randomisation to the date of death or to the date of censoring for 
censored patients, regardless of treatment.
&
∋
(
)
∗
+
#
V
U
HR
exp
&&
∋
(
,
−
.
/01
2
/01
)
∗
+
,−.
%
#
V
V
U
V
V
U
96
.1
exp
,
96
.1
exp
HR
for 
CI
95%
3
3
3
%
#
#
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ki
ki
k
k
k
e
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)
,
(
1
1
3
#
k
k
V
V


Statistical Analysis Plan 
Study Code D4191C00001
Edition Number 4.0
Date 22 March 2017
65
Subgroup analyses
Subgroup analyses will be conducted comparing OS between treatments in the following 
subgroups of the FAS:
!
Age at randomisation (<65 vs ≥65 years of age) 
!
Sex (male vs female)
!
Smoking status (smoker vs non-smoker).  
!
Stage of disease at study entry (Stage III A vs Stage III B).
!
Histology (squamous vs all other).
!
Best response to prior anticancer therapy (CR, PR, SD).
!
Type of chemotherapy 1 (gemcitabine-based vs non- gemcitabine -based).
!
Type of chemotherapy 2 (cisplatin-based vs carboplatin-based).
!
Time from last dose of radiation to randomization (<14 days, ≥14 days).
!
WHO performance status at baseline (normal activity [PSTAT=0] vs restricted activity 
[PSTAT=1]).
-
This will be determined from the response to “Performance status” (PSTAT module) 
on the eCRF at screening. Patients with a missing performance status will be included 
in the ‘restricted activity’ category.  
!
Region (Asia, Europe, South America vs North America).
-
This will be determined from the centre number (CENTRE). If there are less than 20 
events in the “South America” category, these patients will be combined with those in 
North America.
!
Race (White, Black/African-American, Asian, Other [Native Hawaiian/Pacific Islander or 
American Indian/Alaska Native or Others]).
!
This will be determined from the response to “Race” (DEM module) on the eCRF at 
screening.
!
PD-L1 status (≥ 25% vs <25%).
-
Only samples with sample date on or before first dose should be used


Statistical Analysis Plan 
Study Code D4191C00001
Edition Number 4.0
Date 22 March 2017
66
-
for multiple evaluable samples with sample date on or before the first dose, the sample 
with the highest PD-L1 % tumour membrane staining result should be used
! EGFR (positive vs negative)
The subgroup analyses will be based on values recorded on the eCRF.
Other baseline variables may also be assessed if there is clinical justification or an imbalance 
is observed between the treatment arms.  The purpose of the subgroup analyses is to assess the 
consistency of treatment effect across expected prognostic factors.
No adjustment to the significance level for testing will be made since all these subgroup
analyses will be considered exploratory and may only be supportive of the primary analysis of 
OS.
For each subgroup, the HR and 95% CI will be calculated from an unstratified Cox 
proportional hazards model with treatment as only covariate. The Cox models will be fitted 
using SAS® PROC PHREG with the Efron method to control for ties, using the by statement 
to obtain HR and 95% CI for each subgroup level separately.
These hazard ratios and associated two-sided 95% CIs will be summarised and presented on a 
forest plot, along with the results of the overall primary analysis.
If there are too few events available for a meaningful analysis of a particular subgroup (it is 
not considered appropriate to present analyses where there are less than 20 events in a 
subgroup), the relationship between that subgroup and OS will not be formally analysed.  In 
this case, only descriptive summaries will be provided.
Effect of covariates on the HR estimate
Cox proportional hazards modelling will be employed to assess the effect of covariates on the 
HR estimate for the primary treatment comparison.  A model will be constructed, containing 
treatment and the stratification factors alone, to ensure any output from the Cox modelling is 
likely to be consistent with the results of the stratified log-rank test.
The result from the initial model and the model containing additional covariates will be 
presented.
Additional covariates for this model will be age at randomization, sex, smoking status, stage 
of disease at study entry, histology, best response to prior anticancer therapy, WHO 
performance status, region and race. 
The model will include the effect regardless of whether the inclusion of effect significantly 
improves the fit of the model providing there is enough data to make them meaningful.
Consistency of treatment effect between subgroups


Statistical Analysis Plan 
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67
Interactions between treatment and stratification factors will also be tested to rule out any 
qualitative interaction using the approach of Gail and Simon 1985.
Impact of switching (crossover outside of this study) to immunotherapies (or other 
potentially active investigational agents) on OS analyses
Exploratory analyses of OS adjusting for the impact of subsequent immunotherapy or other 
treatment may be performed, if a sufficient proportion of patients switch.  
Methods such as Inverse Probability of Censoring Weighting (Robins 1993), Rank Preserving 
Structural Failure Time (Robins and Tsiatis 1991), and other methods in development will be 
explored as appropriate.  The decision to adjust and the final choice of methods will be based 
on a blinded review of the data and the plausibility of the underlying assumptions.  Additional 
supportive analysis by censoring the treatments switchers at the time of initiation of
subsequent therapy will also be conducted. These analyses are intended to further support the 
OS benefit and reimbursement appraisals.
Baseline and time-dependent characteristics will be explored, and summaries of baseline 
characteristics will be provided by treatment arm, splitting between those that have and 
haven’t switched at the time of the analyses.
Subsequent therapies received after discontinuation of treatment will be summarised and listed 
by treatment group.  Patients who subsequently received an immunotherapy agent or entered 
an immunotherapy trial will be summarised and listed by treatment arm according to line of 
subsequent therapy, i.e. immediately after immunotherapy or as a later line.
4.2.1.2
Progression free survival 
PFS based upon the programmatically derived RECIST outcome using the BICR data 
(including all scans regardless of whether they were scheduled or not) will be analysed by 
stratified log-rank tests, the same methodology as described for the OS analyses.
The primary analysis of the co-primary endpoint, PFS, will occur when it is expected that 458 
PFS events have occurred (65% maturity).  PFS based upon the BICR data will be analyzed 
using a stratified log-rank test adjusting for the same factors as for OS.  The effect of 
treatment will be estimated by the HR together with its corresponding (1-alpha adjusted)% CI 
and p-value for the full ITT population.  Kaplan-Meier plots of PFS will be presented by 
treatment arm.  Summaries of the number and percentage of patients experiencing a PFS 
event, and the type of event (RECIST 1.1 or death) will be provided along with median PFS 
for each treatment.
The assumption of proportionality will be assessed in the same way as for OS.  The analysis 
will be based on the programmatically derived PFS using BICR data.  
Supportive summaries/graphs
The treatment status at progression of patients at the time of analysis will be summarised.  
This will include the number (%) of patients who were on treatment at the time of progression, 


Statistical Analysis Plan 
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68
the number (%) of patients who discontinued study treatment prior to progression, the number 
(%) of patients who have not progressed and were on treatment or discontinued treatment. 
This will also provide distribution of number of days prior to progression for the patients who 
have discontinued treatment.
The number of patients prematurely censored will be summarised by treatment arm. A patient 
would be defined as prematurely censored if they had not progressed (or died in the absence 
of progression) and the latest scan prior to DCO was more than one scheduled tumour 
assessment interval plus 2 weeks (10 weeks if time period between randomisation and DCO 
for that patient is 48 weeks or less; 14 weeks otherwise) prior to the DCO date.
Additionally, summary statistics will be given for the number of days from censoring to DCO
for all censored patients.
A summary of the duration of follow-up will be summarised using median time from 
randomisation to date of censoring (date last known to be non-progressor) in censored (not 
progressed) patients only, presented by treatment group.
Additionally, summary statistics for the number of weeks between the time of progression and 
the last RECIST assessment prior to progression will be presented for each treatment group.
Summaries of the number and percentage of patients who miss two or more consecutive 
RECIST assessments will be presented for each treatment group.
All of the collected RECIST 1.1 data will be listed for all randomised patients. In addition, a 
summary of new lesions (i.e., sites of new lesions) will be produced.
Sensitivity Analyses
The following sensitivity analyses will be performed:
!
Evaluation-Time bias
Sensitivity analyses will be performed to assess possible evaluation-time bias that may be 
introduced if scans are not performed at the protocol-scheduled timepoints.  The midpoint 
between the time of progression and the previous RECIST assessment will be analysed using 
a stratified log-rank test, as described for the co-primary analysis of PFS.  For patients whose 
death was treated as PFS event, the date of death will be used to derive the PFS time used in 
the analysis.  This approach has been shown to be robust to even highly asymmetric 
assessment schedules (Sun and Chen 2010). To support this analysis, the mean of subject-
level average inter-assessment times will be tabulated for each treatment.  This approach will 
use the BICR data.
!
Attrition bias


Statistical Analysis Plan 
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69
Attrition bias will be assessed by repeating the co-primary PFS analysis except that the actual 
PFS event times, rather than the censored times, of patients who progressed or died in the 
absence of progression immediately following two, or more,  tumour assessments will be 
included.  In addition, patients who take subsequent therapy prior to their last evaluable 
RECIST assessment or progression or death will be censored at their last assessment prior to 
taking the subsequent therapy.  This analysis will be supported by a Kaplan-Meier plot of the 
time to censoring where the censoring indicator of the PFS analysis is reversed. This approach 
will use the BICR data.
!
Ascertainment bias
Ascertainment bias will be assessed by analysing the site investigator data.  The stratified 
log-rank test will be repeated on PFS using the site investigator data based upon RECIST. If 
there is an important discrepancy between the primary analysis using the BICR assessments 
and this sensitivity analysis using investigator assessments, then the proportion of patients 
with site but no central confirmation of progression will be summarised; such patients have 
the potential to introduce bias in the central review due to informative censoring.  An 
approach that imputes an event at the next visit in the central review analysis may help inform 
the most likely HR value (Fleischer et al 2011), but only if an important discrepancy exists. 
Disagreements between investigator and central reviews of RECIST progression will be 
presented for each treatment group.  The summary will include the early discrepancy rate 
which is the frequency of central review declared progressions before the investigator review 
as a proportion of all central review progressions and the late discrepancy rate which is the 
frequency of central review declared progressions after the investigator review as a proportion 
of all discrepancies.
!
Confirmation bias
An additional sensitivity analysis using the BICR data will be performed to determine the 
effect of confirmation of progression.  The stratified log-rank test will be repeated on PFS 
using BICR data based upon RECIST modified for confirmation of progression.  The HR and 
CI will be presented.
Subgroup/Additional Analysis
An exploratory analysis of PFS using the irRECIST 1.1 data provided by the BICR will be 
performed on the BICR analysis set.  The stratified log-rank test will be repeated on PFS using 
the BICR based upon the irRECIST 1.1 data.  The HR and CI will be presented.
Subgroup analyses and a forest plot will be generated comparing PFS between treatments in 
the same way as previously specified for OS.  Unless there is a marked difference between the 
results of the statistical analyses of the PFS from the BICR data and that of the site 
investigator, this will only be performed upon the PFS endpoint using the BICR data based 
upon RECIST. No adjustment to the significance level for testing will be made since all these 


Statistical Analysis Plan 
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70
subgroup and sensitivity analyses will be considered supportive of the primary analysis of 
PFS.
A forest plot illustrating the hazard ratio and the corresponding 95% confidence interval will 
be provided to compare the primary and sensitivity analyses of progression free survival.
The effect of covariates upon the HR estimate and the consistency of treatment effect between 
subgroups will be analysed for PFS using the same methods as those described for OS.
A further analysis of PFS (using investigator assessed RECIST) may be performed at the time 
of the OS analyses, if requested by health authorities.
Time to first subsequent therapy or death (TFST)
For supportive purposes, the time to the start of subsequent therapy will be analysed using the 
same methodology and model as that used for the co-primary analysis of PFS.  The HR for the 
treatment effect together with its 95% CI will be presented.  In addition, a Kaplan-Meier plot 
of the time to the start of subsequent therapy will be presented by treatment arm and the time 
between progression and starting subsequent therapy will be assessed based upon the 
investigator data defined date of progression.  This will be summarised per treatment arm but 
no formal comparisons will be made. No multiplicity adjustment will be applied as this is 
viewed as a supportive endpoint.
In patients who received a subsequent cancer therapy, a summary table of first subsequent 
cancer therapies by treatment arm will be provided. 
4.2.2
Secondary efficacy endpoints
4.2.2.1
Proportion of patients alive at 24 months (OS24)
OS24 will be analysed (using the Kaplan-Meier curve) and presented by treatment arm.  For 
each treatment arm, the survival rate at 24 months based on Kaplan-Meier method will be 
presented, along with its 95% confidence interval. The computation of the confidence interval 
will be based on a log(-log(.)) transformation.  
For the comparison between treatments (sub-study B only), the test will be based on the 
method described in Klein 2007 (Klein et al 2007).  The test statistic and its variance estimate 
are as follows:
!
test statistic =
)
(
ˆ
ln
)
(
ˆ
ln
ln
2
1
t
S
t
S
!
Variance estimate =
)
(
ln
)
(
ˆ
)
(
ln
)
(
ˆ
2
2
2
2
1
2
2
1
t
S
t
t
S
t
4
4
2


Statistical Analysis Plan 
Study Code D4191C00001
Edition Number 4.0
Date 22 March 2017
71
where 
3
∀
%
#
t
t
i
i
i
i
i
i
d
n
n
d
t
)
(
)
(
ˆ
2
4
is the variance derived from Greenwood’s formula S(t)and can 
be estimated from standard software packages, where di and ni refer to the number of deaths 
and patients at risk for each risk set.  
The z-statistic is then calculated as:  
estimate
variance
statistic
test 
  
For stratified analysis, the test statistic and its variance estimate in each strata will be 
combined by weighting inversely proportionately according to each within stratum variance 
(Whitehead and Whitehead 1991).  A Z-test will be performed and the p-value from the test 
will be presented.
4.2.2.2
Objective response rate
The ORR will be based on the programmatically derived RECIST outcome using the BICR
data.  The treatment comparison of ORR will be based on a Fisher’s exact test using mid p-
values. A binary response variable for ORR will be used for the analysis with the categories of 
CR and PR vs SD, PD and NE. The results of the analysis will be presented in terms of the 
proportion of responders and a p-value.
The mid-p-value modification of the Fisher exact test amounts to subtracting half of the 
probability of the observed table from Fisher's p-value.
Fisher’s exact test mid p-value = Two sided p-value −Table probability
2
This analysis of ORR will be repeated using the results of the programmatically derived 
outcome using the site investigator data based upon RECIST as a sensitivity analysis to 
confirm the results of the primary analysis based on the site investigator tumour data.  An 
additional sensitivity analysis will be performed on programmatically derived outcomes using 
BICR tumour data based upon RECIST modified for confirmation of progression to determine 
if there is any difference when using progression confirmation rules.  Finally, an exploratory 
analysis of ORR using the irRECIST 1.1 data obtained from the BICR will be performed 
where the above analysis will be repeated. 
Summaries will be produced that present the number and percentage of patients with a tumour 
response (CR/PR) based upon the number of patients with measurable disease at baseline per 
BICR or investigator as appropriate (see Section 3.2.2.2). For each treatment arm, best 
objective response (BoR) will be summarised by n (%) for each category (CR, PR, ND, SD, 
PD, NE). This will be produced for the BICR of RECIST only. No formal statistical analyses 
are planned for BoR.


Statistical Analysis Plan 
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Edition Number 4.0
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72
4.2.2.3
Duration of response
Descriptive data will be provided for the DoR in responding patients (ie median duration of 
response and 95% CIs) by treatment arm, including the associated Kaplan-Meier curves 
(without any formal comparison of treatment arms or p-value attached).
4.2.2.4
Proportion of patients alive and progression free at 12 months (APF12)
The proportion of patients alive and progression free at 12 months (i.e. at study day 366) will 
be summarised (using the Kaplan-Meier curve) and presented by treatment arm.  For each 
treatment arm, the APF12 based on Kaplan-Meier method will be presented, along with its 
95% confidence interval. The computation of the confidence interval will be based on a log(-
log(.)) transformation. 
4.2.2.5
Proportion of patients alive and progression free at 18 months (APF18)
The proportion of patients alive and progression free at 18 months (i.e. at study day 549) will 
be summarised (using the Kaplan-Meier curve) and presented by treatment arm. For each 
treatment arm, the APF18 based on Kaplan-Meier method will be presented, along with its 
95% confidence interval. The computation of the confidence interval will be based on a log(-
log(.)) transformation. 
4.2.2.6
Time from randomisation to second progression (PFS2) 
Time from randomisation to second progression (PFS2) will be analysed using the same 
methods as outlined for the analysis of PFS and adjusting for the same set of covariates, but 
no subgroup analysis will be performed.  Medians and Kaplan–Meier plots will be presented 
to support the analysis.  The sensitivity analysis outlined in Section 4.2.1.2 will not be 
repeated for PFS2 with the exception of a Kaplan-Meier plot of the time to censoring where 
the censoring indicator of PFS2 is reversed.
The number and percentage of subjects experiencing a PFS2 event and the type of progression 
(objective progression by RECIST, symptomatic progression, new or worsening of soft 
tissue/visceral or bone metastases or other) will also be summarised by treatment arm. 
Time to second subsequent therapy or death (TSST)
For supportive purposes, the time to the start of second subsequent therapy will be analysed 
using the same methodology and model as that used for the analysis of PFS2.  The HR for the 
treatment effect together with its 95% CI will be presented.  In addition, a Kaplan-Meier plot 
of the time to the start of second subsequent therapy will be presented by treatment arm and 
the time between progression and starting second subsequent therapy will be assessed based 
upon the site investigator data defined date of progression.  This will be summarised per 
treatment arm but no formal comparisons will be made. No multiplicity adjustment will be 
applied as this is viewed as a supportive endpoint.


Statistical Analysis Plan 
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Edition Number 4.0
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73
4.2.2.7
Time to death or distant metastasis 
TTDM will be analysed using identical methods as outlined for the analysis of PFS and 
adjusting for the same set of covariates, but no subgroup analysis will be performed. Medians 
and Kaplan-Meier plots will be presented to support the analysis. The sensitivity analysis 
outlined in Section 4.2.1.2 will not be repeated for TTDM with the exception of a Kaplan 
Meier plot of the time to censoring where the censoring indicator of TTDM is reversed.
4.2.2.8
Change in tumour size
The absolute values and percentage change in TL tumour size from baseline will be 
summarized using descriptive statistics and presented at each timepoint by treatment arm. The 
best change in TL tumour size from baseline, (where best change in TL size is the maximum 
reduction from baseline or the minimum increase from baseline in the absence of a reduction) 
will also be summarised and presented for each treatment arm.
Tumour size will also be presented graphically using waterfall plots for each treatment arm, to 
present each subject’s best percentage change in tumour size as a separate bar, with the bars 
ordered from the largest increase to the largest decrease. Reference lines at the +20% and –
30% change in tumour size levels will be added to the plots, which correspond with the 
definitions of progression and ‘partial’ response respectively. On each of the waterfall plots
the PD-L1 status (positive vs negative), the histology categorization (squamous vs other) and 
the disease status at study entry (IIIA vs IIIB) of each patient will be indicated as appropriate.
Additional waterfall plots showing percentage change in tumour size at specific timepoints 
may be produced if it is felt that these are warranted to provide greater clarity. 
The above outputs will be programmed on data based upon BICR RECIST assessments. They 
will be repeated for the irRC (irRECIST 1.1) data obtained from BICR where tumour size is 
defined as the sum of the diameters of TLs and the new measured lesions.
4.2.3
Secondary patient reported outcome endpoints
The PRO endpoints that have been identified as primary are EORTC QLQ-C30 time to 
HRQoL deterioration for global health status and LC13 time to symptom deterioration for 
each of dyspnoea, cough, haemoptysis, and chest pain.  These are not part of the main 
multiple testing procedure and as supportive endpoints will need a Bonferroni adjustment to 
the significance level to aid interpretation.  Therefore, these 5 endpoints will be tested at a 1% 
significance level and 99% CIs will be produced. 
The other time to symptom deterioration endpoints will be tested at a 5% significance level 
and 95% CIs will be produced.


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4.2.3.1
EORTC QLQ-C30
Time to symptom deterioration will be analysed for each of the 3 symptom scales (fatigue, 
pain, nausea/vomiting) and the 5 individual symptom items (dyspnoea, insomnia, appetite 
loss, constipation, diarrhoea).  
Time to HRQoL/function deterioration will be analysed for the 5 function scales (physical, 
role, emotional, cognitive, and social) and global health status/HRQoL.  For treatment 
comparison, a stratified log-rank test will be used, as described for the primary analysis of OS. 
The HR and 95% CI for each scale/item will be presented graphically on a forest plot. 
A summary of the symptom improvement rate for each of the 3 symptom scales and the 
5 individual symptom items will be produced.  Similarly, a summary of HR QoL/function 
improvement rate for each of the 5 function scales (physical, role, emotional, cognitive, and 
social) and global health status/HR QoL will be produced.  Symptom improvement rate and 
HR QoL/function improvement rate will be analysed by comparing between treatment arms 
using a logistic regression model adjusting for the same factors as the co-primary endpoints.  
The results of the analysis will be presented in terms of an odds ratio (an odds ratio greater 
than 1 will favour treatment A) together with its associated profile likelihood 95% CI (e.g. 
using the option ‘LRCI’ in SAS procedure GENMOD) and p-value (based on twice the 
change in log-likelihood resulting from the addition of a treatment factor to the model).  The 
odds ratio and 95% CI for each scale/item will be presented graphically on a forest plot. If 
there are very few responses in one treatment arm, a Fisher’s exact test will be considered.
For each of the 3 symptom scales (fatigue, pain, nausea/vomiting), 5 individual symptom 
items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea), 5 functional scales 
(physical, role, emotional, cognitive, and social), and global health status/HR QoL, time to 
deterioration will be presented using a Kaplan-Meier plot.  Summaries of the number and 
percentage of patients experiencing a clinically meaningful deterioration or death, and the 
median time to deterioration will also be provided for each treatment arm.  
Summaries of original and change from baseline values of each symptom scale/item, the 
global HRQoL score and each functional domain will be reported by visit for each treatment 
arm.  Graphical presentations may also be produced as appropriate.  Summaries of the number 
and percentage of patients in each response category at each visit for each ordinal item (in 
terms of the proportion of patients in the categories of improvement, no change, and 
deterioration as defined in Section 3.3.1) will also be produced for each treatment arm.
A summary of compliance rate and evaluability rate will be provided for each treatment arm, 
by assessment time point and also for overall.
4.2.3.2
EORTC-QLQ-LC13
Time to symptom deterioration for each of the 6 individual symptoms (dyspnoea, cough, 
haemoptysis, chest pain, arm/shoulder pain, other pain) will be compared between treatment 
arms using a stratified log-rank test as described for the primary analysis of OS.  


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The HR and 95% CI for each scale/item will be presented graphically on a forest plot.
For each of the 6 symptoms items in LC13, time to deterioration in symptoms will be 
presented using a Kaplan-Meier plot.  Summaries of the number and percentage of patients 
experiencing a clinically meaningful deterioration or death, and the median time to 
deterioration will also be provided for each treatment arm.  
A summary of the symptom improvement rate for each of the 6 individual symptom items will 
be produced.  The symptom improvement rate will be compared between treatment arms 
using a logistic regression model as described for EORTC-QLQ-C30.  The odds ratio and 
95% CI for each symptom will be presented graphically on a forest plot. If there are very few 
responses in one treatment arm, a Fisher’s exact test will be considered. 
Summaries of original and change from baseline values of each symptom (dyspnoea, cough, 
haemoptysis, chest pain, arm/shoulder pain, other pain) and each treatment-related side effect 
(sore mouth, dysphagia, peripheral neuropathy and alopecia) will be reported by visit for each 
treatment arm.  Graphical presentations may also be produced as appropriate.  Summaries of 
the number and percentage of patients in each response category at each visit for each ordinal 
symptom item (in terms of the proportion of patients in the categories of improvement, 
no change, and deterioration as defined in Section 3.3.2 will also be produced for each 
treatment arm.  
A summary of compliance rate and evaluability rate will be provided for each treatment arm, 
by assessment time point and also for overall.
4.2.3.3
Mixed models repeated measures of change from baseline in PRO symptoms
In addition to the time to deterioration endpoints listed above the following longitudinal
endpoints are of interest:  EORTC QLQ-C30 global health status, physical functioning, 
fatigue and appetite loss; LC13 dyspnoea, cough and chest pain. These are not part of the 
main multiple testing procedure and are considered a separate set of PRO endpoints from the 
time to deterioration endpoints listed above. A Bonferroni adjustment to the significance level 
will be applied to the tests described below to control the overall Type I error at the 5% level.  
Change from baseline in these pre-specified the PRO symptom scores of dyspnea, cough, 
chest pain, fatigue and appetite loss, global health status and physical functioning will be
analysed using a mixed model for repeated measures (MMRM) analysis making use of all 
data from baseline up to 12 months. The analysis will be to compare the average treatment 
effect from the point of randomisation until PD or 12 months (whichever is earlier) unless 
there is excessive missing data (defined as >75% missing data). It is acknowledged that 
patients will discontinue treatment at different timepoints during the study and that this is an 
important time with regards to symptoms and HRQoL data collection. To account for this, and 
in order to include the discontinuation and follow up visits, a generic visit variable will be 
derived for each subject in order that the average treatment effect can be analyzed using the 
above method. Each visit will be assigned a sequential number. The time from randomization 


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to each of these will be derived in order to select only those visits occurring within the first 12
months of randomization or until PD.
As an example, say a patient X attends the first 4 scheduled visits of a 4-weekly schedule and
then discontinues treatment, whilst patient Y discontinues treatment after the first scheduled 
visit, the first 6 generic visits would be as follows:
Generic visit
Study Day
Patient X
Patient Y
Baseline
Baseline
Baseline
1
29
28
2
57
50 (discontinuation)
3
85
85
4
113
113
5
130 (discontinuation)
141
6
169
169
The MMRM model will include the fixed, categorical effects of treatment, visit, and 
treatment-by-visit interaction, age at randomisation (<65 vs ≥65 years of age), sex (male vs 
female), smoking history (smoker vs non-smoker as well as the continuous fixed covariate of 
baseline score and the baseline score-by-visit interaction. Restricted maximum likelihood 
(REML) estimation will be used. An overall adjusted mean estimate will be derived that will 
estimate the average treatment effect over visits giving each visit equal weight. For this 
overall treatment comparison, adjusted mean estimates per treatment group and corresponding 
95% CIs will be presented along with an estimate of the treatment difference, 95% CI and p-
value
An unstructured covariance matrix will be used to model the within-subject error and the 
Kenward-Roger approximation will be used to estimate the degrees of freedom. If the fit of 
the unstructured covariance structure fails to converge, the following covariance structures 
will be tried in order until convergence is reached: toeplitz with heterogeneity, autoregressive 
with heterogeneity, toeplitz, autoregressive and compound symmetry. 
Multiple imputation techniques for missing values may be considered to explore the 
robustness of any treatment effect.


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An effect size estimate to interpret the magnitude of the effect and potential therapeutic 
benefit will be further specified in the PAP.
4.2.4
Safety data
Safety and tolerability data will be presented by treatment arm using the safety population.  
Safety summaries will be descriptive only. No formal statistical analyses will be performed on 
the safety variables.
Any safety summaries examining re-treatment of study medication will be produced 
separately as needed.
The following sections describe the planned safety summaries for AEs, vital signs, laboratory 
parameters, ECG and WHO performance status. However, additional safety summaries (not 
specified in this SAP) may need to be produced to aid interpretation of the safety data.
4.2.4.1
Adverse events
All AEs, both in terms of current MedDRA preferred term and CTCAE grade, will be 
summarised descriptively by count (n) and percentage (%) for each treatment group. Any AE 
occurring before randomized treatment (i.e. before the administration of the first infusion on
Study Day 1) will be included in the AE listings, but will not be included in the summary 
tables (unless otherwise stated). These will be referred to as ‘pre-treatment’.
AEs observed up until 90 days following discontinuation of the study treatment (i.e., the last 
dose of randomised treatment) or until the initiation of the first subsequent anti-cancer therapy 
(including radiotherapy, with the exception of palliative radiotherapy) following 
discontinuation of study treatment (whichever occurs first) will be used for reporting of all of 
the AE summary tables. This will more accurately depict AEs attributable to study treatment
only as a number of AEs up to 90 days following discontinuation of the study treatment are 
likely to be attributable to subsequent therapy. 
However, to assess the longer term toxicity profile, all of the AE summaries will also be 
produced containing AEs observed up until 90 days following discontinuation of the study 
treatment (ie without taking subsequent therapy into account). 
All reported AEs will be listed along with the date of onset, date of resolution (if AE is 
resolved) and investigator’s assessment of severity and relationship to study drug. Frequencies 
and percentages of patients reporting each preferred term will be presented (i.e. multiple 
events per patient will not be accounted for apart from on the episode level summaries). 
Summary information (the number and percent of patients by system organ class (SOC) and 
PT separated by treatment group) will be tabulated for:
!
All AEs 
!
All AEs causally related to study medication (as determined by the reporting investigator)


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!
AEs with CTCAE grade 3 or higher
!
AEs with CTCAE grade 3 or higher, causally related to study medication  (as determined 
by the reporting investigator)
!
Most common AEs 
!
Most common AEs with CTCAE grade 3 or higher
!
AEs with outcome of death
!
AEs with outcome of death causally related to study medication  (as determined by the 
reporting investigator)
!
All SAEs
!
All SAEs causally related to study medication  (as determined by the reporting 
investigator)
!
AEs leading to discontinuation of study medication
!
AEs leading to discontinuation of study medication, causally related to study medication  
(as determined by the reporting investigator)
!
AEs leading to dose interruption of study medication
!
Other significant AEs
!
Immune mediated AEs (as determined by the reporting investigator)
!
Infusion reaction AEs  (as determined by the reporting investigator)
An overall summary of the number and percentage of patients in each category will be 
presented, as will an overall summary of the number of episodes in each category.  In 
addition, a truncated AE table of most common AEs and another table showing most common 
AEs  with CTCAE grade 3 or higher, showing all events that occur in at least 5% of patients 
overall will be summarised by preferred term, by decreasing frequency in the total column 
(although the total column may not be displayed in the AE tables).  This cut-off may be 
modified after review of the data. When applying a cut-off (i.e., x %), the raw percentage 
should be compared to the cut-off, no rounding should be applied first (i.e., an AE with 
frequency of 4.9% will not appear if a cut-off is 5%). Summary statistics showing the time to 
onset and the duration of the first AE may also be presented as appropriate.
Each AE event rate (per 100 patient years) will also be summarised by preferred term within 
each SOC for the output summarising all AEs. For each preferred term, the event rate is 
defined as the number of patients with that AE divided by the total drug exposure of patients 


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at risk of AE divided by the total drug exposure of patients and then multiplied by 365.25 x 
100 to present in terms of per 100 patient years. 
Summaries of the number and percentage of patients will be provided by maximum reported 
CTCAE grade, SOC, PT and treatment group.
Fluctuations observed in CTCAE grades during study will be listed for those AEs which are 
CTCAE ≥ 3.
In addition, all AEs will be listed. 
Deaths
Two summaries of all deaths will be provided with number and percentage of patients by 
treatment group, categorised as:
!
Total number of deaths (regardless of date of death)
!
Related to disease under investigation only
!
AE outcome of death only and onset date prior to initiation of subsequent anti-cancer 
therapy
!
AE outcome of death only and onset date falling after 90 days following last dose of study 
medication or initiation of subsequent anti-cancer therapy (whichever is earlier)
!
Both related to disease under investigation and with AE outcome=death and onset date 
prior to initiation of subsequent anti-cancer therapy
!
Death related to disease under investigation and AE with outcome=death > 90 days after 
last dose of study medication or ≥ date of subsequent therapy, whichever occurs first
!
Deaths > 90 days after last dose of study medication or ≥ date of subsequent therapy 
(whichever occurs first), unrelated to AE or disease under investigation 
!
Patients with unknown reason for death. 
!
Other deaths
This summary will be repeated for all deaths within 90 days of last dose of study medication.
Adverse events of special interest 
PTs used to identify adverse events of special interest (AESI), as defined in Section 3.4.1, will 
be listed before DBL and documented in the Study Master File. 


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Grouped summary tables of certain MedDRA PTs will be produced.  For each ‘grouped’ term, 
the number (%) of patients experiencing any of the specified terms will be presented by 
maximum CTCAE grade. Additional summaries will include Time to Onset of first CTCAE 
grade 3 or higher. Time to onset of first AE for each grouped term and preferred term within it 
will also be produced. Groupings will be based on preferred terms provided by the medical 
team prior to DBL, and a listing of the preferred terms in each grouping will be provided.
Additional summaries of the above-mentioned grouped AE categories will include number 
(%) of patients who have:
!
At least one AESI presented by outcome
!
At least one AESI causally related to study medication
!
At least one AESI leading to discontinuation of study medication
A summary of total duration (days) of selected AESI will be provided. Additional information 
to be summarised will include number of patients with an event (n %), number of episodes of 
event (n), median total duration of event (days, range) and median duration of CTCAE grades 
1, 2, 3, 4 (days, range).
Additionally, there will be several summaries of AESIs requiring concomitant treatment, and 
particularly the relationship of AESIs to the use of immunosuppressive agents (ie, depicting 
which AESI triggered immunosuppressive use) and, separately, to the use of 
immunosuppressive agents at high doses.”
4.2.4.2
Laboratory assessments
Data obtained up until the 90 days following discontinuation of study treatment or until the 
initiation of the first subsequent anti-cancer therapy (including radiotherapy, with the 
exception of palliative radiotherapy) following discontinuation of study treatment (whichever 
occurs first) will be used for reporting. This will more accurately depict laboratory toxicities 
attributable to study treatment only as a number of toxicities up to 90 days following 
discontinuation of the study treatment are likely to be attributable to subsequent therapy. 
However, to assess the longer term toxicity profile, some summaries of laboratory data may
be produced containing data collected up until 90 days following discontinuation of the study
treatment (i.e., without taking subsequent therapy into account). 
Any data post 90 days after the last dose of the study treatment will not be summarised.
Data summaries will be provided in preferred units.
Scatter plots (shift plots) of baseline to maximum value/minimum value (as appropriate) on 
treatment (i.e. on-treatment is defined as data collected between the start of treatment and the 
relevant follow-up period following the last dose of study treatment) may be produced for
certain parameters if warranted after data review. 


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Box-plots of absolute values by week, and box-plots of change from baseline by week, may be 
presented for certain parameters if warranted after data review.  For continuous laboratory 
assessments absolute value and change from baseline will be summarised using descriptive 
statistics at each scheduled assessment time by actual treatment group.
Shift tables for laboratory values by worst CTCAE grade will be produced, and for specific 
parameters separate shift tables indicating hyper- and hypo- directionality of change will be 
produced. The laboratory parameters for which CTCAE grade shift outputs will be produced 
are:
!
Haematology: Haemoglobin; Leukocytes; Lymphocytes (count, absolute); Neutrophils
(count, absolute);Platelets
!
Clinical chemistry: ALT, AST, ALP, Total Bilirubin, Albumin, Magnesium – hypo and –
hyper, Sodium – hypo and – hyper, Potassium – hypo and – hyper, Corrected Calcium –
hypo and – hyper, Glucose – hypo and – hyper, Creatinine.
Additional summaries will include a shift table for urinalysis (Bilirubin, Blood, Glucose, 
Ketones, Protein) comparing baseline value to maximum on-treatment value.
Liver Enzyme Elevations and Hy's law
The following summaries will include the number (%) of patients who have:
!
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, >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
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 be listed also.


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Plots of ALT and AST vs. Total Bilirubin by treatment group 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.
4.2.4.3
ECGs
ECG data obtained up until the safety follow-up will be included in the summary tables.
Overall evaluation of ECG is collected at each visit in terms of normal or abnormal, and the 
relevance of the abnormality is termed as “clinically significant” or “not clinically 
significant”. A shift table of baseline evaluation to worst evaluation on-treatment will be 
produced.
4.2.4.4
Vital signs
Vital signs data obtained up until the 30 day safety follow-up visit will be included in the 
summary tables.
Box plots for absolute values and change from baseline by week may be presented for certain 
vital signs parameters if warranted after data review. 
Vital signs (systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate, 
temperature, respiratory rate and weight) will be summarised over time in terms of absolute 
values and change from baseline at each scheduled measurement by actual treatment group
4.2.4.5
Physical examination
Individual physical examination data will not be summarised. 
4.2.4.6
Other safety data
Data from positive pregnancy tests will not be summarised. 
4.2.5
WHO performance status
All WHO performance status data will be summarised over time for the ITT population.
4.2.6
PK analysis
MEDI4736 concentration data will be listed, and a summary will be provided for all evaluable 
patients. These outputs will be produced by AstraZeneca/MedImmune Clinical Pharmacology 
group or designee.


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4.2.7
Immunogenicity analysis 
Immunogenicity results will be listed and a summary will be provided of the number and 
percentage of patients who develop detectable anti-MEDI4736 antibodies based on the safety 
population.  The immunogenicity titre and neutralising ADA data will be listed for samples 
confirmed positive for the presence of anti-MEDI4736 antibodies.  The effect of 
immunogenicity on PK, PDx, efficacy and safety will be evaluated if data allow. These 
outputs will be produced by AstraZeneca/MedImmune Clinical Pharmacology group or 
designee. 
4.2.8
PK/PDx relationships 
If the data are suitable, the relationship between MEDI4736 PK exposure and efficacy/safety 
parameters may be investigated graphically or using appropriate data modelling approach.
These outputs will be produced by AstraZeneca/MedImmune Clinical Pharmacology group or 
designee.
4.2.9
Exploratory endpoints
4.2.9.1
EQ-5D-5L
The change from baseline in health state utility values and the visual analogue scale will be 
compared between treatment arms at each visit using a mixed model repeated measures 
analysis, which adjusts for the same factors as the primary analysis and also the baseline 
health state utility value/visual analogue scale as appropriate. Adjusted mean differences 
between treatments and 95% CIs from these analyses will be presented, but, as this analysis is 
exploratory in nature, p-values will not be calculated. Further detail of this analysis will be 
provided in the payer analysis plan.
Descriptive statistics will be reported for health state domain (e.g., proportion in each domain) 
and the visual analogue scale by visit, as well as the change in the visual analogue scale value 
and the derived utility index value from baseline.
To support future economic evaluations, additional appropriate analyses may be undertaken, 
for example, mean health state utility pre- and post-treatment, and pre- and post-progression. 
These exploratory analyses may be carried out to support health authority appraisals and will 
consequently not be reported in the CSR. Further detail will be provided in the payer analysis 
plan.
A summary of compliance rate and evaluability rate will be provided for each treatment arm, 
by assessment time point and also for overall as appropriate.
4.2.9.2
Health resource use
An exploratory health economic analysis of hospital episodes including the number of 
hospitalisations, type of contact (hospitalisation, outpatient, day case), reason, total length of 
hospital stay and total length of ICU stay will be undertaken to examine the impact of disease 
and treatment on resource use to primarily support the economic evaluation of MEDI4736.  
This will include providing descriptive statistics as appropriate, including means, median, 


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ranges or frequencies and percentages and will be summarised by randomised treatment arm.  
These simple summaries will be included in the CSR. However, the exploratory health 
economic analysis to be performed will be described in the payer analysis plan.
4.2.10
Demographic and baseline characteristics data
The following will be summarised for all patients in the FAS (unless otherwise specified) by  
treatment group:
!
Patient disposition (including screening failures and reason for screening failure) 
!
Important protocol deviations
!
Inclusion in analysis populations
!
Demographics (age, age group[<50, >=50-< 65, ≥ 65 years and additionally ≥ 75 years], 
sex, race and ethnicity)
!
Patient characteristics at baseline (height, weight, weight group, body mass index (BMI) 
and BMI group)
!
Patient recruitment by country and centre
!
Previous disease-related treatment modalities
!
Time from initial diagnosis to randomization
!
Disease characteristics at baseline (WHO performance status,  primary tumour location, 
histology type, tumour grade and overall disease classification, best response to previous
therapy)
!
Extent of disease at baseline
!
TNM classification at baseline
!
Medical history (past and current)
!
Relevant surgical history (as appropriate)
!
Physical examination at baseline
!
Disallowed concomitant medications
!
Allowed concomitant medications
!
Post-discontinuation cancer therapy


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!
Nicotine use, categorised (never, current, former)
!
Stratification factors as per IVRS and eCRF data
The AZ drug dictionary (AZDD)  will be used for concomitant medication coding.
Patient disposition data will also be summarised at the time of OS analysis.
4.2.11
Treatment exposure and intensity
The following summaries related to study treatment will be produced for the safety analysis 
set by treatment group:
!
Total exposure
!
Actual exposure
!
Reasons for dose delays/interruptions. Dose interruptions will be based on investigator 
initiated dosing decisions
!
Number of infusions received
!
RDI 
For patients on study treatment at the time of the PFS and OS analysis, the DCO date will be 
used to calculate exposure.
5.
INTERIM ANALYSES
5.1
Analysis Methods
Three interim analyses will be performed, one for PFS and two for OS.  
The DCO for the interim analysis of PFS (the first interim analysis) will occur when it is 
expected that 367 PFS events have occurred (52% maturity, approximately 30 months after 
the first patient is randomised).  
The DCO for the first interim analysis of OS (the second interim analysis) will occur when it 
is expected that 458 PFS events have occurred (65% maturity, approximately 36 months after 
the first patient is randomised). This is also the planned time for PFS final analysis. It is 
expected that approximately 285 death events (41% maturity) will be available for the interim 
OS analysis (assuming OS HR=0.73).  The second interim analysis of OS (the third interim 
analysis) will be conducted when it is expected that 393 OS events have occurred (56% 
maturity, approximately 47 months after the first patient is randomised). The interim analyses 
will be assessed by an IDMC (further details are given in the IDMC charter).  It is expected 
that recruitment will have completed prior to the results of these interim analyses being 
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5.1.1
PFS interim analysis
Approximately 367 PFS events (52% maturity) will be available for the interim PFS analysis.  
The Lan DeMets spending function that approximates an O’Brien Fleming approach will be 
used to account for multiplicity introduced by including an interim analysis for superiority 
(Lan and DeMets 1983).  
The criterion for superiority is a statistically significant improvement in PFS at the interim 
analysis.  If 80% of the PFS events required at the time of the primary PFS analysis is 
available at the time of the interim (i.e., 367/458 PFS events have occurred), the 2-sided 
significance level to be applied for the PFS interim analysis would be 1.04% and the 2-sided 
significance level to be applied for the primary PFS analysis would be 2.19%.
PFS will be analysed using a stratified log-rank test (see Section 4.2.1.2 for details). However 
subgroup, sensitivity, secondary analysis and the global interaction test will not be performed 
at the interim. The hazard ratio will be estimated with corresponding CI and p-value. The size 
of the CI will be determined based on the actual number of events included in the interim 
analysis.
The progression status of patients at the time of the interim analysis will be summarised. A 
Kaplan-Meier plot of PFS will be presented by randomised treatment group, along with 
median PFS. The number of progression events will be presented by randomised treatment 
group.
If the PFS results indicate superiority, then analyses of all other endpoints may also be 
performed.  Patients would continue to be followed for PFS and survival until approximately 
458 PFS events, when the primary PFS analysis and the first interim OS analysis would be 
performed.
If the PFS interim analysis result does not meet the criterion of stopping for superiority, then 
all patients will remain blinded and continue to be followed for PFS and OS. 
The recommendations from the IDMC will not reveal the results of the analysis but will take 
the form of “Continue/Modify/Stop”.
5.1.2
OS interim analyses
Approximately 285 and 393 death events (41% and 56% maturity) will be available for the 
first and second interim OS analysis, respectively (assuming OS HR=0.73).  
The Lan DeMets spending function that approximates an O’Brien Fleming approach will be 
used to account for multiplicity introduced by including an interim analysis for superiority 
(Lan and DeMets 1983).  


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The criterion for superiority is a statistically significant improvement in OS at the interim 
analyses.  If 58% or 80% of OS events required at the time of the primary OS analysis are
available at the time of the interim (i.e., 285/491 or 393/491 events have occurred), the 2-sided 
significance level to be applied for the OS interim analysis would be 0.21% and 0.98%, 
respectively, and the 2-sided significance level to be applied for the primary OS analysis 
would be 2.17%. 
OS will be analysed using a stratified log-rank test (see Section 4.2.1.2 for details). However 
subgroup, sensitivity, secondary analysis and the global interaction test will not be performed 
at the interims. The hazard ratio will be estimated with corresponding CI and p-value. The size 
of the CI will be determined based on the actual number of events included in the analysis.
The survival status and progression status of patients at the time of the interim OS analyses 
and primary PFS analysis will be summarised. Kaplan-Meier plots of OS and PFS will be 
presented by randomised treatment group, along with median OS and PFS. The number of 
death events and progression events will be presented by randomised treatment group.
If the PFS and/or OS results indicate superiority, then analyses of all other endpoints would be 
performed and the results of these analyses will form the basis for submissions for regulatory 
approval.  Patients would continue to be followed for survival until approximately 
491 patients have died, when an updated analysis would be performed.
If the PFS result is not statistically significant and/or the OS interim analyses results do not 
meet the criterion of stopping for superiority, then all patients will remain blinded and 
continue to be followed for survival. 
The recommendations from the IDMC will not reveal the results of the analysis but will take 
the form of “Continue/Modify/Recommend Early Submission/Stop”.
5.2
Independent Data Monitoring Committee
This study will use an external IDMC to assess ongoing safety analyses as well as interim 
efficacy analyses for superiority based on PFS and OS and the primary analysis of PFS:
!
The IDMC will review the safety data from approximately the first 75 patients, or 
approximately 3 months after randomisation of the first patient and then again 3 months 
later.
!
The IDMC will then meet at least every 6 months thereafter to review safety data.
!
Additional reviews of the safety data may be requested by the IDMC at additional points 
during the study.
This committee will be composed of therapeutic area experts and biostatisticians, who are not 
employed by AstraZeneca/MedImmune and do not have any major conflict of interest.


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Following the reviews, the IDMC will recommend whether the study should continue 
unchanged, be stopped, or be modified in any way. Once the IDMC has reached a 
recommendation, a report will be provided to AstraZeneca/MedImmune.  The report will 
include the recommendation and any potential protocol amendments, and will not contain any 
unblinding information.  The final decision to modify or stop the study will sit with the 
sponsor.
In addition:
!
The IDMC will review the efficacy data when 367 progression events (per BICR) have 
occurred, at approximately 30 months post-randomisation, at the time of the interim 
analysis of PFS.
!
The IDMC will review the efficacy data when 458 progression events (per BICR) have 
occurred, at approximately 36 months post-randomisation at the time of the primary 
analysis of PFS and the first interim analysis of OS.
!
The IDMC will review the efficacy data when 393 OS events have occurred, at 
approximately 47 months post-randomisation at the time of the second interim analysis of 
OS.
A separate IDMC charter will be developed, which will contain details of the IDMC members 
and clearly define the responsibilities of the IDMC.
The safety of all AstraZeneca/MedImmune clinical studies is closely monitored on an ongoing 
basis by AstraZeneca/MedImmune representatives in consultation with the Patient Safety 
Department. Issues identified will be addressed; this could involve, for instance, amendments 
to the clinical study protocol and letters to investigators.


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6.
CHANGES OF ANALYSIS FROM PROTOCOL
Table 9
Changes from the planned analysis
Section of SAP 
Affected 
(If applicable)
Change
Rationale
4.2.3 Patient Reported 
Outcomes
Add sensitivity analysis for 
primary PRO endpoints where 
RECIST progression counts as 
an event
To explore the effect of 
RECIST progression on the 
PRO endpoint analyses
2.1 Definition of 
Analysis Sets
Remove criteria that patients 
need to have post-dose data to 
be included in the safety 
analysis set
More widely used 
definition and to be 
consistent with other 
studies 
Section 3.2.2.7 Time to 
death of Distant 
Metastasis
Clarified definition of Time to 
death or distant metastasis
Added further detail based 
on data will be collected
Section 4.2.1.1 Overall 
Survival
Removed global interaction 
test for subgroup analyses, 
subgroups will be tested using 
model only including 
treatment
More widely used 
definition and to be 
consistent with other 
studies
Section 4.2.2.1 
Remove HR and added p-
value to the presentation of 
OS12
p-value required for 
multiple testing procedure
Section 4.2.2.4/5
Change presentation of 
proportion of patients alive 
and progression free at 12 and 
18 months
To match TFL standards
Section 4.2.2.3 Duration 
of Response
Removed analysis of Duration 
of Response
Not required
Section 4.2.3.3 
Added mixed models repeated 
measures for analyses of PRO 
endpoints
To explore the treatment 
effect using change from 
baseline data


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Section 3.2.1.2, 3.2.2.2, 
3.2.2.7
Clarify criteria for censoring 
in the setting of no 
progression or death from last 
evaluable RECIST 1.1 
assessment to last RECIST 1.1 
assessment
*See below
*Rationale for the change:
Patient entry into the study is restricted to locally advanced, stage III NSCLC who have 
received definitive concurrent chemoradiation. These indicates that all patients would have 
localized diseases that have been radiated. It is known that localized post-radiation changes 
may affect lesion sizes and there may be high levels of necrosis/fibrosis with little or no active 
tumor in recently irradiated lesions. However, accepting these limitations in this patient 
population with prior curative radiation treatment, the prior irradiated lesions may be 
considered measurable at baseline and selected as target lesions provided they fulfil the other 
criteria for measurability according to RECIST 1.1. It is anticipated that a proportion of 
patients entering the study may have RECIST assessments being non-evaluable (NE) on-
treatment, even if they have been followed up for multiple assessments and have not shown 
any evidence of PD, based on either their target, non-target or presence of any new lesion.
Therefore, in order to utilize all available tumor assessment follow-up information in the 
primary analysis of PFS, patients without a radiographic disease progression will be censored 
at their last assessment date, instead of the last evaluable assessment date. 
7.
REFERENCES
Berry et al 1991
Berry G, Kitchin RM, Mock PA. A comparison of two simple hazard ratio estimators based 
on the logrank test. Stat Med 1991 May;10(5):749-55.
Breslow, 1974
Breslow, NE. Covariance Analysis of Censored Survival Data. Biometrics 1974; 30:89–99.
Burman et al 2009
Burman CF, Sonesson C, Guilbaud O. A recycling framework for the construction of 
Bonferroni-based multiple tests. Stat Med 2009 Feb 28;28(5):739-61. 
Butts et al 2014
Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, et al, on behalf of 
the START trial team. Tecemotide (L-BLP25) vs placebo after chemoradiotherapy for stage 
III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet 
Oncol 2014;15(1):59-68. 


Statistical Analysis Plan 
Study Code D4191C00001
Edition Number 4.0
Date 22 March 2017
91
Cockcroft and Gault 1976
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron
1976; 16(1):31-41.
Collett 2003
Collett D. Modelling survival data in medical research: 2nd ed. Chapman and Hall/CRC. 2003. 
Available on request.
Ellis et al 2008
Ellis S, Carroll KJ, Pemberton K. Analysis of duration of response in oncology trials. 
Contemp Clin Trials 2008 Jul;29(4):456-65.
Fayers et al 1999
Fayers P, Aaronson NK, Bjordal K, Curran D, Groenvold M on behalf of the EORTC Quality 
of Life Study Group. EORTC QLQ-C30 Scoring Manual: 2nd Edition 1999. Available on 
request.
Fleischer et al 2011
Fleischer F, Gaschler-Markefski B, Bluhmki E. How is retrospective independent review 
influenced by investigator-introduced informative censoring: a quantitative approach. Stat 
Med 2011 Dec 20;30(29):3373-86.
Gail and Simon 1985
Gail M, Simon R. Tests for qualitative interactions between treatment effects and patient 
subsets. Biometrics 1985 Jun;41(2):361–72.
Glimm et al 2009
Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group-sequential 
trials. Statistics in Medicine 2009; 29:219–28.
Hanna et al 2004
Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. 
Randomized phase III trial of pemetrexed vs docetaxel in patients with non-small-cell lung 
cancer previously treated with chemotherapy. J Clin Oncol 2004 May 1;22(9):1589-97.
Klein et al 2007
Klein JP, Logan B, Harhoff M, Andersen PK. Analyzing survival curves at a fixed point in 
time. Stat Med 2007 Oct 30; 26(24): 4505–19.
Lan and DeMets 1983
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 
1983;70:659-63.


Statistical Analysis Plan 
Study Code D4191C00001
Edition Number 4.0
Date 22 March 2017
92
Nishino et al 2013
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH and Hodi FS. Developing a 
common language for tumour response to immunotherapy: Immune-related response criteria 
using unidimensional measurements. Clin Cancer Res 2013;19:3936-43
Oemar and Janseen 2013
Oemar M, Oppe M. EQ-5D-3L User Guide: Basic information on how to use the EQ-5D-3L 
instrument V5.0 (October 2013). Available from URL: 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/EQ-5D-
3L_UserGuide_2013_v5.0_October_2013.pdf. Accessed 07 January 2014.
Osoba et al 1998 
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998 Jan;16(1):139-44.
Pintilie M.  
Competing risks: A practical perspective.  Wiley.
Robins and Tsiatis 1991
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models. Communications in Statistics-Theory and Methods 
1991; 20(8):2609-31.
Robins 1993
Robins JM. Information Recovery and Bias Adjustment in Proportional Hazards Regression 
Analysis of Randomized Trials Using Surrogate Markers. Proceedings of the 
Biopharmaceutical Section, American Statistical Association 1993; 24-33.
Sellke and Siegmund 1983
Sellke T, Siegmund D. Sequential analysis of the proportional hazards model. Biometrika 
1983;70:315-26.
Stone et al 2015
Stone A, Macpherson E, Smith A, Jennison C. Model free audit methodology for bias 
evaluation of tumour progression in oncology. Submitted.
Sun and Chen 2010
Sun X, Chen C. Comparison of Finkelstein's Method with the Conventional Approach for 
Interval-Censored Data Analysis. Stat Biopharm Res 2010;2(1):97-108.
Whitehead and Whitehead 1991
Whitehead A, Whitehead J.  A general parametric approach to the meta-analysis of 
randomized clinical trials.  Statistics In Medicine 1991;10:1665-77.


Statistical Analysis Plan 
Study Code D4191C00001
Edition Number 4.0
Date 22 March 2017
93
Wolchok et al 2009
Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin 
Cancer Res 2009 Dec 1;15(23):7412-20.
Ye et al 2012
Ye Y, Li A, Lui L, Yao B. A group sequential Holm procedure with multiple primary 
endpoints. Statistics in Medicine 2012; 32:1112-1124








Statistical Analysis Plan 
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Edition Number 4.0
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retrocrural 
Lymph nodes - retrocrural 
Lymph Nodes - Retrocrural
45
porta hepatis
Lymph nodes - porta hepatis
Lymph Nodes - Porta Hepatis
46
celiac axis
Lymph nodes - celiac axis
Lymph Nodes - Celiac Axis
47
portocaval
Lymph nodes - portocaval
Lymph Nodes - Portocaval
48
peripancreatic
Lymph nodes -
peripancreatic
Lymph Nodes - Peripancreatic
49
mesenteric
Lymph nodes - mesenteric
Lymph Nodes - Mesenteric
50
peri-aortic
Lymph nodes - peri-aortic
Lymph Nodes - Peri-Aortic
51
peri-caval
Lymph nodes - peri-caval
Lymph Nodes - Peri-Caval
52
retroperitoneal
Lymph nodes -
retroperitoneal
Lymph Nodes - Retroperitoneal
53
iliac left
Lymph nodes - iliac left
Lymph Nodes - Iliac Left
54
iliac right
Lymph nodes - iliac right
Lymph Nodes - Iliac Right
55
pelvic left
Lymph nodes - pelvic left
Lymph Nodes - Pelvic Left
56
pelvic right
Lymph nodes - pelvic right
Lymph Nodes - Pelvic Right
57
inguinal left
Lymph nodes - inguinal left
Lymph Nodes - Inguinal Left
58




Statistical Analysis Plan 
Study Code D4191C00001
Edition Number 4.0
Date 22 March 2017
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Bone- Clavicle, left
Bone - Clavicle, Left
149
Bone- Scapula, right
Bone - Scapula, Right
150
Bone- Scapula, left
Bone - Scapula, Left
151
Bone-
Spine/Sacrum/Coccyx
Bone - Spine/Sacrum/Coccyx
152
Bone- Pelvis
Bone - Pelvis
153
Bone- upper extremity, 
right
Bone - Upper Extremity, Right
154
Bone- upper extremity, 
left  
Bone - Upper Extremity, Left
155
Bone- lower extremity, 
right
Bone - Lower Extremity, Right
156
Bone- lower extremity, 
left
Bone - Lower Extremity, Left
157
Brain
162
Brain - bilateral
Brain - Bilateral
74
Brain - brain stem
Brain - Brain Stem
75
Brain - left cerebellum
Brain - Left Cerebellum
76
Brain - left cerebral 
hemisphere
Brain - Left Cerebral Hemisphere
77
Brain - right cerebellum
Brain - Right Cerebellum
78
Brain - right cerebral 
hemisphere
Brain - Right Cerebral Hemisphere
79
Brain – specify
Brain, Specify
130
Breast - left
Breast – left
Breast - Left
80
Breast - right
Breast – right
Breast - Right
81
Chest wall - anterior
Chest wall - anterior
Chest Wall - Anterior
84
Chest wall - left
Chest wall - left
Chest Wall - Left
85
Chest wall - posterior
Chest wall - posterior
Chest Wall - Posterior
86
Chest wall - right
Chest wall - right
Chest Wall - Right
87