Clinical trial NCT02454933
Conditions: Locally Advanced or Metastatic EGFR T790M+ NSCLC
Keywords: Phase III Open Label Study; AZD9291 plus MEDI4736 versus AZD9291 Monotherapy; NSCLC After Previous EGFR TKI Therapy; T790M Mutation Positive Tumours.
Sponsor: AstraZeneca
Start date: 2015-07-15; Completion date: 2023-06-21
Enrollment: 29 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase III, Multi-Centre, Open Label, Randomized Study to Assess the Efficacy and Safety of AZD9291 in Combination with MEDI4736 versus AZD9291 Monotherapy in patients with Locally Advanced or Metastatic Epidermal Growth Factor Receptor T790M mutation-positive Non-Small Cell Lung Cancer who have received Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy

Detailed description:
This a phase III, Multi Centre, Open Label, Randomized, Study to Assess the Efficacy and Safety of AZD9291 (80 mg, orally, once daily) in Combination with MEDI4736 (10 mg/kg (IV) infusion q2w) versus AZD9291 Monotherapy (80 mg, orally, once daily) in patients with a confirmed diagnosis of Epidermal Growth Factor Receptor (EGFR) T790M mutation positive NSCLC, who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) agent. The randomization will be stratified by previous lines of treatment (2nd or 3rd+) and ethnicity (Asian or Non-Asian). A mandatory biopsy will be needed for central testing of T790M mutation status following confirmed disease progression on the most recent treatment regimen. The primary objective of the study is To investigate the safety and tolerability profile of AZD9291 in combination with MEDI4736.

350 patients were originally planned to be evaluated across the two below populations. The recruitment was stopped due to new information on safety of the combination, received from another trial in similar patient population

1. 2nd line: patients who have progressed following an approved first-line EGFR-TKI treatment but who have not received further treatment.
2. 3rd line or higher: patients who have progressed following prior therapy with an approved EGFR-TKI and an additional anti-cancer treatment. Patients may have also received additional lines of treatment.

Arms: arm 1: 10mg/kg q2w (IV) infusion \& once daily tablet 80 mg arm 2: Once daily tablet 80 mg
Interventions: intervention 1: AZD9291 intervention 2: MEDI4736
Intervention descriptions: intervention 1: Once daily tablet 80 mg intervention 2: 10mg/kg q2w (IV) infusion

Protocol documents:
Prot_000.pdf: 
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SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D5165C00001/CAURAL
Edition Number
2.0 final
Date
21st August 2017
A Phase III, Multi-Centre, Open Label, Randomized Study to Assess the
Efficacy and Safety of AZD9291 in Combination with MEDI4736 versus
AZD9291 Monotherapy in Patients with Locally Advanced or Metastatic
Epidermal Growth Factor Receptor T790M mutation-positive Non-Small
Cell Lung Cancer who have received Prior Epidermal Growth Factor
Receptor Tyrosine Kinase Inhibitor Therapy (CAURAL)


33'


33'


Statistical Analysis Plan 
Study Code D5165C00001/CAURAL
Edition Number 2.0 final
Date 21st August 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 ..............................................................................7
AMENDMENT HISTORY................................................................................10
1.
STUDY DETAILS............................................................................................. 11
1.1
Study objectives................................................................................................. 11
1.2
Study design ...................................................................................................... 13
1.3
Number of subjects ............................................................................................ 15
2.
ANALYSIS SETS ............................................................................................. 16
2.1
Definition of analysis sets .................................................................................. 16
2.1.1
Full Analysis Set................................................................................................16
2.1.2
Safety Analysis Set ............................................................................................ 16
2.1.3
PK Analysis Set .................................................................................................16
2.2
Violations and deviations ................................................................................... 17
3.
PRIMARY AND EXPLORATORY VARIABLES............................................ 18
3.1
Derivation of RECIST visit responses................................................................ 18
3.1.1
Investigator assessment using RECIST 1.1......................................................... 20
3.1.1.1
Target lesions..................................................................................................... 20
Rounding of TL data.......................................................................................... 20
Missing TL data.................................................................................................20
Lymph nodes ..................................................................................................... 21
TL visit responses subsequent to CR.................................................................. 21
TL too big to measure ........................................................................................ 21
TL too small to measure.....................................................................................22
Irradiated lesions/lesion intervention..................................................................22
Lesions that split in two ..................................................................................... 22
Lesions that merge .............................................................................................22
Change in method of assessment of TLs............................................................. 23
3.1.1.2
NTLs and new lesions........................................................................................23
3.1.1.3
Overall visit response......................................................................................... 24
3.2
Efficacy outcome variables ................................................................................ 24


Statistical Analysis Plan 
Study Code D5165C00001/CAURAL
Edition Number 2.0 final
Date 21st August 2017
5
3.2.1
Progression free survival landmark summary ..................................................... 24
3.2.2
Objective response rate (ORR)........................................................................... 26
3.2.3
Duration of response (DoR) ............................................................................... 26
3.2.4
Disease control rate (DCR) ................................................................................ 26
3.2.5
Best overall response ......................................................................................... 26
3.2.6
Tumour shrinkage ..............................................................................................27
3.2.7
Overall survival landmark summary................................................................... 28
3.3
Safety variables..................................................................................................28
3.3.1
Adverse Events ..................................................................................................28
3.3.2
Other significant adverse events (OAEs)............................................................ 29
3.3.3
Laboratory data.................................................................................................. 29
3.3.4
Vital signs.......................................................................................................... 30
3.3.5
ECGs ................................................................................................................. 30
3.3.6
Left ventricular ejection fraction ........................................................................ 30
3.3.7
Duration of exposure and duration of treatment..................................................31
3.3.8
Dose intensity ....................................................................................................31
3.4
PK and pharmacodynamics................................................................................ 32
3.4.1
Plasma concentrations of AZD9291 and metabolites AZ5104 and AZ7550........ 32
3.4.2
Serum concentrations of MEDI4736 .................................................................. 33
3.4.3
Pharmacodynamics and immunogenicity for ADA............................................. 33
4.
SUMMARY METHODS................................................................................... 33
4.1
General principles.............................................................................................. 33
4.1.1
Baseline measurements and change from baseline variables............................... 34
4.1.2
Study day definitions ......................................................................................... 34
4.1.3
Visit windows.................................................................................................... 35
4.1.4
Handling missing data........................................................................................35
4.1.4.1
Imputation of partial dates.................................................................................. 35
4.1.5
Imputation rules for lab values outside of quantification range ...........................36
4.1.6
Rounding rules for reported percentages ............................................................36
4.2
Summary methods ............................................................................................. 36
4.2.1
Subject disposition and data sets analyzed.......................................................... 36
4.2.2
Protocol deviations.............................................................................................37
4.2.3
Demographic and other baseline characteristics.................................................. 37
4.2.4
Medical history..................................................................................................38
4.2.5
Anti-cancer medications and radiotherapy (prior, during, post-treatment 
with investigational product)..............................................................................38
4.2.5.1
Anti-cancer therapy............................................................................................ 38
4.2.5.2
Radiotherapy......................................................................................................38
4.2.6
Exposure............................................................................................................ 39
4.2.7
Efficacy ............................................................................................................. 39
4.2.7.1
Progression free survival landmark summary ..................................................... 39
4.2.7.2
Sensitivity summary........................................................................................... 39
4.2.7.3
Subgroup summary ............................................................................................ 39


Statistical Analysis Plan 
Study Code D5165C00001/CAURAL
Edition Number 2.0 final
Date 21st August 2017
6
4.2.7.4
ORR .................................................................................................................. 39
4.2.7.5
OS ..................................................................................................................... 40
4.2.7.6
DoR................................................................................................................... 40
4.2.7.7
DCR .................................................................................................................. 40
4.2.7.8
Tumour shrinkage .............................................................................................. 40
4.2.8
Safety outcomes................................................................................................. 40
4.2.8.1
Adverse events................................................................................................... 40
4.2.8.2
AEs of special interest........................................................................................ 41
4.2.8.3
Deaths................................................................................................................ 41
4.2.8.4
Laboratory evaluations.......................................................................................42
4.2.8.5
Vital signs (pulse and BP) and weight ................................................................43
4.2.8.6
Physical examination ......................................................................................... 43
4.2.8.7
ECG................................................................................................................... 43
4.2.8.8
Left ventricular ejection fraction (LVEF) ........................................................... 43
4.2.8.9
WHO performance status................................................................................... 43
4.3
PK, pharmacodynamics and immunogenicity summary...................................... 44
5.
INTERIM ANALYSES ..................................................................................... 44
6.
CHANGES FROM PROTOCOL ....................................................................... 44
7.
REFERENCES ..................................................................................................44
8.
APPENDIX ....................................................................................................... 44


Statistical Analysis Plan 
Study Code D5165C00001/CAURAL
Edition Number 2.0 final
Date 21st August 2017
7
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest 
ALT
Alanine transaminase
AST
Aspartate transaminase
ATC
Anatomical Therapeutic Chemical
BP
Blood pressure
CI
Confidence interval
CR
Complete response
CSP
Clinical study protocol
CSR
Clinical study report
CT
Computerized tomography scan
CTCAE
Common Terminology Criteria for Adverse Events
DCO
Data cut-off
DCR
Disease control rate
DNA
Deoxyribonucleic acid
DoR
Duration of response
ECG
Electrocardiogram
eCRF
Electronic case report form
EGFR
Epidermal growth factor receptor
EGFRm+
EGFR mutation positive
FAS
Full Analysis Set
HIV
Human immunodeficiency virus
IP
Investigational product
IVRS
Interactive Voice Response System
KM
Kaplan-Meier
L858R
An amino acid substitution at position 858 in EGFR, from a Leucine (L) 
to an Arginine (R)


Statistical Analysis Plan 
Study Code D5165C00001/CAURAL
Edition Number 2.0 final
Date 21st August 2017
8
Abbreviation or 
special term
Explanation
LD
Longest diameter
LDH
Lactate dehydrogenase
LLoQ
Lower limit of quantification
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MUGA
Multi-gated acquisition scan
N/A
Not applicable
NE
Not evaluable
NSCLC
Non-small cell lung cancer
NTL
Non-target lesion
OAE
Other significant adverse event
ORR
Objective response rate
OS
Overall survival
PD
Progression of disease
PD-L1
Programmed Death Ligand 1
PFS
Progression Free Survival
PID
Percentage intended dose
PK
Pharmacokinetics
PR
Partial response
PT
Preferred term
QD
Once daily
RDI
Relative dose intensity
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious adverse event
SD
Stable disease
SLD
Sum of longest diameter
SOC
System organ class
T790M
An amino acid substitution at position 790 in EGFR, from a Threonine 
(T) to a Methionine (M)


Statistical Analysis Plan 
Study Code D5165C00001/CAURAL
Edition Number 2.0 final
Date 21st August 2017
9
Abbreviation or 
special term
Explanation
T790M-
T790M mutation negative
T790M+
T790M mutation positive
TKI
Tyrosine kinase inhibitor
TL
Target lesion
ULoQ
Upper limit of quantification
WHO
World Health Organization


Statistical Analysis Plan 
Study Code D5165C00001/CAURAL
Edition Number 2.0 final
Date 21st August 2017
10
AMENDMENT HISTORY
Date
Brief description of change
21st August 2017
To reflect changes documented in Protocol Version 2.0 02-Mar-2017. 


Statistical Analysis Plan 
Study Code D5165C00001/CAURAL
Edition Number 2.0 final
Date 21st August 2017
11
1.
STUDY DETAILS
1.1
Study objectives
Primary objective
Objective:
Outcome Measure:
To investigate the safety and tolerability 
profile of AZD9291 in combination with 
MEDI4736.
Adverse events (graded by Common 
Terminology Criteria for Adverse Events 
(CTCAE v4))
Clinical chemistry, haematology and 
urinalysis
Vital signs (pulse and blood pressure),
Physical Examination, Weight
Digital Electrocardiogram (ECG)
Echocardiogram/Multi Gated Acquisition 
Scan (MUGA) (for Left Ventricular Ejection 
Fraction)
WHO Performance Status
Exploratory objectives
Objective:
Outcome Measure:
To assess the safety and tolerability of 
AZD9291 as a single agent
Adverse events (graded by CTCAEv4)
Clinical chemistry, haematology and 
urinalysis
Vital signs (pulse and blood pressure), 
Physical examination, Weight 
Centrally reviewed digital Electrocardiogram 
(ECG)
Echocardiogram/Multi gated Acquisition 
Scan (MUGA) (for left ventricular Ejection 
fraction)
WHO performance status 
Serious Adverse events (graded by 
CTCAEv4)


Statistical Analysis Plan 
Study Code D5165C00001/CAURAL
Edition Number 2.0 final
Date 21st August 2017
12
Objective:
Outcome Measure:
To obtain a preliminary assessment of the 
efficacy of AZD9291 in combination with 
MEDI4736 and AZD9291 monotherapy
Objective Response Rate (ORR)
Progression Free Survival (PFS) landmark at 
6 and 12 months
Overall Survival (OS) landmark at 12 months
Duration of Response (DoR)
Disease Control Rate (DCR)
Tumour shrinkage using Investigator 
assessments according to RECIST 1.1
To assess the PK of AZD9291 as a single 
agent and in combination with MEDI4736.
Plasma concentrations of AZD9291 and 
metabolites AZ5104 and AZ7550.
To characterise the PK and immunogenicity 
of MEDI4736 after single dosing and at 
steady state after multiple dosing when given 
intravenously to patients with EGFRm non 
small-cell lung cancer (NSCLC) in 
combination with AZD9291 
Plasma concentrations of MEDI-4736 to 
characterise PK
Blood samples for anti-drug antibodies 
(ADA) to characterise immunogenicity.
The following exploratory objectives may be reported separately from the main Clinical Study 
Report (CSR) and will not be covered in this Statistical Analysis Plan.
To characterise the pharmacodynamics of 
MEDI4736 after single dosing and at steady 
state after multiple dosing when given 
intravenously to patients with EGFRm non 
small-cell lung cancer (NSCLC) in 
combination with AZD9291 
Blood samples for soluble PD-L1 to 
characterise pharmacodynamics
.
To investigate the relationship of response 
and PFS in patients who are PD-L1 positive 
and those that are PD-L1 negative.
Retrospective evaluation of baseline PD-L1 
expression in tumour (based on
immunohistrochemistry assessment).
To collect and store deoxyribonucleic acid 
(DNA) for future exploratory research into 
genes/genetic variation that may influence 
PK or response AZD9291 as a single agent 
and in combination with MEDI4736 (i.e. 
absorption, distribution, metabolism, 
excretion, safety and efficacy) and/or 
susceptibility to/development of cancers.
Correlation of polymorphisms with variation 
in Pharmacokinetics (PK), 
pharmacodynamics, safety or response 
observed in patients treated with AZD9291 as 
a single agent and in combination with 
MEDI4736.


Statistical Analysis Plan 
Study Code D5165C00001/CAURAL
Edition Number 2.0 final
Date 21st August 2017
13
Objective:
Outcome Measure:
To collect and store tumour samples and 
blood-based (plasma and serum) samples for 
potential exploratory research into factors 
that may influence susceptibility 
to/development of NSCLC/cancer and/or 
AZD9291 as a single agent and in 
combination with MEDI4736 (where 
response is defined broadly to include
efficacy, tolerability or safety).
Collection of tumour and blood-based 
samples to include, but not be limited to, 
investigation of biomarkers such as Epidermal 
growth factor receptor (EGFR) mutations 
(T790M, L858R, etc). These samples may be 
shared with a diagnostic partner for 
development of a companion diagnostic if 
needed. The samples may also be used to 
investigate the relationship between PK and 
blood-borne biomarkers.
Samples may be analysed retrospectively. 
Any biomarker data generated may be 
reported separately and may also form part of 
a pooled analysis with other AZD9291 
studies.
1.2
Study design
This trial was initially designed as a phase III, multi-centre, open label, randomized study to 
assess the efficacy and safety of AZD9291 (80 mg, orally, once daily) in combination with 
MEDI4736 (10 mg/kg, IV infusion every 2 weeks [q2w]) versus AZD9291 monotherapy 
(80 mg, orally, once daily) in patients with a confirmed diagnosis of EGFR T790M mutation 
positive (T790M+) locally advanced or metastatic NSCLC (Stage IIIB-IV), who have 
progressed following prior therapy with an approved EGFR-TKI agent.
All patients must have documented radiological progression on EGFR-TKI treatment and on 
the last treatment administered prior to enrolling in the study. 
A mandatory biopsy was needed for central testing of T790M mutation status following 
confirmed disease progression on previous treatment.
Three hundred fifty patients were planned to be randomized, however recruitment was 
stopped after enrolling 29 patients. Early termination of enrolment into the study was decided 
in the light of a higher than anticipated incidence of interstitial lung disease-like events in 
patients receiving the combination of AZD9291 with MEDI4736 in a separate multi-arm 
Phase 1b open label study D5160C00006 (TATTON).
Two summaries of the study data are planned:
Primary Summary
A primary summary will be performed with a data cut-off date representative of when the last 
country with active patients receives ethics and regulatory approval for protocol version 2.0.  
This summary will be used for the CSR and will report data according to the randomised or 
actual treatment groups as specified in Section 2.  


Statistical Analysis Plan 
Study Code D5165C00001/CAURAL
Edition Number 2.0 final
Date 21st August 2017
14
Final Summary
Patients had been initially randomized to receive either AZD9291 in combination with 
MEDI4736 or AZD9291 monotherapy. Depending on the treatment being received, the 
patients will be categorized as follows for the purpose of delineating the required study plan 
and assessments:
GROUP A - Patients on AZD9291 monotherapy
Group A includes patients continuing to receive AZD9291 monotherapy following data cut-
off (DCO) for the primary analysis, who were either randomised to receive 
AZD9291 monotherapy or were randomised to receive AZD9291 in combination 
with MEDI4736 but who have discontinued MEDI4736 and been followed up for 
90 days post discontinuation of MEDI4736
Patients may continue dosing with the drug according to the protocol as long as they are 
continuing to show clinical benefit, as judged by the Investigator, and in the absence of a 
discontinuation criterion. These patients have no pre-scheduled visits until treatment 
discontinuation (apart those needed for the drug accountability and dispensing) and will 
follow the normal clinical site approach. Following approval of clinical study protocol (CSP) 
version 2.0 at the site only SAE, outcomes of pregnancy and drug dispensing/ accountability
data will be collected for Group A patients. This may result in sparse data in some of the 
summaries in the primary summary.
GROUP B - Patients on MEDI4736 in combination with AZD9291 or MEDI4736 
monotherapy 
Group B includes patients randomised to receive MEDI4736 and AZD9291 and who are 
continuing to receive MEDI4736 either in combination with AZD9291 or as a 
monotherapy
Patients may continue treatment with MEDI4736 monotherapy or in combination with 
AZD9291 as long as they are continuing to show clinical benefit, as judged by the 
Investigator, and in the absence of a discontinuation criterion. Group B patients should follow 
the schedule / assessments specified in the CSP. Group B patients that discontinue MEDI4736 
during the study can be switched to Group A and follow the AZD9291 Monotherapy 
assessment schedule following completion of the 90 day safety follow up.  Following 
approval of CSP version 2.0
The overall study design is shown in Figure 1 below. The study schedule for Group A and 
Group B subjects is detailed in Tables 1 and 2 of the CSP, respectively.
A final addendum summary will be performed when the last patient discontinues MEDI4736 
and completes their required safety follow up. All outputs from the primary summary will be 
repeated at the final summary, except those relating to change in tumour size at 6 weeks, 
which will have been fully reported during the primary analysis.  Only data collected between 


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the primary summary data cut-off and the time when last patient receiving MEDI4736 reaches 
the end of safety follow up, will be summarised. If three or fewer patients are included in this 
summary, then only listings will be produced, with no summary tables. 
If all patients have discontinued from MEDI4736 treatment at the time of DCO for the 
primary study summary, the primary summary will be the only summary of data for the study.
Final summary will show data summarized by Group A and Group B as defined above.  For 
demography, exposure and SAEs data will be summarized for both Groups A and B.  Other 
data will be reported for Group B only. Patients that do not meet criteria for either Group A or 
Group B definition will be listed along with any relevant data that has been collected.
Figure 1
Study flow chart
1.3
Number of subjects
The original plan was to recruit approximately 350 subjects, stratified by current line of 
treatment (2nd/3rd line plus) and ethnicity (Asian/non-Asian) , randomized in a 1:1 ratio to the 
treatments as specified below:
!
AZD9291 80mg QD
!
AZD9291 80mg QD and MEDI4736 10mg/kg q2w


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The study was terminated early with only 29 patients randomized.  This number is not
considered sufficient for statistical comparison of the treatment groups, and all data reporting 
will be using summaries and listings.  
2.
ANALYSIS SETS
2.1
Definition of analysis sets
These analysis sets apply only to the primary summary.  The final summary will include only 
data collected between the primary summary data cut-off and the time when last patient 
receiving MEDI4736 reaches the end of safety follow up.
2.1.1
Full Analysis Set
The Full Analysis Set (FAS) will include all randomized subjects. The FAS will be used for 
all efficacy summaries and treatment groups will be presented on the basis of randomized 
treatment, regardless of the treatment actually received.
2.1.2
Safety Analysis Set
The Safety Analysis Set will consist of all subjects who received at least one dose of 
randomized treatment. Safety data will be summarized using the Safety Analysis Set, 
according to the treatment that patients received in their first cycle. Patients who received at 
least one dose of MEDI4736 in the first treatment cycle (15 +/-3 days) will be regarded as 
being in the combination treatment. Additional summaries might be provided for the patients 
who were randomised and received the combination but later discontinued MEDI4736 as 
appropriate.
2.1.3
PK Analysis Set
Patients in the FAS who have at least one measurable PK concentration, supported by the 
relevant date and time of this sample, and for each time a PK sample was taken the dosing 
data for that day, and for samples taken after multiple dosing the dosing data for the 2 days 
prior to the sample day as well as the sample day. For any individual sample to be included in 
the PK Analysis Set the full sample data and dosing data needs to be present for that sample.
Table 1 below shows the analysis set to be used for each outcome variable. 


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Table 1
Summary of outcome variables and analysis populations
Outcome variable
Populations
Demography 
Safety
Efficacy Data
PFS
ORR
DoR
DCR
Tumor shrinkage
OS
FAS
PK data
Plasma concentrations
Metabolites
PK
Pharmacodynamics and 
immunogenicity
ADA
Safety
Safety Data 
Adverse Event (AE)
Laboratory data
Vital signs
ECG
Left ventricular ejection fraction (LVEF)
World Health Organization (WHO) performance status
Safety
2.2
Violations and deviations
All important deviations related to the study inclusion or exclusion criteria and study conduct 
will be listed and summarised by randomized treatment group. None of the deviations will 
lead to any subjects 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 
respectively). 
The following general categories will be considered important deviations. This list is not 
exhaustive and additional important deviations may be added prior to database lock. A full list 
is provided within the study Protocol Deviations documentation. 
!
Informed consent procedure deviation (e.g., no informed consent signed prior to any 
screening procedure)
!
Eligibility criteria deviation (e.g., any inclusion criteria not met or exclusion criteria 
met)
!
Prohibited medication deviation (e.g., subject received other anticancer agents, 
investigational agents, or radiotherapy while on study treatment)


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The categorization 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 by the clinical team 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 prior to database 
lock.
Incorrect stratifications will be summarized and listed, separately to the important protocol 
deviations. For this, a comparison will be made between the stratification factors entered into 
Interactive Voice Response System (IVRS) vs. the electronic case report form (eCRF) data.
A summary will be produced showing any subjects who received a treatment different to that 
assigned by the randomization for any duration of treatment (for example if a subject 
randomized to AZD9291 monotherapy but did receive at least one dose of MEDI4736). Note, 
this is not due to tolerability issues where subjects experience a drug interruption and/or drug 
delay. 
Subjects who receive the wrong treatment at any time will be included in the Safety Analysis 
Set as described in Section 2.1.2. During the study, decisions on how to handle these 
situations will be made on an individual basis with written instruction from the study team 
leader/physician and/or statistician.
3.
PRIMARY AND EXPLORATORY VARIABLES
3.1
Derivation of RECIST visit responses
All RECIST assessments, whether scheduled or unscheduled, will be included in the 
calculations. This is also regardless of whether a patient discontinues study drug.
For all patients, the RECIST version 1.1 (see further Appendix C of the CSP) 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 overall response.
The baseline tumour assessment is part of the screening procedures and should be performed 
within 28 days before the start of study treatment.
Prior to approval of CSP version 2.0, efficacy for all patients will be assessed by objective 
tumour assessments every 8 weeks (relative to the first dose) for the first 48 weeks, 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 progression of 
disease (PD), objective tumour assessments should be continued every 8 weeks for 48 weeks 
(relative to first dose) then every 12 weeks thereafter until confirmed objective disease 


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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. 
Patients on monotherapy AZD9291 will be assessed according to local practice until 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. Study treatment will continue between the 
initial assessment of progression and confirmation for progression.
Progression would be considered confirmed if the following criteria are met:
!
L20% 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 L20% 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 L20% 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.
Patients who discontinue treatment for reasons other than progression would undergo a 3-
month follow-up.  Progressions occurring during this follow-up will not necessarily have a 
second confirmatory scan.
Following approval of CSP version 2.0, objective tumour assessments every 8 or 12 weeks 
will only be carried out for Group B patients up to disease progression or up to 3 months 
following treatment discontinuation, and confirmation of progression will only be required for 
Group B patients who continue to receive MEDI4736 following progression , while patients 
discontinuing treatment may not have scans to confirm progression.  Following approval of 
CSP version 2.0, patients in Group A will not have tumour assessment scans.
RECIST 1.1 without confirmation of progression will be regarded as primary in terms of the 
efficacy reporting. A sensitivity summary requiring confirmation will be conducted. The 
confirmation should occur at least 28 days from the first scan documenting radiological 
progression. 
At each visit for the site investigator data, an overall visit response will be programmatically 
determined - using the information from TLs, NTLs and new lesions.


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RECIST outcomes (i.e., PFS and ORR etc) will be calculated using a computer program for 
site investigator data.  
RECIST results based on blinded independent central review were planned in the original 
protocol, but were not included in version 2.0 of the protocol, and no such review was 
performed. 
3.1.1
Investigator assessment using RECIST 1.1
3.1.1.1
Target lesions
Measurable disease is defined as having at least one measurable lesion which is L10 mm in 
the longest diameter (LD) (except lymph nodes which must have short axis L15 mm) with CT 
or magnetic resonance imaging (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.
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.
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 CSP Appendix C for the definitions of complete response (CR), partial 
response (PR), stable disease (SD) and PD and the derivations of overall visit response using 
the information from target lesions (TL), non-target lesions (NTL) and new lesions.
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 be assigned if any of the following occurred:


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!
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 L5 mm from nadir even assuming the non-recorded TLs have 
disappeared.
The nadir can only be taken from assessments where all the TLs had an LD recorded.
Lymph nodes
For lymph nodes, if the size reduces to <10 mm, 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, 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 response can only be followed by CR, PD or NE. If a CR has occurred, 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), 
the response will be set to CR irrespective of whether the criteria for PD of TL is 
also met (i.e., if a lymph node 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), the 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, the response will be set to PD.
!
Step 4:  If, after steps 1 through 3, a response cannot be determined, the response 
will be set to remain as CR.
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.


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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 measured reliably. If a TL response of PD results then this will be reviewed by the 
study team blinded to treatment assignment.
Irradiated lesions/lesion intervention
Previously irradiated lesions (i.e., lesion irradiated prior to entry into the study) should be 
recorded as NTLs and should not form part of the TL assessment.
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:
!
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, the lesion diameter (for 
those lesions with intervention) will be treated as missing and scaled up as 
described previously as long as there remain R1/3 of the TLs with missing 
measurements. If the scaling results in a visit response of PD then the subject will 
be assigned a TL response of PD.
!
Step 3: If after both steps PD has not been assigned, then a scaled sum of diameters 
will be calculated, treating the lesion with intervention as missing, and PR or SD 
then assigned as the visit response. Subjects with intervention are evaluable for CR 
as long as all non-intervened lesions are 0 (or <10 mm for lymph nodes) and the 
lesions that have been subject to intervention also have 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 (as per step 2 above).
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 tumors.
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 0mm.


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Change in method of assessment of TLs
Computerized tomography (CT) scan and MRI are the only methods of assessment that can be 
used within this trial. If a change in method of assessment occurs between CT scan and MRI 
this will be considered acceptable and no adjustment within the programming is needed.
3.1.1.2
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.
Please refer to CSP Appendix C for the definitions of CR, PR, SD and PD and the derivations 
of overall visit response using the information from target lesions (TL), non-target lesions 
(NTL) and new lesions.
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 
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 RECIST 1.1 
tumour assessments where possible until objective disease progression is observed.


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3.1.1.3
Overall visit response
Table 2 defines how the previously defined TL and NTL visit responses will be combined 
with new lesion information to give an overall visit response.
Table 2
Overall visit response
Target Lesion
Non-target Lesion
New lesion(s)
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
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
Efficacy outcome variables
Following approval of CSP version 2.0 tumour based efficacy assessments will not be 
collected for Group A patients.
3.2.1
Progression free survival landmark summary
The endpoint PFS, as assessed by the investigator, using RECIST 1.1 will be reported both 
with and without confirmation of progression.  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 summary will be censored at the time 
of the latest date of assessment from their last evaluable RECIST 1.1 assessment. However, if 


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the patient progresses or dies after 2 or more missed visits, the patient will be censored at the 
time of the latest evaluable RECIST 1.1 assessment prior to the two missed visits with the 
exception of 2 missed visits from baseline (i.e. if the subject dies within 119 days of the last 
evaluable visit), the event of death will be used in the PFS summary). 
Given the scheduled visit assessment scheme (i.e. eight-weekly for the first 48 weeks then 
twelve-weekly thereafter) the definition of 2 missed visits will change. If the previous 
RECIST assessment is less than study day 232 (i.e. week 32 + 7 day visit window) then two 
missing visits will equate to 17 weeks (2 x 8 week scans + 7 day visit window) since the 
previous RECIST assessment, allowing for late visits.
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 21 weeks. The 
time period for the previous RECIST assessment will be from study day 287. From week 49 
(week 48 + 7 days) onwards, two missing visits will equate to 25 weeks (2 x 12 week scans + 
7 day visit window). 
If the patient has no evaluable visits or does not have baseline data they will be censored at 
baseline unless they die within 112 days of baseline (2 x 8 week scans).
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:
!
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
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 site investigator tumour data. An additional 
sensitivity summary using a modified version of the algorithm will be used, 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 
summary.
The proportion of patients alive and progression free at 6 months (i.e., APF6) will be defined 
as the Kaplan-Meier (KM) estimate of PFS at 6 months.
The proportion of patients alive and progression free at 12 months (i.e., APF12) will be 
defined as the KM estimate of PFS at 12 months.


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3.2.2
Objective response rate (ORR)
ORR (per RECIST 1.1 as assessed by the investigator) is defined as the number and 
percentage of patients with measurable disease with at least 1 visit response of CR or PR.  
Summaries will be produced based on both unconfirmed and confirmed response, where the 
response is confirmed at least 4 weeks later. ORR will be based on all randomised patients. 
Therefore, data obtained up until progression, or the last evaluable assessment in the absence 
of progression, will be included in the assessment of ORR. 
A subject who goes off treatment without progression to receive a subsequent anti-cancer 
therapy, and then responds (CR or PR), will not be included as a responder in the ORR.
3.2.3
Duration of response (DoR)
DoR (per RECIST 1.1 as assessed by the investigator) will be defined as the time from the 
date of first documented response (CR or PR) 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). 
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.  Summaries will be 
produced based on both confirmed and unconfirmed progression.
DoR will not be defined for those patients who do not have documented response.
3.2.4
Disease control rate (DCR)
DCR is defined as the percentage of subjects who have a best overall response of CR or PR or 
SD at L4 weeks, prior to any PD event. Summaries will be produced based on both confirmed 
and unconfirmed response.
A subject’s best overall response is calculated as defined below. 
3.2.5
Best overall response
Best overall 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 anti-cancer therapy and prior to RECIST progression or the 
last evaluable assessment in the absence of RECIST progression and subsequent anti-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 investigator assessment data including all data up until the first progression, 


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the start of any subsequent cancer therapy or the last evaluable 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 16 weeks +/-
1 week, i.e. at least 119 days (to allow for the assessment window), after randomisation (i.e. 
study day 120). 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.
For patients whose PFS event is death, BOR will be calculated based upon all evaluable 
RECIST assessments prior to death.
For patients who die with no evaluable RECIST assessments, if the death occurs R17 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 evaluable 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 evaluable assessment will not contribute to the BOR derivation.
Summaries will be produced based on both confirmed and unconfirmed response.
3.2.6
Tumour shrinkage
Tumour shrinkage will be assessed using RECIST 1.1 tumour response. The absolute change 
and percentage change from baseline in sum of tumour size at each assessment will be 
calculated. Tumour size is the sum of the longest diameters (SLD) of the TLs. The percentage 
change in SLD at each week for which data are available will be obtained for each subject 
taking the difference between the SLD at each week and the SLD at baseline divided by the 
SLD at baseline multiplied by 100 (i.e., [week n – baseline] / baseline x 100). The change 
from baseline will be obtained for each subject taking the difference between the SLD at each 
week and the SLD at baseline (i.e., week n - baseline).
The best percentage change in SLD from baseline or the minimum increase from baseline in 
the absence of a reduction from baseline based on all post-baseline assessments prior to 
progression or start of subsequent anti-cancer therapy.
If best percentage change cannot be calculated due to missing data, a value of +20% will be 
imputed as the best percentage change from baseline in the following situations (otherwise 
best percentage change will be left as missing):
!
If a subject has no post-baseline assessment and has died;
!
If a subject has new lesions or progression of NTLs;
!
If a subject has withdrawn due to PD and has no evaluable TL data before or at PD.


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3.2.7
Overall survival landmark summary
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 the summary 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 which were originally planned for the 2 weeks following the date of data 
cut-off (DCO), will no longer be made following approval of CSP version 2.0.
The proportion of patients alive at 12 months (i.e., OS12) will be defined as the KM estimate 
of OS at 12 months
3.3
Safety variables
Following approval of CSP version 2.0 safety assessments will not be collected for Group A 
patients, except for SAEs.
3.3.1
Adverse Events
All AEs will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA) and graded according to the National Cancer Institute CTCAE (version 
4.0.3 or later).
Preferred terms used to identify adverse events of special interest (AESI) will be listed before 
database lock and documented in the Study Master File. Groupings of certain MedDRA 
preferred terms will be based on preferred terms provided by the medical team and a listing of 
the preferred terms in each grouping will be produced. 
The grouped preferred terms for AESI for AZD9291 are shown below.  A separate list will be 
produced for MEDI 4736.  The individual preferred terms will be available in the 
programming specification documentation: 
!
Ocular surface effects
!
Dry eye/conjunctivitis
!
Interstitial lung disease and acute interstitial pneumonitis
!
Nail and nail bed conditions
!
Skin disorders including dermatitis
!
Upper GI tract inflammatory events
!
Cardiotoxicity
!
Diarrhoea


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!
Colitis/Enterocolitis (Gastrointestinal Disorder)
!
Hepatitis/ Hepatic Toxicity (Hepatic Function Abnormality)
!
Infusion-related Reactions
!
Anaphylaxis and Serious Allergic Reactions (Hypersensitivity)
!
Neuromuscular Toxicity/Neuropathy
!
Endocrinopathy
Any AE occurring before study treatment will be included in the data listings but will not be 
included in the summary tables of AEs.
Any AE occurring within 30 days of discontinuation of AZD9291 and within 90 days for 
MEDI4736 will be included in the AE summaries. Any events in this period that occur after a 
subject has received further therapy for cancer (following discontinuation of AZD9291) will 
be flagged in the data listings.  If AZD9291 is discontinued less than 60 days after 
MEDI4736, subjects should be followed up to 90 days from the date of MEDI4736 
discontinuation. 
3.3.2
Other significant adverse events (OAEs)
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and AEs leading to treatment discontinuation.
Based on the expert’s judgment, 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 (pulse, blood pressure [BP] and 
weight), and/or ECG data will be performed for identification of OAEs.
Examples of these could be marked haematological and other laboratory abnormalities, and 
certain events that lead to intervention (other than those already classified as serious), dose 
reduction or significant additional treatment.
3.3.3
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 5.2.1 of the CSP. For the 
definition of baseline and the derivation of post baseline visit values considering visit window 
and how to handle multiple records, derivation rules as described in Section 4 below will be 
used.  Values recorded as “<x” will be reported as the maximum number of this range, i.e. x. 
Change from baseline in haematology and clinical chemistry variables will be calculated for 
each post-dose visit on treatment. 


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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. 
3.3.4
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 
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 below will 
be used. 
3.3.5
ECGs
Baseline is the pre-dose time point on the first dosing day (Day 1 Cycle 1). For each time 
point three ECG recordings should be taken within an approximate 5 minute period. The 
variables to be reported from the continuous ECG measurements are RR, PQ, QRS, and QT 
intervals. The QT interval will be corrected for RR (the duration of a heart beat) to obtain 
corrected (QTc) variables.
QTcF will be calculated using the formula:
QTcF=QT/RRb
where b=1/3.
To obtain a single value of QTcF, RR, PR, QRS and QT at each specified time point, the 
mean of the triplicate values at that time point will be used. For each subject, the change-from 
baseline in an ECG variable at each time point will be calculated as the difference between the 
mean of the replicate value at each post-dose time point and the mean of pre-dose baseline 
replicate value. All ECG data will be obtained from the vendor, eRT, and there will be no site 
interpretation.
QTc outliers are defined as QTcF values following dosing that are greater than 450 ms or are 
increases from baseline greater than 30 ms. 
3.3.6
Left ventricular ejection fraction
Echocardiogram/MUGA data will be collected every 16 weeks throughout the study, from 
screening to treatment discontinuation as described in the CSP.
Change from baseline in LVEF will be calculated for each post-dose visit on treatment.
Abnormal LVEF are defined as values less than the lower limit of normal (project reference). 
Absolute values will also be flagged if they meet either of the following criteria (considered as 
outliers):
!
L10 percentage points decrease from baseline and <50% LVEF, or


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!
L15 percentage points decrease from baseline and L50% LVEF.
3.3.7
Duration of exposure and duration of treatment
Total and actual exposure will be calculated separately for AZD9291 or MEDI4736.  Total 
exposure to each drug (AZD9291 or MEDI4736) will be time (days) from the first dose to the 
last dose:
Total exposure = (last dose date where dose >0 mg - first dose date) + 1
Actual exposure to each drug (AZD9291 or MEDI4736) will be time (days) from first dose to 
the last dose, taking account of dose interruptions.
Actual exposure = ((last dose date where dose >0 mg - first dose date) + 1) - total 
duration of dose interruption (i.e., number of days with dose = 0mg).
Dose reductions are not permitted per the CSP for MEDI4736. The actual exposure 
calculation makes no adjustment for any dose reductions that may have occurred.
The duration of treatment will be the time (days) from the first dose to the last dose of either 
treatment:
The last dose date for the combination arm is defined as the latest of the last non-zero dose of 
either agent. For the AZD9291 monotherapy arm, this will be the last non-dose dose of 
AZD9291. 
Duration of treatment = (last dose date where dose >0 mg - first dose date) + 1
3.3.8
Dose intensity
Relative dose intensity (RDI) is the percentage of the actual dose intensity delivered relative 
to the intended dose intensity through to treatment discontinuation. Percentage intended dose 
(PID) is the percentage of the actual dose delivered relative to the intended dose through to 
progression. Both will be derived using the date of objective disease progression as defined by 
RECIST v1.1 using the investigator site assessments. If the investigator considered that it was 
in the patient’s best interest to continue study treatment past this time, this was not included in 
the derivation of RDI and PID.
RDI and PID will be defined as follows:
!
RDI = 100% * d/D, where d is the actual cumulative dose delivered up to the earlier of 
progression (or a censoring event) or the actual last day of dosing and D is the 
intended cumulative dose up to the earlier of progression (or a censoring event) or the 
actual last day of dosing.
!
PID = 100% * d/D, where d is the actual cumulative dose delivered up to progression 
(or a censoring event) and D is the intended cumulative dose up to progression (or a 


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censoring event). D is the total dose that would be delivered, if there were no 
modifications to dose or schedule.
RDI and PID for AZD9291 and MEDI4736 will be calculated for the entire intended 
treatment period (censored at data cut-off).
3.4
PK and pharmacodynamics 
3.4.1
Plasma concentrations of AZD9291 and metabolites AZ5104 and AZ7550
All plasma concentrations of AZD9291, AZ5104 and AZ7550 will be listed. Summaries of 
plasma concentrations by nominal sample window will be presented for the PK Analysis Set.  
Following approval of CSP version 2.0, PK samples were only collected in the combination 
treatment group.
The ratio of metabolite to AZD9291 in each PK sample will be listed. Summaries of ratio of 
metabolite to AZD9291 by nominal sample window will be presented for the PK Analysis Set. 
The following summary statistics will be presented: 
!
The geometric mean (gmean, calculated as exp [Y], where Y is the mean of the data on 
a logarithmic scale).  
!
Coefficient of variation (CV, calculated as 100 Z [exp(s2)-1], where s is the standard 
deviation of the data on a log scale).
!
Gmean ± standard deviation (calculated as exp[Y±s]).
!
Geometric Standard Deviation (GeoSD) calculated using transformed data.
!
Arithmetic mean calculated using untransformed data.
!
Standard Deviation calculated using untransformed data.
!
Minimum, median, maximum and number of observations (n).
Non-quantifiable (NQ) values of plasma concentrations will be handled as follows:· If, at a 
given time point, 50% or less of the plasma concentrations are NQ, the gmean, CV, geoSD, 
arithmetic mean and standard deviation will be calculated by substituting the limit of 
quantification (LOQ) for values which are NQ.· If more than 50%, but not all, of the 
concentrations are NQ, the gmean, CV, geoSD, arithmetic mean and standard deviation will 
be reported as not calculable (NC). The max value will be reported from the individual data, 
and the min and median will be set as NQ.· If all the concentrations are NQ, the gmean and 
arithmetic mean will be reported as NQ and the CV, geoSD and standard deviation as NC. 
The number of values above lower limit of quantification (LLOQ) will be reported for each 
time-point along with the total number of collected values. If data are available for less than 


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3 patients, no summary statistics other than minimum, maximum and n will be presented. The 
plasma concentration data for AZD9291 and its metabolites will also be analysed using a 
population PK approach, which may include exploring the influence of covariates on PK, if 
the data allows. 
A pharmacokinetic-pharmacodynamic approach may be used to investigate the relationship 
between PK and selected primary, secondary and/or exploratory endpoints, where deemed 
appropriate. These results of these analyses will be reported separately from the study CSR. A 
separate data analysis plan will be prepared to describe such analyses.
3.4.2
Serum concentrations of MEDI4736
PK analysis of the serum concentration data for MEDI4736 will be performed by Clinical 
Pharmacology, AstraZeneca/MedImmune or delegate on behalf of Clinical Pharmacology.
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 not be reported as the data 
collected will not be sufficient for their determination.
3.4.3
Pharmacodynamics and immunogenicity for ADA
Analyses to evaluate the pharmacokinetics and immunogenicity of MEDI4736 will be 
performed by AstraZeneca/MedImmune Clinical Pharmacology group or designee.
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 who have at least one measurable ADA blood sample. 
4.
SUMMARY METHODS
All reporting of data will be descriptive, using summary tables and listings.  No statistical 
hypothesis testing will be performed.  
Due to the small numbers of patients, summaries will not be grouped by the stratification 
factors involved in the randomization. 
4.1
General principles
Continuous data will be summarized using descriptive statistics (number of observations, 
mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum). 
Frequencies and percentages will be used for summarizing categorical (discrete) data. 
Confidence intervals (CIs), when presented, will generally be 2-sided and constructed at the 
95% level. For binomial variables, exact methods will be employed unless otherwise 
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A month is operationally defined to be 30.4375 days. 
For the primary summary, data will be presented in data listings by the randomized treatment 
group and subject number. All summaries will be presented by randomized treatment group 
unless otherwise specified.
For the final summary, data will be presented in data listings by Group A / Group B and 
subject number. All summaries will be presented by Group A / Group B unless otherwise 
specified.
4.1.1
Baseline measurements and change from baseline variables
In general, for efficacy endpoints the last observed measurement prior to randomization will 
be considered the baseline measurement. 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
Study day definitions
For the purpose of efficacy data summary, Study Day 1 is defined as the date of 
randomization to study treatment. For visits (or events) that occur on or after randomization, 
study day is defined as (date of visit [event] - date of randomization + 1). For visits (or events) 
that occur prior to randomization, study day is defined as (date of visit [event] - date of 
randomization). There is no Study Day 0.
For the purpose of safety data summary, Dose Day 1 is defined as the date of first dose of
study treatment (referred to in the protocol as Week 1 Day 1). For visits (or events) that occur 
on or after first dose, dose day is defined as (date of visit [event] - date of first dose of study 
treatment + 1). For visits (or events) that occur prior to first dose, dose day is defined as (date 
of visit [event] - date of first dose of study treatment). There is no Dose Day 0.
For listings (such as for AEs) that include the derivation of “days since last dose,” this is 
defined as (event date - date of last dose). Events that occur on the same day as the last dose of 
study drug will therefore be described as occurring zero days from the last dose of study drug.


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4.1.3
Visit windows
For summaries of vital signs, laboratory data, ECG and target lesion size, assessments will be 
assigned to calculated visit windows (using study day).
The time windows should be exhaustive so that data recorded at any time point have the 
potential to be summarized. Inclusion within the visit window should be based on the actual 
date and not the intended date of the visit. For summaries at a subject level, all values should 
be included, regardless of whether they appear in a corresponding visit-based summary, when 
deriving a subject level statistic such as a maximum.
The window for the visits following baseline (including unscheduled visits) will be 
constructed in such a way that the upper limit of the interval falls half way between the two 
visits.
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 subject; they should also highlight the 
value for that subject that was used in the summary table, wherever feasible.
For visit based summaries:
!
If there is more than one value per subject within a visit window then the closest to the 
planned study day value should be summarized, or the earlier in the event the values 
are equidistant from the planned study day. The visit will be missing if no assessment 
was reported within the specified visit window around the planned study day.
!
To prevent very large tables or plots being produced that contain many cells with 
meaningless data, summary statistics will be presented where at least 10 subjects in 
either treatment group have data recorded at a particular visit.
4.1.4
Handling missing data
In general, other than for partial dates, missing data will not be imputed and will be treated as 
missing.
4.1.4.1
Imputation of partial dates
Initial diagnosis date:
!
If year is missing (or completely missing), do not impute.
!
If only day is missing, impute day as 15th of the month.
!
If day and month are missing, impute as July 1st.
Concomitant medication start date


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!
If year is missing (or completely missing), do not impute.
!
If (year is present and month and day are missing) or (year and day are present and 
month is missing), impute as January 1st.
!
If year and month are present and day is missing, impute day as first day of the month.
Concomitant medication end date
!
If year is missing (or completely missing), do not impute.
!
If (year is present and month and day are missing) or (year and day are present and 
month is missing, impute as December 31st.
!
If year and month are present and day is missing, impute day as last day of the month.
4.1.5
Imputation rules for lab values outside of quantification range
Lab values below the lower limit of quantification (LLoQ) that are reported as “<LLoQ” or 
“RLLoQ” in the database will be imputed by LLoQ x 0.99 for reporting purposes. The original 
value will be listed.
Lab values above the upper level of quantification (ULoQ) that are reported as “>ULoQ” or 
“LULoQ” in the database will be imputed by ULoQ x 1.01 for reporting purposes. The 
original value will be listed.
4.1.6
Rounding rules for reported percentages
For percentages L10%:
!
Values LX.5 or above round to X+1.
!
Values >X but <X.5 round to X.
For percentages <10%:
!
Values LX.Y5 or above round to X.Y+0.1.
!
Values >X.Y but <X.Y5 round to X.Y.
4.2
Summary methods
4.2.1
Subject disposition and data sets analyzed
Subject disposition will be listed and summarized for all patients. Summaries will include the 
number and percentage of subjects:
!
Randomized


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!
Treated
!
Subjects ongoing study treatment at the data cut-off
!
Included in each analysis set (FAS, Safety, and PK)
In addition, the number and percentage of subjects who discontinued treatment and who 
discontinued the study, including a breakdown of the main reason for discontinuation will be 
presented for all subjects.
4.2.2
Protocol deviations
All important protocol deviations will be listed. All protocol deviations will be defined by the 
study team and identified before database lock.
4.2.3
Demographic and other baseline characteristics
Demographic and baseline subject characteristics will be listed and summarized for the Safety 
Analysis Set. Standard descriptive statistics will be presented for the continuous variables of:
!
Age (years).
!
Weight (kg).
!
Height (cm).
!
Body mass index (kg/m2) (calculated as [weight/height2] where weight is in kg and 
height is in m).
The total counts and percentages of subjects will be presented for the categorical variables of:
!
Age group (years) (grouped as <50, L50 to <65, L65 to <75 and L75).
!
Sex.
!
Race.
!
Ethnicity.
!
Overall disease classification (metastatic, locally advanced, both).
!
Site of disease.
!
Baseline TL size (mean and categories: <40, 40-79, 80-119, and L120mm).
!
Histology.
!
Smoking status.


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!
WHO performance status (0/1).
Receptor status at baseline will be summarised.
4.2.4
Medical history
Disease related medical history and relevant surgical history will be coded using MedDRA. 
All disease related medical and surgical history will be listed.  
4.2.5
Anti-cancer medications and radiotherapy (prior, during, post-treatment with 
investigational product)
Medications received prior to, concomitantly, or post-treatment will be coded using the 
AstraZeneca Drug Dictionary Anatomical Therapeutic Chemical (ATC) Classification codes. 
Concomitant medications/radiotherapy will be listed and summarized for the Safety Analysis 
Set by ATC classification codes.
For the purpose of inclusion in prior and/or concomitant mediation or therapy summaries, 
incomplete medication or radiotherapy start and stop dates will be imputed as detailed in 
Section 4.1.5.1.
Prior medications, concomitant and post-treatment medications are defined based on imputed 
start and stop dates as follows:
!
Prior medications are those taken prior to screening with a stop date prior to the first 
dose of study treatment.
!
Concomitant medications are those with a stop date on or after the first dose date of 
study treatment (and could have started prior to or during treatment).
!
Post-treatment medications are those with a start date after the last dose date of study 
treatment.
EGFR-TKI therapies will be defined as approved EGFR-TKI therapies and will include 
gefitinib, erlotinib and afatinib.
4.2.5.1
Anti-cancer therapy
All anti-cancer therapies at baseline and post discontinuation will be summarized for the 
Safety Analysis Set. The number of anti-cancer therapy regimens and number of cycles will 
be summarized using descriptive statistics. The anti-cancer therapy agent, therapy class, best 
response, and treatment status will be summarized using frequencies and percentages. Any 
anti-cancer therapies will also be listed.
4.2.5.2
Radiotherapy
All radiotherapies will be summarized for the Safety Analysis Set.  Any radiotherapy will also 
be listed.


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4.2.6
Exposure
Exposure will be listed and summarized for Safety Analysis Set. The following summaries 
will be produced:
!
Summary of duration of exposure of AZD9291
!
Summary of duration of exposure of MEDI4736
!
Summary of duration of treatment for each arm
!
RDI and PID of AZD9291
!
RDI and PID of MEDI4736
!
Summary of interruptions and reductions of AZD9291
!
Summary of interruptions and delays of MEDI4736
4.2.7
Efficacy
All efficacy summaries will be produced using the FAS. 
4.2.7.1
Progression free survival landmark summary
Progression status assessed by investigator at time of landmark summary (at Month 6 and 
Month 12 from the last subject first dose) will be summarised. 
Kaplan-Meier plots and estimates will be produced at time of landmark summary along with 
other descriptive summaries based on the FAS.
4.2.7.2
Sensitivity summary
The following sensitivity summary will be conducted:
(a) With confirmation of progression: RECIST 1.1 criteria will be used to assess PFS with the 
requirement for confirmation of progression (by investigator). Progressions will only be used 
in the summary where there is a scan no earlier than 4 weeks later that documents progression 
or where there is no following scan. The first scan documenting radiological progression will 
be used regardless. 
4.2.7.3
Subgroup summary
No subgroup summaries are planned.
4.2.7.4
ORR
The ORR will be based on the programmatically derived RECIST outcome using the 
investigator data.


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ORR will be analyzed in terms of the proportion of responders out of the number of available 
patients per treatment arm.  The associated 95% confidence intervals will also be provided 
using the Clopper-Pearson exact method for binomial proportions.  
4.2.7.5
OS
The proportion of patients alive at 12 months will be reported. Kaplan-Meier plots and 
estimates will be produced at the time of summary.
4.2.7.6
DoR
DoR will be reported using summary statistics (n, median and quartiles) and KM plots to 
describe the duration of response in those patients with an initial response on study.   
4.2.7.7
DCR
DCR will be presented as the proportion of patients with disease control, out of the number of 
patients available per treatment arm.  The associated 95% confidence intervals will also be 
provided using the Clopper-Pearson exact method for binomial proportions.
4.2.7.8
Tumour shrinkage
The best absolute change in target lesion tumour size from baseline, and percentage change in 
in target lesion tumour size from baseline will be summarised using descriptive statistics and 
presented at each time point by randomized treatment group.
4.2.8
Safety outcomes 
The Safety Analysis Set will be used for all safety and tolerability tables, figures and listings 
except were expressly noted. 
4.2.8.1
Adverse events
All AEs, both in terms of MedDRA PT and CTCAE grade, will be listed and summarized 
descriptively by count (n) and percentage (%) for each treatment group. MedDRA will be 
used for coding. Any AE occurring before study treatment (i.e., before 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’. The summary tables will include all AEs 
that occurred after the start of treatment up until the end of the follow-up period.
All reported AEs will be listed along with the date of onset, date of resolution (if AE is 
resolved), investigator’s assessment of severity and relationship to study drug. Frequencies 
and percentages of subjects reporting each preferred term will be presented (i.e., multiple 
events per subject will not be accounted for apart from on the episode level summaries).
Summary information (the number and percent of subjects by treatment) will be tabulated for:
!
All AEs
!
All AEs causally related to study treatment


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!
AEs with CTCAE grade 3 or higher
!
AEs with CTCAE grade 3 or higher, causally related to study treatment
!
Fatal AEs 
!
All SAEs
!
AEs leading to discontinuation
!
OAEs
An overall summary of the number and percentage of subjects 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 the most common AEs, showing all events that occur in at least 5% of 
subjects overall will be summarized by preferred term, by decreasing frequency. This cut-off 
may be modified after review of the data.
AEs will be assigned CTCAE grades and summaries of the number and percentage of subjects 
will be provided by maximum reported CTCAE grade, SOC, PT and actual treatment group. 
In addition, AEs with an outcome of death, SAEs, and OAEs will be listed. 
4.2.8.2
AEs of special interest
Summary tables of AESIs will be produced. The number (%) of patients experiencing any of 
the specified terms will be presented overall, by maximum CTCAE grade, and by outcome. 
4.2.8.3
Deaths
A summary of deaths will be provided with the number and percentage of subjects, 
categorized as:
!
Related to disease under investigation,
!
Fatal AE,
!
Both related to disease under investigation and fatal AE,
!
Fatal AE >30 days after last treatment dose,
!
Deaths >30 days after last treatment dose, unrelated to AE or disease under 
investigation, and
!
Subjects with unknown reason for death.
A corresponding listing will also be produced. 


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4.2.8.4
Laboratory evaluations
All laboratory data recorded in the eCRF will be listed. If any additional analytes to those in 
Table 5 are also recorded then these will be listed only. 
All values will be classified as low (below range), normal (within range) and high (above 
range) based on reference ranges provided by the local or central laboratory. As applicable, 
values will be graded using CTCAE v4.0.
Plots of both the maximum post-baseline alanine transaminase (ALT) and aspartate 
transaminase (AST) versus the maximum post-baseline total bilirubin, expressed as multiples 
of their upper limit of reference range will be produced. 
The laboratory variables to be summarised are shown in Table 3 below.
Table 3
Laboratory safety variables
Clinical chemistry
(Serum/Plasma)
Hematology 
(Blood)
Urinalysis
(Urine)
Albumin
Hemoglobin
Glucose
Alanine transaminase (ALT)
Leukocytes
Protein
Aspartate transaminase (AST)
Hematocrit
Blood
Alkaline phosphatase
Red blood cell (RBC) count
Bilirubin, total
Absolute leukocyte differential count:
Calcium, total
          Neutrophils
Creatinine
          Lymphocytes
Glucose 
          Monocytes
Magnesium
          Basophils
Phosphate
          Eosinophils
Potassium
Platelet count
Sodium
Reticulocytes
Urea nitrogen/Blood urea nitrogen (BUN)
TSH1
Lactate dehydrogenase (LDH)2
Hepatitis B surface antigen2
Hepatitis C antibody2
Human immunodeficiency virus (HIV) 
antibody2
Activated partial thromboplastin time2
International normalised ratio2
1 Free T3 and Free T4 to be measured only if TSH is abnormal.


Statistical Analysis Plan 
Study Code D5165C00001/CAURAL
Edition Number 2.0 final
Date 21st August 2017
43
2 measured at the screening visit only
4.2.8.5
Vital signs (pulse and BP) and weight
All vital signs data will be listed. Absolute and percentage change from baseline for pulse, BP 
and weight will be summarized by treatment group, overall and by visit.
4.2.8.6
Physical examination
Abnormalities identified from physical examination will be listed. 
4.2.8.7
ECG
All ECG data received will be presented in data listings. QTc summaries will be presented for 
subjects in the Safety Analysis Set. The ECG parameters that will be summarized (absolute 
values, change and percentage change from baseline) are: QTcF, RR, PR, QRS and QT.
The observed values and change from baseline in QTcF will be summarized by visit using 
summary statistics. 
QTc outliers are defined as QTcF values following dosing that are greater than 450 ms or are 
increases from baseline greater than 30 ms. QTcF outliers will be highlighted in the data 
listings and summarized using the following categories:
!
Values >450 ms, >480 ms, >500 ms
!
Increase from baseline of >30 ms, increase from baseline of >60 ms, increase from 
baseline of >90 ms,
!
Values >450 ms and increases of >30 ms. Values >500 ms and increases of >60 ms.
The number and percentage of subjects who meet the ECG outlier criteria at any assessment 
post-date of first dose will be summarized.
4.2.8.8
Left ventricular ejection fraction (LVEF)
Abnormal LVEF are defined as values less than the lower limit of normal. LVEF outliers and 
abnormal values will be highlighted in the data listings and LVEF will be summarized.
Further, subjects with outliers that are associated with an AE (related or unrelated to 
AZD9291) will be listed and summarized as appropriate, along with the duration of the 
abnormality.
4.2.8.9
WHO performance status
WHO performance status will be listed.


Statistical Analysis Plan 
Study Code D5165C00001/CAURAL
Edition Number 2.0 final
Date 21st August 2017
44
4.3
PK, pharmacodynamics and immunogenicity summary
AZD9291, MEDI4736 and metabolites AZ5104 and AZ7550 PK concentrations will be 
summarised.  AZD9291 and MEDI4736 concentrations will be plotted using box-blots. 
Individual concentrations and ratios of metabolites will be listed. 
ADA concentrations will be summarised and listed. 
5.
INTERIM ANALYSES
No interim analysis is planned.
6.
CHANGES FROM PROTOCOL
OS is defined as the time from the date of randomisation until death due to any cause, whereas 
in the CSP it is defined as the time from the date of first dose until death due to any cause.  As 
this is a randomised study the principle that efficacy analyses are measured from the date of 
randomisation is adhered to.
7.
REFERENCES
None
8.
APPENDIX
N/A.