Clinical trial NCT02474355
Conditions: Lung Cancer
Keywords: NSCLC EGFRm T790M
Sponsor: AstraZeneca
Start date: 2015-09-18; Completion date: 2019-04-18
Enrollment: 3017 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The aim of this study is to assess the efficacy and safety of single agent AZD9291 in a real world setting in adult patients with advanced or metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC), who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy.

Detailed description:
Objective: The primary objective of this study is to assess the efficacy and safety of single agent AZD9291 in a real world setting in adult patients with advanced or metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC), who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy.

Study site(s) and number of patients planned: Approximately 1500 patients will be recruited in Europe. The recruitment will be increased beyond that as the study will expand in other regions of the world (America, Asia).

Study Design This will be an open-label, single-arm, multinational, multicenter, real world treatment study.

Target patient population: Adult patients (fulfilling the definition of "age of majority" per local regulations) with locally advanced (stage IIIB) or metastatic (stage IV) NSCLC with confirmed T790M mutation, who have received prior EGFR-TKI therapy.

Investigational product (IP), dosage, and mode of administration: AZD9291 is an oral, potent, selective, irreversible inhibitor of both EGFR-TKI sensitising and resistance mutations in NSCLC with a significant selectivity margin over wild-type EGFR. AZD9291 will be administered orally as one 80 mg tablet once a day.

Duration of IP administration: Patients may continue to receive AZD9291 as long as they continue to show clinical benefit, as judged by the investigator, and in the absence of discontinuation criteria). The study will be closed in each participating country as soon as possible following national reimbursement of AZD9291 in that country (up to a max of 90 days post reimbursement). Enrolment will be closed within 6 months after market license approval in that country or at national reimbursement, whichever is sooner. Patients withdrawing from the treatment prior to national reimbursement will be followed up as part of this study. Patients on treatment will receive commercial supply until documented disease progression as per investigator assessment.

In the event that national reimbursement should not be granted following a reasonable time after market license approval in the country, the study will be closed in a maximum period of 18 months after the last patient is enrolled in that country. If applicable, timelines for conversion to commercial drug will be agreed with local bodies which may include regulatory agencies, ethics committees, and institutions. Patient will be followed until death or lost to follow-up.

Study measures: Data collected will include patient demographics, information needed to determine patient eligibility (including medical history, past and current disease characteristics, and tumor EGFR mutational status), AZD9291 exposure, investigator-reported efficacy (including tumor response and disease progression), overall survival (OS), and safety (including serious adverse events \[SAEs\], adverse events leading to dose modification, and adverse events of special interest \[interstitial lung disease/pneumonitis-like events, and QTc prolongation events\]).

Statistical methods: All data will be presented for the overall full analysis/evaluable set, and also by cohorts defined by number and type of previous treatment lines for the advanced disease. Descriptive statistics will be used for all variables, as appropriate. 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. OS and PFS will be summarized using Kaplan-Meier estimates of the median time to death or censoring and quartiles together with their 95% confidence intervals.

Arms: arm 1: Single arm of AZD9291, starting dose of 80mg
Interventions: intervention 1: T790M+ Testing intervention 2: Baseline Visit Blood & Urine Testing intervention 3: Baseline ECG intervention 4: Visual Slit-Lamp Testing intervention 5: AZD9291 Dosing
Intervention descriptions: intervention 1: If a previous lab report is unavailable, the patient will need to have T790M+ testing. intervention 2: Blood count and standard chemistry testing to ensure patient meets inclusion/exclusion criteria intervention 3: ECG to ensure absence of any cardiac abnormality intervention 4: Slit-lamp testing performed to ensure patients do not have any eye abnormalities or symptoms intervention 5: Patients to be provided with AZD9291 every 6 weeks (+/- 7 days)

Protocol documents:
Prot_000.pdf: 
Protocol: D5160C00022 
Confidential - Proprietary Information 

Protocol number: D5160C00022 

Document title: Open Label, Multinational, Multicenter, Real World 
Treatment Study of Single Agent AZD9291 for Patients with 
Advanced/Metastatic Epidermal Growth Factor Receptor (EGFR) T790M 
Mutation-Positive Non-Small Cell Lung Cancer (NSCLC) Who Have 
Received Prior Therapy with an EGFR Tyrosine Kinase Inhibitor (EGFR-
TKI). 

Version numbers: CSP Version 3.0 

Date of the documents: 20 Oct 2016 

NCT number: NCT02474355 


The following Amendment(s) and Administrative Changes have been made to this protocol since the date of 
preparation:
Amendment No.
Date of Amendment
Local Amendment 
No:
Date of Local Amendment
1
30 June 2015
2
23 June 2016
3
20 October 2016
Administrative 
Change No.
Date of Administrative 
Change
Local Administrative 
Change No.
Date of Local 
Administrative Change
1
18 May 2015
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
This Real World Treatment Study Protocol has been subject to an internal review process 
according to AstraZeneca Standard procedures.  The Real World Treatment Study is publicly 
registered and the results are disclosed and/or published according to the AstraZeneca Global 
Policy on Bioethics and in compliance with prevailing laws and regulations.
Clinical Study Protocol 
Drug Substance
AZD9291
Study Code
D5160C00022
Version
3
Date
20 October 2016
Open Label, Multinational, Multicenter, Real World Treatment Study of Single 
Agent AZD9291 for Patients with Advanced/Metastatic Epidermal Growth 
Factor Receptor (EGFR) T790M Mutation-Positive Non-Small Cell Lung 
Cancer (NSCLC) Who Have Received Prior Therapy with an EGFR Tyrosine 
Kinase Inhibitor (EGFR-TKI)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden


Real World Treatment Study – Revised Protocol
Drug Substance AZD9291
Study Code D5160C00022
Edition Number 3
Date 20 October 2016
Clinical Study Protocol (CSP), ANGEL
Version 17.0
Template Form Doc ID: LDMS_001_00026737
Parent Doc ID: SOP AZDoc0018580
PROTOCOL SYNOPSIS
Open Label, Multinational, Multicenter, Real World Treatment Study of
Single Agent AZD9291 for Patients with Advanced/Metastatic Epidermal 
Growth Factor Receptor (EGFR) T790M Mutation-Positive Non-Small Cell 
Lung Cancer (NSCLC) Who Have Received Prior Therapy with an EGFR 
Tyrosine Kinase Inhibitor (EGFR-TKI)
Objective
The primary objective of this study is to assess the efficacy and safety of single agent 
AZD9291 in a real world setting in adult patients with advanced or metastatic, epidermal 
growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer
(NSCLC), who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy.
Study site(s) and number of patients planned
Approximately 600 patients will be enrolled (dosed) in Europe. The recruitment will be 
increased beyond that as the study will expand in other regions of the world (America, Asia). 
Total recruitment for all regions (including China) is expected to be approximately 3500 
patients, depending on recruitment speed and national reimbursement timelines
Study period
Estimated date of first patient enrolled
Q3 2015
Estimated date of last patient completed
Q2 2020*
*depends on the date the last country obtains national reimbursement plus 90 days or 18 
months after the last patient is enrolled.
Study Design
This will be an open-label, single-arm, multinational, multicenter, real world treatment study.
Target patient population
Adult patients (fulfilling the definition of “age of majority” per local regulations) with locally 
advanced (stage IIIB) or metastatic (stage IV) NSCLC with confirmed T790M mutation, who 
have received prior EGFR-TKI therapy.


Clinical Study Protocol
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Study Code D5160C00022
Version 3
Date 20 October 2016
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Investigational product (IP), dosage, and mode of administration
AZD9291 is an oral, potent, selective, irreversible inhibitor of both EGFR-TKI sensitising and 
resistance mutations in NSCLC with a significant selectivity margin over wild-type EGFR.  
AZD9291 will be administered orally as one 80 mg tablet once a day.
Duration of IP administration
Patients may continue to receive AZD9291 as long as they continue to show clinical benefit, 
as judged by the investigator, and in the absence of discontinuation criteria (see section 4.3).
Enrolment will be closed within 6 months of market license approval in that country or at 
national reimbursement, whichever is sooner.
The study will be closed in each participating country as soon as possible following national 
reimbursement of AZD9291 in that country (up to a max of 90 days post reimbursement). 
Patients withdrawing from the treatment prior to national reimbursement will be followed up 
as part of this study until death or lost to follow-up.
At national reimbursement patients still on treatment will be transitioned to commercial 
supply as long as the patient is benefitting from treatment as per investigator assessment, and 
in accordance with national regulations in the countries where the study is conducted. 
In the event that national reimbursement should not be granted following a reasonable time 
after market license approval in the country, the study will be closed in a maximum period of 
18 months after the last patient is enrolled in that country. Contingencies will be made locally 
to ensure continued drug supply for patients who are still deriving benefit from AZD9291 at 
that time.
If applicable, timelines for conversion to commercial drug will be agreed with local bodies 
which may include regulatory agencies, ethics committees, and institutions.
Study measures
Data collected will include patient demographics, information needed to determine patient 
eligibility (including medical history, past and current disease characteristics, and tumor 
EGFR mutational status), AZD9291 exposure (including starting dose, dose adjustments or 
discontinuations), investigator-reported efficacy (including tumor response and disease 
progression), overall survival (OS), and safety (including serious adverse events [SAEs], 
adverse events leading to dose modification, and adverse events of special interest [interstitial 
lung disease/pneumonitis-like events, and QTc prolongation events]).
Statistical methods
As the objective of the study is to collect physician-reported real world efficacy and safety 
data while offering access to AZD9291 to patients with significant unmet medical need, a total 
pre-defined recruitment target of treated patients is not applicable for this study.


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Date 20 October 2016
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All data will be presented for the overall full analysis set, and also by cohorts defined by 
number and type of previous treatment lines for the advanced disease.  Descriptive statistics 
will be used for all variables, as appropriate.  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.  OS, time to treatment discontinuation (TTD) and progression-free survival (PFS) 
will be summarized using Kaplan-Meier estimates of the median event time and quartiles
together with their 95% confidence intervals. 


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TABLE OF CONTENTS
PAGE
PROTOCOL SYNOPSIS .........................................................................................................2
TABLE OF CONTENTS .........................................................................................................5
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................8
1.
INTRODUCTION .................................................................................................10
1.1
Current non-small cell lung cancer (NSCLC)-related treatment patterns .............10
1.2
Background and rationale for AZD9291 ...............................................................11
1.3
Rationale for dose selection...................................................................................11
1.4
Benefit/risk and ethical assessment........................................................................12
1.4.1
Nonclinical data .....................................................................................................12
1.4.2
Clinical data ...........................................................................................................12
1.4.2.1
Study D5160C00005..............................................................................................13
1.4.2.2
Study D5160C00001..............................................................................................14
1.4.2.3
Study D5160C00002..............................................................................................15
1.4.2.4
Study D5160C00003..............................................................................................15
1.4.3
Conclusions............................................................................................................15
2.
STUDY OBJECTIVE............................................................................................17
3.
PATIENT SELECTION ........................................................................................17
3.1
Inclusion criteria ....................................................................................................17
3.2
Exclusion criteria ...................................................................................................18
4.
STUDY CONDUCT..............................................................................................19
4.1
Study Plan ..............................................................................................................19
4.2
Restrictions ............................................................................................................23
4.3
Discontinuation from study treatment ...................................................................24
4.3.1
Procedures for discontinuation of a subject from study treatment.........................25
4.4
Patient Withdrawal or Study Termination .............................................................25
5.
STUDY MEASURES............................................................................................26
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT ..............................28
6.1
Definition of adverse events ..................................................................................28
6.2
Definition of serious adverse events......................................................................28
6.2.1
Handling of deaths .................................................................................................29
6.2.2
Hy’s Law................................................................................................................30


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6.3
Reporting of serious adverse events.......................................................................30
6.4
Overdose ................................................................................................................30
6.5
Pregnancy...............................................................................................................31
6.5.1
Maternal exposure..................................................................................................31
6.5.2
Paternal exposure...................................................................................................31
6.6
Management of toxicities related to AZD9291......................................................32
6.6.1
Pulmonary Symptoms............................................................................................32
6.6.2
QTc Prolongation (using Fredericia’s formula –QTcF–) ......................................33
6.6.3
Corneal Ulceration.................................................................................................33
6.6.4
Skin reactions.........................................................................................................33
6.6.5
Diarrhoea................................................................................................................33
6.7
Study governance and oversight ............................................................................33
7.
DATA MANAGEMENT.......................................................................................34
7.1
Collection, monitoring, processing of data and archiving .....................................34
7.2
Reporting and publication of data..........................................................................34
8.
INVESTIGATIONAL PRODUCT........................................................................35
8.1
Identity and dose of investigational product – AZD9291......................................35
8.2
Labeling .................................................................................................................36
8.3
Storage ...................................................................................................................36
8.4
Compliance ............................................................................................................36
8.5
Accountability........................................................................................................36
9.
STATISTICAL ANALYSES ................................................................................36
9.1
Statistical evaluation-general aspects ....................................................................36
9.2
Description of outcome variables in relation to objectives and hypotheses ..........37
9.3
Description of analysis sets....................................................................................37
9.4
Methods for statistical analyses .............................................................................37
9.4.1
Evaluation of primary efficacy objective...............................................................38
9.4.2
Evaluation of secondary efficacy objectives..........................................................38
9.4.3
Safety analysis .......................................................................................................38
9.4.4
Interim analysis......................................................................................................38
9.5
Determination of sample size.................................................................................39
10.
STUDY MANAGEMENT BY ASTRAZENECA REPRESENTATIVE ............39
10.1
Training of site personnel ......................................................................................39
10.2
Monitoring of the study .........................................................................................40
10.2.1
Source data.............................................................................................................40
10.2.2
Study agreements...................................................................................................40


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10.2.3
Archiving of study documents...............................................................................40
10.2.4
Timetable and End of Study ..................................................................................40
11.
ETHICAL AND REGULATORY REQUIREMENTS.........................................41
11.1
Ethical conduct of the study...................................................................................41
11.2
Patient data protection............................................................................................41
11.3
Ethics and regulatory review..................................................................................41
11.4
Informed consent ...................................................................................................42
11.5
Changes to the protocol and informed consent form.............................................42
11.6
Audits and inspections ...........................................................................................43
12.
LIST OF REFERENCES.......................................................................................44
VERSION HISTORY ............................................................................................................58
LIST OF TABLES
Table 1
Most common (≥ 2) SAEs observed to date in the ongoing 
AZD9291 clinical studies considered related to AZD9291 
treatment...................................................................................................13
Table 2
Estimated cumulative subject exposure to AZD9291 from 
completed and ongoing clinical trials by age and sex ..............................16
Table 3
Estimated cumulative subject exposure to AZD9291 from 
completed and ongoing clinical trials by racial group..............................16
Table 4
Study Plan.................................................................................................20
Table 5
Dose Interventions....................................................................................32
LIST OF APPENDICES
Appendix A
Additional Safety Information..................................................................48
Appendix B
Guidance regarding Potential Interactions with Concomitant 
Medications ..............................................................................................50
Appendix C
Actions Required in Cases of Combined Increase of 
Aminotransferase and Total Bilirubin - Hy’s Law...................................53


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this Study Protocol.
Abbreviation or 
special term
Explanation
AE
Adverse event
AESI
Adverse Event of Special Interest
AZ
AstraZeneca
CI
Confidence Interval
CNS
Central nervous system
CRF
Case Report Form (electronic/paper)
CTCAE
Common Terminology Criteria for Adverse Event
CYP
Cytochrome P450
CT
Computer Tomography
DCO
Data cut-off
DLT
Dose limiting toxicity
ECG
Electrocardiogram 
EGFR
Epidermal Growth Factor Receptor
EGFRm
EGFR Mutation positive; EGFR Sensitizing Mutation positive
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ILD
Interstitial Lung Disease
ICMJE
International Committee of Medical Journal Editors
IP
Investigational Product 
IVRS/IWRS
Interactive Voice Response System/ Interactive Web Response System
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
NSCLC
Non-Small Cell Lung Cancer
ORR
Objective response rate


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Abbreviation or 
special term
Explanation
OS
Overall Survival
PFS
Progression Free Survival
PT
Preferred Term
QT
Interval on the electrocardiogram representing the duration of 
depolarization and repolarization of the heart
QTc
The QT interval corrected for heart rate
QTcF
QT  interval corrected per Fredericia’s formula
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
SAE
Serious adverse event 
SOC
System Organ Class
SmPC
Summary of Product Characteristics
T790M
An amino acid substitution at position 790 in EGFR, from a Threonine (T) 
to a Methionine (M). Presence of T790M
TKI
Tyrosine Kinase Inhibitor
TTD
Time to treatment discontinuation
US
United States
WBDC
Web based data capture
WHO
World Health Organization


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1.
INTRODUCTION
1.1
Current non-small cell lung cancer (NSCLC)-related treatment 
patterns
Lung cancer has been the most common cancer in the world for several decades, and by 2012, 
there were an estimated 1.8 million new cases, representing 12.9% of all new cancers.  It was 
also the most common cause of death from cancer, with 1.59 million deaths (19.4% of the 
total) (GLOBOCAN 2012).  Non-small Cell Lung Cancer (NSCLC) represents approximately 
80% to 85% of all lung cancers.  At the time of diagnosis approximately 70% of patients with 
NSCLC already have locally advanced or metastatic disease not amenable to surgical 
resection.  Patients presenting with unselected advanced NSCLC have a median overall 
survival (OS) of 10 to 12 months (Bonomi 2010). 
The development of epidermal growth factor receptor (EGFR)-targeted tyrosine kinase 
inhibitors (TKI) have led to significant advances in patients with tumours harbouring EGFR 
mutations (EGFRm).  Such types of mutations are seen in 10 to 15% of patients with NSCLC 
in the Western world and 30 to 40% in Asia.  As a result of first-line studies comparing a TKI 
versus chemotherapy in EGFRm patients (IRESSA Pan-Asia Study [IPASS] and EURopean 
TArceva versus Chemotherapy [Mok et al 2009a, Rosell et al 2012]), the National 
Comprehensive Cancer Network (NCCN) and the European Society of Medical Oncology 
(ESMO) currently recommend treatment with an EGFR-TKI (e.g., erlotinib, gefitinib, or 
afatinib) in the front-line setting for those patients with documented EGFRm. 
In patients with sensitizing mutations of EGFR, response rates of 50 to 80% have been 
reported with first-line TKI treatment, compared with less than 30% with conventional 
chemotherapy.  Patients ultimately develop acquired resistance to these agents with 
progression of disease after approximately 9 to13 months (Engelman et al 2008, Pao et al 
2005, Nguyen et al 2009, Mok et al 2009b, Rosell et al 2012).
For patients whose tumors have progressed after treatment with an EGFR-TKI, the median OS 
rate is up to 2 years (Wang et al 2012, Wu et al 2010, Fukuoka et al 2011).  Although EGFR-
TKI (e.g., erlotinib, afatinib, gefitinib) are established therapies for patients with NSCLC 
known to have sensitising mutations in EGFR, the emergence of T790M mutation in patients 
treated with an EGFR-TKI agent has been described as the major route of development of 
resistance to this class of therapy (Pao et al 2005, Kobayashi et al 2005, Yu et al 2013).  
There is no global standard of care for later lines of therapy after failure of both EGFR-TKI 
therapy and chemotherapy; current treatment options for this selected patient population are 
generally limited to chemotherapy or clinical trials (Langer et al 2012).  No targeted therapy is 
currently approved for this specific disease setting.
Re-treatment with an EGFR-TKI (eg, switching to erlotinib following failure of gefitinib) 
confers response rates of around 10% and median progression-free survival (PFS) of 1.7 to 


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6.2 months (Lee et al 2013, Watanabe et al 2011). Afatinib, a second-generation EGFR-TKI, 
has shown similar efficacy (LUX-Lung 1 trial; Miller et al 2012), with a 7% response rate, 
2-month improvement over placebo in PFS (median 3.3 versus 1.1 months) and no OS benefit 
shown; a similar 8% response rate and 4.4 months PFS was seen in the LUX-Lung 4 trial 
(Katakami et al 2013).  
Second-line platinum-based chemotherapy post EGFR-TKI for EGFRm NSCLC generally 
provides response rates in the range of 20 to 30% (Gridelli et al 2012, Goldberg et al 2012, 
Maemondo et al 2010, Wang et al 2012, Wu et al 2010). 
1.2
Background and rationale for AZD9291
AZD9291 is a potent irreversible inhibitor of both the single mutant EGFRm (TKI sensitivity 
conferring mutation) and double mutant EGFRm/T790M (TKI resistance conferring mutation) 
receptor forms of EGFR with a significant selectivity margin over wild-type EGFR (Collett 
1994, Cross et al 2014). AZD9291 can effectively block EGFR signalling both in EGFR 
single mutant cells with sensitising EGFR mutations and in double mutant cells bearing both 
the primary EGFR sensitising and secondary resistance T790M mutation (Collett 1994,Cross 
et al 2014).  Preliminary data from an ongoing phase I study (D5160C00001) in 
EGFRm/T790M NSCLC patients has shown good evidence of anti-tumour activity while 
administration of AZD9291 has shown good tolerability across a range of doses (Ranson et al, 
Janne et al 2014). 
In the clinical programme, at the data cut-off (DCO) of 1 August 2014, a total of 253 patients 
had received at least one dose of AZD9291 in study D5160C00001 (31 in the dose escalation 
cohorts and 222 in the dose expansion cohorts).  A total of 138 patients had tumour 
harbouring the T790M mutation as assessed by central testing.  The median age was 60 years 
and 62% of patients were female, 62% of patients were Asian and 36% were Caucasian, and 
60% of patients had received immediate prior EGFR-TKI therapy.  For all evaluable patients, 
confirmed Response Evaluation Criteria In Solid Tumours (RECIST 1.1) responses were 
observed at all dose levels (20–240 mg once daily).  For the 78 patients with centrally tested 
T790M tumours and confirmed response, the longest duration of response is ongoing at 
>11 months.  Preliminary median duration of response at 80 mg was 8.2 months. Preliminary 
median progression-free survival was 9.6 months (30% maturity, 41/138 events) (Yang et al 
2014).
For further clinical details please refer to the AZD9291 Investigator’s Brochure (IB).
1.3
Rationale for dose selection
The selected AZD9291 starting dose of 80 mg is the recommended phase II dose, as defined 
from study D5160C00001 (AZD9291 IB).  This is not the maximum tolerated dose (MTD) as 
AZD9291 was administered up to 240 mg daily with no dose-limiting toxicity (DLT) 
observed.  In the phase III registration study, the same dose of 80 mg AZD9291 is used.


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1.4
Benefit/risk and ethical assessment
1.4.1
Nonclinical data
In a modified embryofoetal development study in the rat, AZD9291 caused embryolethality 
when administered to pregnant rats prior to embryonic implantation, at a maternally tolerated 
dose of 20 mg/kg (approximately 1.4x the recommended human dose of 80 mg daily).  It is 
not known whether AZD9291 is excreted in human milk.  Women of childbearing potential 
and men must use adequate contraception prior to study entry, for the entire duration of study 
participation.  Women who are breast feeding are excluded from the study.  Both women and 
men must be fully informed of the reproductive toxicity testing, and women must have a 
negative pregnancy test prior to enrolment (refer to inclusion criteria 8 and 9).
For further preclinical detail please refer to the AZD9291 IB.
1.4.2
Clinical data
At the time of this protocol writing, one phase I study (study D5160C00005) was completed 
and 15 studies are ongoing.  A total of 945 subjects were exposed to AZD9291, including 
93 subjects exposed to a combination of AZD9291 plus another treatment and 45 healthy 
volunteers exposed to a single dose of AZD9291 20 mg.  Dose levels of AZD9291 ranged 
from 20 to 240 mg, with exposure ranging from 1 to 609 days. The emerging safety profile is 
based on preliminary data from studies with AZD9291 using a DCO of 16 January 2015.
The key efficacy findings from the clinical programme at the DCO of 01 Aug 2014 are 
summarised below:

Treatment with AZD9291 has resulted in tumour shrinkage (including an effect on 
brain metastases) with objective response rates (ORRs) for the dose cohorts in the 
D5160C00001 study ranging from 43% to 58% for the population of ≥2nd line patients 
as a whole.

Patients with tumors harboring the T790M appeared to have improved responses 
(ORRs in these patients ranged from 50% to 70%) compared with responses in patients 
with tumors without the presence of T790M.

Responses were durable, with the preliminary median duration of response calculated 
as 8.2 months for the 80 mg dose in patients with tumors harboring the T790M.  
Preliminary median PFS was 9.6 months in patients with centrally tested T790M+ 
NSCLC (30% maturity, 41/138 events) and 2.8 months in patients with centrally 
confirmed T790M negative NSCLC (71% maturity, 44/62 events).

The most commonly reported adverse events (AEs) were rash, diarrhoea, pruritus and 
nausea.  The most common SAEs by System Organ Class (SOC) were respiratory, 
thoracic and mediastinal disorders, gastrointestinal disorders, metabolism and nutrition 
disorders, and blood and lymphatic system disorders (Table 1). 

A total of 23 deaths were reported across all studies with AZD9291, for which the 
cause of death was not attributed by the Investigator to their underlying disease.  Of 


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these, 1 death was considered by the Investigator to be related to AZD9291 treatment 
(an event of respiratory failure/left lung interstitial lung disease (ILD) reported in the 
D5160C00002 study).  A further 62 patients died while participating in studies with 
AZD9291, but for whom the cause of death was attributed to their underlying disease; 
of these deaths, 2 were considered by the Investigator to be related to AZD9291 
treatment by the Investigator (an event of sepsis/pneumonia/lung cancer and an event 
of ILD, both reported in the D5160C00001 study).
Table 1 shows the most common SAEs observed at safety DCO in the ongoing clinical studies 
considered to be related to AZD9291 treatment by the Investigators, by Medical Dictionary 
for Regulatory Activities (MedDRA) SOC and Preferred Term (PT).
Table 1
Most common (≥ 2) SAEs observed to date in the ongoing AZD9291 
clinical studies considered related to AZD9291 treatment
MedDRA SOC and PT
Number of events
Respiratory, thoracic and mediastinal disorders
15
Pneumonitis
8
Interstitial lung disease
4
Pulmonary embolism
2
Gastrointestinal disorders
9
Diarrhoea
5
Nausea
2
Metabolism and nutrition disorders
6
Decreased appetite
3
Dehydration
2
Blood and lymphatic system disorders
3
Thrombocytopenia
2
Infections and infestations
3
Investigations
3
Nervous system disorders
2
General disorders and administration site conditions
2
Skin and subcutaneous tissue disorders
2
Abbreviations: MedDRA Medical Dictionary of Regulatory Activities; PT preferred term; SOC system organ class.
1.4.2.1
Study D5160C00005
A total of 32 healthy male volunteers were enrolled in this study: 16 subjects in Part A (the 
relative bioavailability part of the study) and 16 subjects in Part B (the food effect part of the 
study).  All healthy volunteers received a single dose of 20 mg AZD9291, either as an oral 
solution, tablet, or capsule formulation.  Part B of the study was conducted using the tablet 
formulation only.  There were no deaths or SAEs reported during the study.  There were no 
events leading to discontinuation during Part A of the study.  One healthy volunteer had an 


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Drug Substance AZD9291
Study Code D5160C00022
Version 3
Date 20 October 2016
14 (63)
event of alanine aminotransferase increased of mild intensity which led to discontinuation 
during Part B of the study; this event was considered to be related to AZD9291.
In Part A, 10 out of the 16 healthy volunteers (62.5%) reported at least one AE.  The most 
commonly reported AEs were in the SOC “infections and infestations” (5 AEs); within this 
SOC, the most commonly reported PT, was influenza (3 out of 16 healthy volunteers 
[18.8%]).  All other PTs were reported in 1 healthy volunteer only.  A similar pattern of AEs 
was observed in Part B, where 6 out of 16 volunteers (37.5%) reported at least one AE.  In 
Part B, the most commonly reported AEs were also in the SOC “infections and infestations” 
with 2 AEs (PT upper respiratory tract infections).  All other PTs were reported in 1 healthy 
volunteer only.
1.4.2.2
Study D5160C00001
Phase I (dose escalation and expansion)
The following data are based upon the phase I database lock performed on December 2014.  
No new or relevant safety data have been reported in patients receiving AZD9291 in this 
phase I study subsequent to this time point.  Exposure ranged from 2 to 609 days.  The MTD 
of AZD9291 in patients with advanced NSCLC was not established as the DLT criteria were 
not met at doses as high as 240 mg.  Although a DLT was not identified as defined in the 
protocol, dose interruptions, dose reductions and EGFR wild type effects were observed at 
higher frequencies at the 160 mg and 240 mg dose levels.  Adverse events were reported in 
97% of patients, SAEs were reported in 24% (87/362) of patients.  The majority of AEs were 
mild to moderate in intensity (Common Terminology Criteria for Adverse Event [CTCAE] 
Grade 1 or 2), and 37.8% (137/362) of patients reported CTCAE Grade ≥ 3 events.  In the 
overall study population, a total of 11 fatal AEs were reported, only one of which (pneumonia) 
was considered by the Investigator to be related to AZD9291.
Phase II (extension phase)
In the Phase II study, at the safety DCO, 201 patients had received treatment with 80 mg 
AZD9291.  A pre-planned preliminary database lock was performed on November 2014 and 
safety data are based upon this database lock.  No new or relevant safety data has been 
reported in patients receiving AZD9291 in this phase II study subsequent to this time point.  
Exposure ranged from 0.1 to > 6.0 months, with 55.5% (111/201) of patients receiving 
treatment for a total duration of 3 to 6 months.  Adverse events were reported in 87% 
(174/201) of patients, severe AEs (CTCAE Grade ≥ 3) were reported for 13.5% (27/201) of 
patients.  The majority of AEs were mild to moderate in intensity (CTCAE Grade 1 or 2).  The 
most commonly reported AEs (in >5% of patients) were diarrhoea, rash, and paronychia.  
These AEs are consistent with the most frequently reported AEs in the Phase 1 study.  Serious 
AEs were reported in 10.5% (21/201) of patients on study treatment. A total of 4 patients had 
fatal AEs, 1 fatal AE of interstitial lung disease considered by the Investigator to be related to 
AZD9291 and 3 others fatal AEs were attributed to disease progression.  The reported AEs 
infrequently led to AZD9291 dose modification or permanent discontinuation, with 1.5 % 
(3/201) of reported AEs resulting in permanent discontinuation of AZD9291.


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Study Code D5160C00022
Version 3
Date 20 October 2016
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1.4.2.3
Study D5160C00002
In study D5160C00002, at the DCO of January 2015, 210 patients had been exposed to 80 mg 
AZD9291 daily.  Safety data are based on a pre-planned database lock (December 2014), and 
no new or relevant safety data have been identified from the study D5160C00002 subsequent 
to this time point.  Exposure ranged from 0 to 5.7 months with the majority of patients 
receiving AZD9291 for a total duration of 3 to 6 months.  Adverse events were reported in 
approximately 79% (166/210) of patients and were infrequently severe (12.9%, [26/210] of 
AEs were CTCAE ≥ Grade 3).  The majority of AEs were mild to moderate in intensity 
(CTCAE Grade 1 or 2).  The most commonly reported AEs (in ≥5% of patients) were 
diarrhoea, rash and dry skin.  The types of AEs were consistent with the known safety profile 
of AZD9291.  Serious AEs were reported in 9.4% (19/210) of patients on study treatment.  
One fatal AE occurred (dyspnoea) which was not considered to be related to AZD9291 or 
attributed to disease progression by the Investigator.  The reported AEs infrequently led to 
AZD9291 dose modification or permanent discontinuation, with permanent discontinuation of 
AZD9291 due to AEs reported in <2% of patients.
1.4.2.4
Study D5160C00003
At the DCO of January 2015, 23 patients with advanced NSCLC had been exposed to 
AZD9291 in the study D5160C00003.  A single case of pneumonitis was reported in one 
patient enrolled in the study D5160C00002 prior to dosing with AZD9291.
For further clinical detail please refer to the AZD9291 IB.
1.4.3
Conclusions
Based on the identified and potential risks associated with AZD9291 treatment, this clinical 
study protocol incorporates safety monitoring procedures and guidance to assist with early 
diagnosis and rapid management of potential AZD9291 drug-related symptoms.  Dose 
modification algorithms are also included in this clinical study protocol.  
All trials of AZD9291 exclude patients with clinically significant toxicities related to prior 
treatments in addition to specifically excluding patients with a history of any of the following:

Clinically active interstitial lung disease 

Current or concurrent risk factors for severe arrhythmias
Given the clinical activity noted to date with AZD9291, the acceptable safety profile 
demonstrated thus far, and the inclusion/exclusion criteria stipulated in this study protocol, it 
is reasonable and appropriate to make AZD9291 available to patients with NSCLC no longer 
responding to previous EGFR-TKI and whose tumors harbor the T790M mutation. 
Cumulative summary tabulations of exposure by age/sex and by racial group are presented in 
Table 2 and Table 3, respectively.


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Study Code D5160C00022
Version 3
Date 20 October 2016
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Table 2
Estimated cumulative subject exposure to AZD9291 from completed 
and ongoing clinical trials by age and sex
Number of subjects
Age range (years)
Male
Female
Total
<18
0
0
0
18-65
415
212
627
66-75
143
69
212
76-85
42
31
73
86-95
5
2
7
>95
0
1
1
Total
605
315
920
Data from completed and ongoing clinical trials as of 16 January 2015.
Table 3
Estimated cumulative subject exposure to AZD9291 from completed 
and ongoing clinical trials by racial group
Racial group
Number of subjects
Asian
515
White
359
Black or African American
48
Other
13
American Indian or Alaska Native
4
Native Hawaiian or other Pacific Islander
2
Unknown
2
Total
945
Data from completed and ongoing clinical trials as of 16 January 2015.
The difference of 25 subjects between Table 2 and Table 3 is due to subjects with missing age 
and/or race data.  These 25 subjects had dosing information and thus were considered to have 
received AZD9291 while enrolled in the study.  However, due to missing age and/or race 
information these patients are counted in a different table (i.e., Table 3). 


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Study Code D5160C00022
Version 3
Date 20 October 2016
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2.
STUDY OBJECTIVE
The primary objective of this study is to assess the efficacy and safety of single agent 
AZD9291 in a real world setting in adult patients with advanced or metastatic, epidermal 
growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer
(NSCLC), who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy.
The primary efficacy outcome is OS, with secondary efficacy outcomes including investigator 
assessed response rate, investigator assessed PFS and Time to Treatment Discontinuation 
(TTD).
3.
PATIENT SELECTION 
Each patient must meet all of the applicable inclusion criteria and none of the exclusion 
criteria for this Real World Treatment Study.  Under no circumstances can there be exceptions 
to this rule.
3.1
Inclusion criteria
For inclusion in the study patients must fulfill the following criteria:
1. Provision of signed and dated written informed consent by the patient or legally acceptable 
representative prior to any study-specific procedures
2. Adults (according to each country regulations for age of majority)
3. Locally advanced (stage IIIB) or metastatic (stage IV) EGFRm NSCLC, not amenable to 
curative surgery or radiotherapy, with confirmation of the presence of the T790M 
mutation 
4. Prior therapy with an EGFR-TKI.  Patients may have also received additional lines of 
treatment
5. World Health Organization (WHO) performance status 0-2
6. Adequate bone marrow reserve and organ function as demonstrated by complete blood 
count, biochemistry in blood and urine at baseline
7. ECG recording at baseline showing absence of any cardiac abnormality as per exclusion 
criterion #6
8. Female patients of childbearing potential must be using adequate contraceptive measures 
(see Restrictions, Section 4.2), must not be breast feeding, and must have a negative 
pregnancy test prior to start of dosing.  Otherwise, they must have evidence of non-
childbearing potential as defined below:
a.
Post-menopausal defined as aged more than 50 years and amenorrheic for at least 
12 months following cessation of all exogenous hormonal treatments
b. Women under 50 years would be consider post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 


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Drug Substance AZD9291
Study Code D5160C00022
Version 3
Date 20 October 2016
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treatments and with luteinizing hormone and follicle-stimulating hormone levels in 
the post-menopausal range for the institution
c.
Documentation of irreversible surgical sterilisation by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation
9. Male patients must be willing to use barrier contraception, i.e., condoms (see Restrictions, 
Section 4.2)
3.2
Exclusion criteria
Patients will not be enrolled in this study if any of the following exclusion criteria are met:
1. Previous (within 6 months) or current treatment with AZD9291 
2. Patients currently receiving (or unable to stop use at least 1 week prior to receiving the 
first dose of AZD9291) any treatment known to be potent inhibitors or inducers of 
cytochrome P450 (CYP) 3A4 (Appendix B)
3. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled 
hypertension, active bleeding diatheses, active infection* including hepatitis B, hepatitis C 
and human immunodeficiency virus, or significantly impaired bone marrow reserve or 
organ function, including hepatic and renal impairment, which in the investigator’s opinion 
would significantly alter the risk/benefit balance. 
* active infection will include any patients receiving intravenous treatment for any infection 
and patients with hepatitis B or C surface antigen (+) – Patients receiving oral antiviral 
suppressive therapy for hepatitis B or C will be permitted to enrol in the study.
4. Patient with symptomatic central nervous system (CNS) metastases who is neurologically 
unstable or has required increasing doses of steroids to manage CNS symptoms within the 
2 weeks prior to start AZD9291 administration
5. Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid 
treatment, or any evidence of clinically active ILD
6. Any of the following cardiac criteria:
a.
Mean resting corrected QT interval (QTcF) > 470 ms  using Fredericia’s formula :
b. Any clinically important abnormalities in rhythm, conduction or morphology of 
resting ECG (e.g., complete left bundle branch block, third degree heart block, 
second degree heart block)
c.
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events


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Study Code D5160C00022
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Date 20 October 2016
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7. Any unresolved toxicity from prior therapy CTCAE > grade 3 at the time of starting
treatment 
8. History of hypersensitivity to excipients of AZD9291 or to drugs with a similar chemical 
structure or class to AZD9291
4.
STUDY CONDUCT 
The following section outlines the study implementation plan, details on the study measures 
that will be collected as part of it are provided in Section 5.
4.1
Study Plan
This study has been subject to an internal review according to AstraZeneca standard 
procedures. 
Concomitant treatments, other than anti-cancer treatments, should be taken according to local 
medical practice.  There are no restrictions on concomitant use in this study except per 
exclusion criteria.  However, it is advised that those medical products and other products 
known to have interactions with AZD9291 should be avoided (see Appendix B).
The latest version of the IB and any subsequent updates will be supplied to the investigator.  
Investigators need to become familiar with the content of the IB and appendices associated 
with this protocol.
Table 4 below outlines data collection measures that are considered for this study:


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Study Code D5160C00022
Version 3
Date 20 October 2016
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Table 4
Study Plan
Screening/
Enrolment visit
Treatment 
visit 
Treatment
Discontinuation 
30 day follow 
up(c)  
Progression 
Follow-up (e)
Survival follow 
up(g)
-28 days
Day 1
(every 6 
weeks)
(every 
6 
weeks)
(every 6 
weeks)
Windows (days)
+/- 7 days
+/- 7 days
+/- 7 
days
+/- 7 
days
+/- 7 
days
Informed Consent
X
Inclusion/Exclusion criteria check
X
Complete enrolment form
X
Confirm T790M mutation
X(d)
Patient demographics 
X
Medical history
X
Disease characteristics
X
Cancer treatment history
X
Concomitant medications
X
X
X
X
Complete blood count
X
If clinically 
indicated or 
per 
institutional 
standard of 
care
If clinically 
indicated or 
per 
institutional 
standard of 
care
Biochemistry in blood and urine
X
If clinically 
indicated or 
per 
institutional 
standard of 
care
If clinically 
indicated or 
per 
institutional 
standard of 
care
Pregnancy test
X (f)
Physical examination
X
X
WHO Performance status
X
X
X
Weight
X
X
X
ECG recording
X
If clinically 
indicated or 
per 
institutional 
standard of
care
If clinically 
indicated or 
per 
institutional 
standard of 
care
Visual test (slit-lamp)
X
If clinically 
indicated or 
per 
institutional 
standard of 
care
If clinically 
indicated or 
per 
institutional 
standard of 
care
Dispense  AZD9291 (IVRS/IWRS)
X
AZD9291 
start-dose
X
AZD9291 
re-supply
AZD9291 dosing (daily): 
- current dose; dose adjustment; 
X


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Study Code D5160C00022
Version 3
Date 20 October 2016
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Screening/
Enrolment visit
Treatment 
visit 
Treatment
Discontinuation 
30 day follow 
up(c)  
Progression 
Follow-up (e)
Survival follow 
up(g)
interruption/discontinuation 
reason for change
Drug accountability
X
Investigator-reported efficacy
X
X
X
SAE, including overdose and 
pregnancy reporting(a)(f)
X
X
X
X
X
Adverse event of special interest (b)
AEs leading to dose modification 
including drug discontinuation
X
X
X
X
Reason for withdrawal
X
Survival status
X
(a)
Following AZD9291 discontinuation, SAEs considered related to study procedures should continue to be 
collected until disease progression
(b) ILD/pneumonitis-like event; cardiac event (see section 6.6.1 and 6.6.2).
(c) A 30 day post last dose follow up contact (visit or by telephone) should be made with the subject to collect 
new SAEs, andAESI and to follow up on any ongoing SAEs andAESI.
(d) Before initiating treatment with AZD9291 the T790M mutation status after progression needs to be known. 
T790M mutation test may have been done per routine practice earlier than 28 days prior to day 1 as long as 
this was obtained following the progression on prior TKI therapy (patients may also have received 
additional lines of treatment).
(e) For subjects withdrawn from treatment but who had not progressed at the time of AZD9291 
discontinuation. Follow up to be performed every 6 weeks (± 1 week) relative to the date of enrolment until 
end of study (including survival follow-up period).
(f) 
Pregnancy test to be performed in accordance with local standards
(g)
Survival status to be performed every 6 weeks (± 1 week) relative to the date of enrolment until end of 
study 
Patient enrolment:
1. The investigator will determine patient eligibility based on criteria outlined in Section 3.1
and 3.2.
2. The investigator will inform the patients about the study, AZD9291, the potential benefits 
and risks, AE reporting, as well as other information collected within the scope of the 
study.  Subsequently, the investigator will obtain signed informed consent from the 
potential patient or  legally acceptable representative, as appropriate per local regulations
Each patient will be assigned a unique identifier through the Interactive Voice Response 
System (IVRS)/ Interactive Web Response System (IWRS) in the following format 
ECCNN3XX: CC being the country code, NN being the centre number and 3XX being the 
subject enrolment code at the centre into the study. 


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Drug Substance AZD9291
Study Code D5160C00022
Version 3
Date 20 October 2016
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In the event of a patient having an SAE delaying the start of treatment, the screening 
assessments will need to be performed within 28 days prior to treatment and entered in the 
CRF in the extended screening visit.
If a subject withdraws from participation in the study, then his/her enrolment code cannot be 
reused.
3. The investigator will provide a completed enrolment form 
The laboratory report describing the test and specimen used to confirm the presence of T790M 
mutation must be available on site. Before initiating treatment with AZD9291 the tumor’s 
T790M mutation status after progression with an EGFR TKI needs to be known. The test will 
be performed via a local laboratory wherever possible, and always in an accredited, certified 
or quality assured clinical laboratory as required by country-specific guidelines, using an 
appropriately validated test. If T790M mutation status is not known, a new sample following 
progression on the latest line of therapy may need to be obtained to be sent to a suitable local 
laboratory or a designated central laboratory (*) for analysis.  In that circumstance the patient 
will be requested to provide consent prior to carrying out this procedure. 
(*) Note:  No other genetic tests will be performed other than EGFR mutation test and samples 
will not be retained by the central lab if a central lab needs to be used. The samples provided 
will be destroyed at the end of the study or returned upon request as per the Laboratory 
Manual of the designated central laboratory.
4.
The study site must receive enrolment confirmation for each patient from AstraZeneca 
(or designee) prior to drug dispensation
5. Patient visits (e.g. physical exam, laboratory tests, etc.) must be performed according to 
the institutional standard of care and investigator’s best medical judgment. AZD9291 
re-supply must always be preceded by a treatment visit per Table 4. 
Additionally, at each visit:
a.
Drug accountability must be documented in the case report form (CRF) and 
necessary paper logs.
b. Patient needs to be screened for reportable safety events outlined in Section 6
c.
Investigator-reported efficacy measures described in Section 5 needs to be 
documented in the CRF
d. Investigators are required to assess the patient’s performance status and confirm 
that the patient continues to be deriving benefit from AZD9291 at the time of study 
drug re-supply.
e.
If a patient withdraws from the treatment and/or completely from the study, the 
investigator will record the reason for withdrawal


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Study Code D5160C00022
Version 3
Date 20 October 2016
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**Please note that if the reason for withdrawal is an event meeting the definition 
of SAE, it must be recorded in both the safety and clinical forms**
f.
For patients lost to follow-up, every reasonable effort must be made to establish 
the survival status and document this in the CRF
6. As an investigational drug, AZD9291 must be stored appropriately and dispensed from a 
secure storage area (or site pharmacy).  Study sites are required to maintain accountability 
logs for drug receipt, dispensation, destruction and return (as applicable per local 
regulations).  
a.
AZD9291 may only be used for the specific patient enrolled into the study.
7.
Patients must be followed through the designated follow-up period (30 days post last 
dose of AZD9291 study medication) to collect SAEs occurring during this period and 
other required reporting per Section 6 and follow-up on any ongoing SAEs.
Consenting patients who do not fulfil the eligibility criteria must not be enrolled (dosed) into 
the study and will be discontinued. They will be considered screening failures and only 
demography data, reason for discontinuation will be recorded. Supporting safety information 
can be collected in case of SAE, if applicable. 
4.2
Restrictions
The following restrictions apply while the patient is receiving AZD9291 and for the specified 
times before and after:
1. Females of childbearing potential must use reliable methods of contraception from the 
time of screening until 3 months after discontinuing AZD9291.  Acceptable methods of 
contraception include true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence for the duration of a trial, and 
withdrawal are not acceptable methods of contraception], tubal ligation, hormonal 
contraceptives that are not prone to drug-drug interactions (e.g., IUS Levonorgestrel Intra 
Uterine System, Medroxyprogesterone injections), copper-banded intra-uterine devices, 
and vasectomized partner. All hormonal methods of contraception should be used in 
combination with the use of a condom by their male sexual partner(s) for intercourse.
2. Male patients must be asked to use barrier contraceptives (i.e., by use of condoms) during 
sex with all of their female partners during the trial and for a period of 6 months.  Patients 
should not father a child for 6 months after completion of AZD9291 treatment.  Patients 
must refrain from donating sperm from the start of dosing until 6 months after 
discontinuing AZD9291 treatment.  If male patients wish to father children they should be 
advised to arrange for freezing of sperm samples prior to the start of AZD9291treatment.
3. If medically feasible, patients taking regular medication, with the exception of potent 
inducers of CYP3A4 (see Appendix B), should be maintained on it throughout the study 


Clinical Study Protocol
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Study Code D5160C00022
Version 3
Date 20 October 2016
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period (30 days post-last dose).  Patients taking concomitant medications whose 
disposition is dependent upon CYP3A4 and breast cancer resistance protein and which 
have a narrow therapeutic index should be closely monitored for signs of changed 
tolerability as a result of increased exposure of the concomitant medication whilst 
receiving AZD9291.  Patients taking concomitant medications whose disposition is 
dependent upon CYP3A4, CYP1A2, CYP2C or p-glycoprotein and which have a narrow 
therapeutic index should be closely monitored for reduction in therapeutic activity as a 
result of the reduced exposure of the concomitant medication while receiving AZD9291.  
Guidance on medications to avoid, medications that require close monitoring and on 
washout periods is provided (see Appendix B).
Up to 3-fold increase in exposure may occur in statin exposure when co-administered with 
AZD9291.  It is recommended that the starting and maintenance dose of statins should be 
as low as possible and should be guided by the statin prescribing information. 
Patients taking warfarin should be monitored regularly for changes in prothrombin time or 
international normalized ratio.
Patients who wear contact lenses must discontinue wearing their lenses if they have any 
mild to moderate eye symptoms (CTCAE grade ≤2) while receiving treatment with 
AZD9291 until at least one week after symptoms have resolved.  If a patient has a 
recurrence of eye symptoms or experiences any severe (CTCAE grade ≥3) ocular events, 
they must discontinue wearing their contact lenses until at least one week after treatment 
with AZD9291 is permanently discontinued.  Patients must not use any eye drops or 
ointment for treatment of eye symptoms, unless agreed to by a study doctor, at any time 
during the study until 1 week after AZD9291 has been permanently discontinued.  
Patients must consult their investigator promptly if they have any concerns. 
4.3
Discontinuation from study treatment
Patients may be discontinued from AZD9291 treatment in the following situations:

The investigator thinks that it is in the patient’s best interest to stop therapy (i.e. 
disease progression or patient is no longer receiving clinical benefit)

Patient decision: the patient is at any time free to discontinue treatment, without 
prejudice to further treatment.

Confirmed diagnosis of ILD 

Ulcerative ocular events 

QTc interval prolongation with signs/symptoms of serious arrhythmia

Other manifestation of unacceptable toxicity

Pregnancy

Patient incorrectly enrolled or treated on the study

Patient starts receiving additional anti-cancer therapy


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Study Code D5160C00022
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Date 20 October 2016
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
Lost to follow up (unsuccessful contact with patient despite every effort made by 
investigator)

Termination of the study (see Sections 4.4 and 10.2.4)
All unused investigational product (IP) must be returned by the patient or representative (e.g. 
caregiver, family member).
4.3.1
Procedures for discontinuation of a subject from study treatment 
Any subject who discontinues study treatment for reasons other than disease progression 
should have tumour assessments performed as scheduled in the protocol (see Table 4) until 
disease progression is documented or death occurs, unless consent is withdrawn. 
Patients may continue study treatment beyond disease progression if they are still receiving 
clinical benefit, as judged by the Investigator, and in the absence of any other discontinuation 
criteria.
4.4
Patient Withdrawal or Study Termination 
At any time, patients are free to discontinue AZD9291 treatment or withdraw from the study 
without prejudice to further treatment. 
Reasons for withdrawal from the study:

Eligibility criteria not fulfilled

Death

Withdrawal of consent.
If a subject wishes to withdraw their consent to both treatment and study assessments, they 
should be asked if they are willing to continue with survival follow-up (which can be 
conducted by telephone). If a subject wishes to withdraw their consent to further participation 
in the study entirely, including survival follow-up, this should be clearly documented in the 
subject notes and in the CRF. 
The status of ongoing, withdrawn (from the study) and “lost to follow-up” subjects at the time 
of an overall survival analysis should be obtained by the site personnel by checking the 
subjects notes, hospital records, contacting the subjects general practitioner and checking 
publicly available death registries.  In the event that the subject has actively withdrawn 
consent to the processing of their personal data, the vital status of the subject can be obtained 
by site personnel from publicly available resources where it is possible to do so under 
applicable local laws.
The withdrawal reasons must be documented and SAEs reported appropriately in the CRF.  If 
the patient agrees, the investigator must follow the patient for safety reasons until 30 days 
post-last dose, and then for survival status (and also for progression status if the subject had 
not progressed).  If patient declines, the investigator will separately follow up and manage any 


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Study Code D5160C00022
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Date 20 October 2016
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SAEs as a matter of clinical practice.  The patient or representative will return unused 
AZD9291 tablets.  
AstraZeneca reserves the right to terminate the study.  The study will be terminated if in the 
judgment of AstraZeneca, patients are placed at undue risk because of clinically significant 
findings or AZD9291 received national reimbursement.
The study will be closed in each participating country as soon as possible following national 
reimbursement of AZD9291 in that country (up to a max of 90 days post reimbursement). 
Enrolment will be closed within 6 months after market license approval in that country or at 
national reimbursement, whichever is sooner.
Patients withdrawing from the treatment prior to national reimbursement will be followed up 
as part of this study.
At national reimbursement, patients still on treatment will be transitioned to commercial 
supply as long as patient is benefitting from treatment as per investigator assessment and in 
accordance with national regulations in the countries where the study is conducted.. Once the 
study is closed no further data will be collected.  Reasons for termination or withdrawal must 
be documented in the CRF.  All data, collected as part of the study, that is available at the time 
of discontinuation from treatment, withdrawal from study or study termination, must be 
recorded. 
5.
STUDY MEASURES
The sources of information for all study variables collected for this study will be patient 
medical records or charts and patients surveys.  All data collected will be entered by the 
investigator into a CRF.  All patients participating in the study will be followed from 
enrolment until completion of the study, discontinuation of AZD9291 administration 
(determined by investigator due to adverse events, toxicities or other relevant reasons), 
discontinuation due to disease progression, or death, whichever occurs earlier.
Study measures will be collected at baseline and during the follow-up period.  For each 
patient, physicians will be required to provide date of enrolment, and thereafter during the 
follow-up visits, the date and outcome of the more recent disease assessment, and date of 
progression and death (if applicable).  The variables described in the following sections will 
be collected to address the study objectives. 
The study measures that will be assessed among patients participating in this study are listed 
below: 

Baseline demographic characteristics: patient characteristics including age, gender, 
race (if available or allowed by local regulations) will be collected

T790M positive mutation status results and type of test performed and receptors


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
Relevant Medical history: comorbidities and relevant medical history (this includes 
any chronic conditions currently requiring medication)

Physical examination: at baseline and at treatment discontinuation

Weight: at each visit

Visual test: at screening, a slit-lamp examination should be obtained. Ophthalmologic 
exams to be performed as clinically indicated. A 30-day follow-up assessment will be 
required if an on treatment assessment was abnormal at the time of discontinuation of 
study therapy, to confirm reversibility of the abnormality.

Disease characteristics: tumor histology, stage at diagnosis, current stage, presence of 
leptomeningeal /brain metastases at baseline, WHO performance status at study 
enrollment and subsequent follow-up visits 

Cancer treatment history: first-line therapy type (targeted or non-targeted) and 
agents received, start and end-dates, subsequent-lines type and start and end-date, 
radiation therapy (yes/no), surgery (yes/no) received prior to study enrollment must be 
documented

Relevant Concomitant medication: in case of SAE, AE of special interest, AE 
leading to dose modification (including study medication discontinuation).

AZD9291 dosing: starting dose, dose adjustments, dose interruptions, dose 
discontinuation and reason for any dose change.

Disease assessment: as per institutional standard of care, physicians will report in the 
CRF date, procedure, and best overall response at each follow-up visit time-point as 
well as if the patient is taking benefit from the study medication (yes/no). In case of 
disease progression, the physician will assess, date, and document in the CRF the 
progression and methods (eg CT scan) used as per standard definitions and routine 
institutional standard of care.  Physician will also indicate if the patient progressed 
with leptomeningeal/brain metastasis.
o
Imaging assessments (CT scans or MRI) from baseline and following visits 
(where available and provided an Informed Consent is obtained) will be 
collected from a subset of patients where a T790M positive mutation was 
identified via the cobas® EGFR Mutation Test performed on a plasma or tissue 
specimen,
o
Imaging assessments (CT scans or MRI) from baseline and following visits 
(where available and provided an Informed Consent is obtained) may also be 
collected from patients where a T790M positive mutation was identified via 
other molecular testing methods.

Progression follow-up: after study medication discontinuation for reasons other than 
disease progression, the patient will continue assessments as per institutional standard 
of care and the physicians will report in the CRF date, procedure, and best overall 
response at each follow-up visit.


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
Survival status: patient survival status (dead, alive, unknown) at each follow-up must 
be documented in the CRF.  The time from the date of first dose in the study until 
death will be used to evaluate OS.  Lost to follow-up patients will be censored at last 
documented contact with patient status “alive”.

Laboratory assessments: laboratory parameters will not be collected. If done, they 
will be assessed by the investigator as normal or abnormal and details about 
abnormality will be entered in the CRF.

Safety will be assessed by collection of SAEs, AEs leading to dose-modification, AEs 
of special interest, and on-study deaths.
Central reading of imaging assessments
All imaging assessments from a selected subset of patients (where available and Informed 
Consent is obtained), including unscheduled visit scans, should be collected and sent to an 
AstraZeneca appointed Clinical Research Organisation to enable independent central analyses. 
The central imaging review is required only for this selected subset of patients where a 
selected T790M positive mutation test was performed on a plasma or tissue specimen.  The 
baseline scan should ideally be performed within 28 days of the start of treatment.  The results 
of this independent review will not be communicated to investigators.  The purpose of this 
review is to assess tumour response according to RECIST 1.1 in order to evaluate the 
objective response rate in these subsets of patients with various methods of T790M molecular 
testing.  
Further details will be provided in the Statistical Analysis Plan.
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The investigator is responsible for reporting all serious adverse events and the other adverse 
events specifically defined on Table 4 and ensuring that all staff involved in the study is 
familiar with the content of this section.
6.1
Definition of adverse events
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition occurring at any time from signing informed consent, whether 
or not considered causally related to the investigational drug.  An undesirable medical 
condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) 
or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram). 
6.2
Definition of serious adverse events
An SAE is an event occurring from the time the patient signs informed consent (as per local 
regulations) through the end of the post-treatment follow-up visit (30 days post-last dose) or 


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until disease progression, whichever is the latest, which fulfils one or more of the following 
criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above.
For further guidance on the definition of an SAE, see Appendix Ato the study protocol. 
Follow-up of unresolved adverse events
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the CRF.  
AstraZeneca retains the right to request additional information for any subject with ongoing 
AE(s) at the end of the study, if judged necessary.
6.2.1
Handling of deaths
All deaths that occur during the study or within the follow-up period after the administration 
of the last dose of AZD9291 (30 days post-last dose) or until disease progression, whichever 
is the latest, must be reported as follows:
-
Death, which is unequivocally due to disease progression, must be reported to the study 
representative and must be documented in the CRF, but must not be reported as an SAE 
during the study.
-
Where death is not clearly due to progression of the disease being treated as part of the 
study, the primary and most likely event causing the death must be reported to 
AstraZeneca’s representative as an SAE within 24 hours.  The report must contain a 
comment regarding the co-involvement of progression of disease, if appropriate, and must 
assign a single primary cause of death together with any contributory causes.
-
Deaths with an unknown cause must always be reported as an SAE but every effort should 
be made to establish a cause of death.  A post-mortem may be helpful in the assessment of 
the cause of death, and if performed a copy of the post-mortem results must be reported in 
an expedited fashion to an AstraZeneca representative within the usual timeframes.


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6.2.2
Hy’s Law
Cases where a subject shows an AST or ALT ≥3xULN or total bilirubin ≥2xULN may need to 
be reported as SAEs.  The investigator is responsible for, without delay, determining whether 
a subject meets potential Hy’s law (PHL) criteria. Details of identification of PHL cases and 
actions to take are detailed in Appendix C. Those SAE will be collected until 30 days post last 
dose of study medication.
6.3
Reporting of serious adverse events
All SAEs must be reported through the completion and submission of the SAE report form, 
from the time of signature of informed consent through 30 days post-last dose, whether or not 
considered causally related to AZD9291. 
If any SAE occurs in the timeframe mentioned above, then the investigator or other site 
personnel must inform the appropriate AstraZeneca representatives within one day i.e., 
immediately but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigator or other site personnel must inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day, i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
The investigator or other study site personnel must report SAEs to the appropriate 
AstraZeneca representative through the completion and submission of the AstraZeneca SAE 
report form.
The AstraZeneca representative will advise the investigator/study site personnel how to 
proceed. 
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug AZD9291.
6.4
Overdose
There is no definition of what constitutes an overdose.  In the Phase I study, 355 patients with 
advanced NSCLC were administered AZD9291 at single and multiple oral doses ranging from 
20 mg to 240 mg daily (as of data cut-off date 02 December 2014).  All doses were well 
tolerated.  Experiences of excessive doses (i.e. in excess of the optimal 80 mg indicated dose) 
in this study did not show any DLTs or acute toxicities.


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There is no known antidote.  Investigators are advised that any patient, who receives a higher 
dose than intended should be monitored closely, managed with appropriate supportive care, 
and followed up expectantly.
Such overdose must be recorded in the CRF.  If an overdose occurs in the course of the study, 
then the investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca representative through the completion and 
submission of the overdose report form.
For overdoses associated with an SAE, the standard reporting timelines apply, see Section 6.3.  
For other overdoses, reporting must occur within 30 days.
6.5
Pregnancy
All pregnancies, including partner’s pregnancy and outcomes of pregnancy, must be reported 
to AstraZeneca during the course of the study and within 30 days of the last dose of AZD9291 
treatment through completion and submission of the pregnancy reporting form. (for partner 
pregnancies see Section 6.5.2)
6.5.1
Maternal exposure
If a patient becomes pregnant during the course of the study, AZD9291 treatment must be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the AZD9291 may 
have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages must be reported and handled as 
SAEs.  The outcome of all pregnancies (spontaneous miscarriage, elective termination, 
ectopic pregnancy, normal birth, or congenital abnormality) must be followed up and 
documented even if the patient was discontinued from the study.
If any pregnancy occurs in the course of the study or within 30 days of the final dose of the 
AZD9291, the investigator or other site personnel must inform the appropriate AstraZeneca 
representatives within 1 day, i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.  The designated AstraZeneca representative works with the investigator 
to ensure that all relevant information is provided to the AstraZeneca Patient Safety data entry 
site within 1 or 5 calendar days for SAEs (see Section 6.3) and within 30 days for all other 
pregnancies.
The same timelines apply when outcome information is available.
6.5.2
Paternal exposure 
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 


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birth or congenital abnormality) should, if possible, be followed up and documented.  If 
allowed by local regulations, information about a pregnancy from the partner of a male patient 
can be captured.  If so, 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 6 months after 
dosing must be followed up and documented.
6.6
Management of toxicities related to AZD9291
If a patient experiences a CTCAE grade 3 or higher and/or unacceptable toxicity (any grade), 
where the investigator considers the event of concern to be specifically associated with 
AZD9291 (and not attributable to the disease or disease-related processes for which patient is 
being treated), dosing will be interrupted and supportive therapy administered as required in 
accordance with local practice/guidelines.  
If the toxicity resolves or reverts to CTCAE grade ≤ 2 within 3 weeks of onset, treatment with 
AZD9291 may be restarted at the same dose (80 mg, daily) or a lower dose (40 mg, daily) 
using the rules below for dose modifications (Table 5) as per the investigator’s evaluation 
and/or in discussion and agreement with the study Medical Monitor as needed.  There will be 
no individual modifications to dosing schedule in response to toxicity, only potential dose 
reduction or dose interruption.  Once a dose reduction is implemented, the dose of AZD9291 
cannot be reverted back to 80 mg.
If the toxicity does not resolve to CTCAE grade ≤ 2 after 3 weeks, then the patient must be 
withdrawn from the study treatment and kept in observation until resolution of the toxicity.
Table 5
Dose Interventions
Intervention
AZD9291 Dose
Starting Dose
80 mg daily
Reduced Dose
40 mg daily
If an event subsequently requires dose interruption, AZD9291 may restart at the same dose or 
the reduced dose, on resolution/improvement of the event at the discretion of the investigator.
6.6.1
Pulmonary Symptoms 
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormality 
suggestive of interstitial lung disease are observed, the administration of AZD9291 needs to 
be interrupted and the study Medical Monitor must be informed.  It is strongly recommended 
to perform a full diagnostic workup, to exclude alternative causes such as lymphangitic 
carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage.  The results 
of the full diagnostic workup (including high-resolution computed tomography, blood and 
sputum culture, haematological parameters) will be recorded in the CRF by the investigator.  
Where ILD is suspected, local practice must be followed in discussion with the study Medical 


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Monitor.  In the absence of a confirmed diagnosis of ILD, AZD9291 may be restarted 
following consultation with the study Medical Monitor.  In case of a confirmed diagnosis of 
ILD, AZD9291 must be permanently discontinued. (refer to “Guidance for the Management 
of AE in studies using 80mg AZD9291”)
6.6.2
QTc Prolongation (using Fredericia’s formula –QTcF–) 
Patients with Grade 3 QTcF with QTcF prolongation (i.e., confirmed QTcF prolongation to > 
500 ms absolute or a > 60 ms increase from baseline) should have AZD9291 interrupted and 
regular ECGs performed until resolution to baseline.  If the QTcF interval resolves to Grade 1 
(<481 msec), AZD9291 may be restarted at the reduced dose of 40 mg. If the QT 
prolongation does not resolve to ≤CTCAE grade 1 (<481 msec) after 3 weeks, then the patient 
will be permanently withdrawn from AZD9291 and observed until resolution of the toxicity.
All QTcF prolongation of >470 ms at any point during the study must be reported to 
AstraZeneca, and ECGs sent to the Study Team upon request for further analysis.  This does 
not alter the management guidance outlined above.
6.6.3
Corneal Ulceration 
Following an ocular event, the results of eye investigation must be recorded in the CRF by the 
investigator.  Patients experiencing corneal ulceration will not be permitted to restart 
AZD9291 treatment. 
6.6.4
Skin reactions 
Recommendations for appropriate management of skin reactions, including guidance on dose-
adjustments for clinically significant and/or intolerable skin reactions that are considered by 
the investigator to be causally related to AZD9291 will be provided to clinicians.
6.6.5
Diarrhoea
Recommendations for appropriate management of diarrhoea, including uncomplicated 
CTCAE grade ≤2, and dose-adjustments for AEs of diarrhoea that are of CTCAE grade ≥3 or 
that are clinically significant and/or intolerable and considered by the investigator to be 
causally related to AZD9291, will be provided to participants in the study. 
For further guidance on skin reactions and diarrhoea, please refer to “Guidance for the 
Management of Adverse Events in Studies using 80 mg AZD9291”
6.7
Study governance and oversight
An Executive Steering Committee will be set up. It will involve 7 experts with the relevant 
knowledge and experience required for the study. This Executive Committee will have the 
executive oversight and supervision of the study. It will also be involved in the publication 
strategy of the study.


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7.
DATA MANAGEMENT 
7.1
Collection, monitoring, processing of data and archiving
Data management will be performed by PAREXEL staff according to the Data Management 
Plan.
Data collected will include descriptive patient demographics, information needed to determine 
patient eligibility (including medical history, past and current disease characteristics, and 
tumor EGFR mutational status), AZD9291 exposure (including starting dose, dose 
adjustments or discontinuations), investigator-reported efficacy (including tumor response and 
disease progression), OS, and safety (including serious adverse events, adverse events leading 
dose-modification, and adverse event of special interest [interstitial lung disease/pneumonitis-
like events, and QTc prolongation events]).
Data will be entered in the web-based data capture (WBDC) system at the Investigator’s site.  
The Investigator (or delegate) will be responsible for entering data into the WBDC system and 
according to the Investigator Instructions Manual.  The Investigator Instructions Manual will 
also provide the study site with data entry instructions.
Data entered in the WBDC system will be immediately saved to a central database and 
changes tracked to provide an audit trail.  When data have been entered, reviewed and edited, 
the Investigator will be notified to sign the CRF electronically as per the agreed project 
process.  A copy of the CRF will be archived at the Investigator’s site.
7.2
Reporting and publication of data
AstraZeneca will prepare a Study Report within 12 months after database lock or completion 
of the study.  AstraZeneca is obliged to analyse and report all study data as described in the 
protocol. 
In accordance with the Declaration of Helsinki, both authors and publishers have ethical 
obligations.  In publication of the results of this study, the authors are obliged to preserve the 
accuracy of the results.  AstraZeneca endeavours to publish the results of this study and is 
committed to ensure that the data are reported in a responsible and coherent manner.
AstraZeneca seeks to ensure that publications in biomedical journals follow the guidelines 
established by the International Committee of Medical Journal Editors (ICMJE) and published 
in its Uniform Requirements of Manuscripts Submitted to Biomedical Journals. 
AstraZeneca is committed to ensuring that authorship for all publications must comply with 
the criteria defined by the ICMJE.  These state that: "Each author must have participated 
sufficiently in the work to take public responsibility for the content."
AstraZeneca believes that participation solely in the collection of data or drafting the 
manuscript does not justify authorship.  These conditions apply equally to external 
investigators and to AstraZeneca employees.


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Other members of the group should be listed in the acknowledgments as appropriate.
Publication or presentation of data subsets from individual institutions, regions or countries 
participating in this global multicentre study may precede the primary manuscript with the 
approval of the AZ global study team.  The AZ global study team will determine if in certain 
instances publication of institution, regional or country-specific data by the participating 
country may precede the primary global publication.
8.
INVESTIGATIONAL PRODUCT 
8.1
Identity and dose of investigational product – AZD9291
AZD9291 will be supplied as tablets for oral administration as a single daily dose of 80 mg. 
Each bottle will contain sufficient AZD9291 treatment for 21 days, plus overage. 40 mg 
tablets will be supplied as needed upon request to the AstraZeneca representative.
Investigational product
Dosage form and strength
AZD9291
40 mg Tablets
80 mg Tablets
The tablets can be taken with or without food and should be swallowed whole with water. The 
tablet should not be crushed, split or chewed. 
If the patient is unable to swallow the tablet, it may first be dispersed in 50 mL of non-
carbonated water. The tablet should be dropped in the water, without crushing, stirred until 
dispersed and immediately swallowed. An additional half a glass of water should be added to 
ensure that no residue remains and then immediately swallowed.
If administration via nasogastric tube is required, the same process as above should be 
followed but using volumes of 15 mL for the initial dispersion and 10 mL for the residue 
rinses. The total liquid should be administered as per the nasogastric tube instructions with 
appropriate water flushes
The initial dose of AZD9291 80 mg daily can be reduced to 40 mg once daily under 
circumstances described in Section 6.6.  
Doses should be taken approximately 24 hours apart at the same time point each day.  Doses 
should not be missed.  If a patient misses taking a scheduled dose, within a window of 
12 hours, it is acceptable to take the dose.  If it is more than 12 hours after the scheduled dose 
time, the missed dose must not be taken, and patients must be instructed to take the next dose 
at the next scheduled time.  If a patient vomits after taking their AZD9291 treatment, they 
must not make up for this dose, but must take the next scheduled dose.
Any change from dosing schedule, dose interruptions, or dose reductions must be recorded in 
the CRF.  


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Tablets will be packed in high-density polyethylene bottles with child-resistant closures.  
Bottles will be dispensed to patients in the packaging provided.  The packaging includes 
bottles, caps and a label. Bottle tampers must not be broken prior to dispensing AZD9291 to a 
patient.
Additional information about AZD9291 may be found in the IB.
8.2
Labeling
Labels for AZD9291 will be prepared in accordance with Good Manufacturing Practice 
(GMP) and local regulatory guidelines.  Label text will be translated into local language.
The label will include the Name of the Sponsor, Protocol Code, For Clinical Trial use only, 
and/or any other market specific requirements.
Patient’s leaflet will be inserted if required per local regulations
8.3
Storage
All IP must be kept in a secure place under appropriate storage conditions.  The IP label on the 
bottles specifies the appropriate storage.
8.4
Compliance
The administration of AZD9291 must be documented in the appropriate sections of the CRF.  
Patients must return all unused IP and empty containers to the investigator.
8.5
Accountability
The IP provided for this study will be used only as directed in the study protocol.  The study 
personnel will account for all IP dispensed to and returned from the patient. 
The study personnel at the investigational site will account for all treatments dispensed and for 
appropriate return or destruction.  The site is required to maintain documentation of the 
delivery, return and destruction of IP.  AstraZeneca representatives will review and collect this 
documentation.  
9.
STATISTICAL ANALYSES
Statistical analysis and generation of all tables, listings and figures will be performed by using 
SAS® (SAS Institute, North Carolina), version 9.2 or higher. 
The analyses of the data collected within this study will be descriptive only.
9.1
Statistical evaluation-general aspects
A Statistical Analysis Plan (SAP) will be prepared and finalised prior to first subject in (FSI). 
The aim of the study is to assess efficacy and safety of AZD9291 in a real world setting.


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9.2
Description of outcome variables in relation to objectives and 
hypotheses
Analysis will be conducted to evaluate the following as available in the CRF:

Baseline characteristics: demographics, relevant medical history, disease 
characteristics, cancer treatment history.  

Exposure to AZD9291

Response Rate (RR): 
RR is defined as the percentage of patients with a best response of ‘responding’ by 
investigator assessment as recorded in the CRF.

Overall Survival (OS): 
Overall survival is defined as the time from the date of first dose of AZD9291 in this 
study until death due to any cause. Any subject not known to have died at the time of 
analysis will be censored based on the last recorded date on which the subject was 
known to be alive.

Progression Free Survival (PFS) 
PFS is defined as the time from first dose of AZD9291 in this study until the date of 
disease progression as recorded in CRF or death (by any cause in the absence of 
progression) regardless of whether the subject withdraws from therapy or receives 
another anti-cancer therapy prior to progression. Subjects who have not progressed or 
died at the time of analysis will be censored at the time of the latest date of assessment.

Time to treatment discontinuation (TTD): 
TTD is defined as the time from the date of first dose of AZD9291 in this study until 
the date of AZD9291 discontinuation for any reason including disease progression, 
treatment toxicity, death or other reason as recorded in CRF. Subjects who are still on 
treatment at the time of analysis will be censored at the date of last dose received.

Adverse events
Serious Adverse Events [SAEs], adverse events leading to dose modification, and 
adverse events of special interest
9.3
Description of analysis sets
Full analysis set (FAS)
The full analysis set will include all subjects who received at least one dose of study 
treatment. 
9.4
Methods for statistical analyses
All analyses will be performed on the FAS population. No statistical tests will be performed, 
the statistical analyses will be descriptive.


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Efficacy analyses will be repeated by cohorts defined by number and type of previous 
treatment lines and by other pre-defined subgroups of interest as pre-specified in the SAP.
Data will be summarized using descriptive statistics as appropriate. Continuous variables will 
be summarised by the number of observations (n), mean, standard deviation (SD), median, 
quartiles (Q1 and Q3), minimum, and maximum. Categorical variables will be summarised by 
frequency counts and percentages for each category.
9.4.1
Evaluation of primary efficacy objective
OS will be summarized using Kaplan-Meier (KM) estimates of the median time to death or 
censoring and quartiles together with their 95% confidence intervals (CIs). KM estimates of 
the OS rate at appropriate time points (to be defined in SAP) will be presented as well. A plot 
of the KM overall survival curve will be produced.
9.4.2
Evaluation of secondary efficacy objectives 
PFS and TTD will be summarized similarly to OS using KM estimates of the median times to 
progression or death or treatment discontinuation, and quartiles together with their 95% CIs . 
KM estimates of the PFS or TTD rate at appropriate time points (to be defined in SAP) will be 
presented as well. A plot of the KM PFS and TTD curve will be produced.
The response rate will be summarised together with the 95% CI.
9.4.3
Safety analysis
Safety and tolerability will be assessed in terms of AEs. These will be collected for all 
subjects.

Adverse events
SAEs and adverse events leading to study drug discontinuation will be summarised by 
MedDRA preferred terms and CTCAE grade.
Any AE occurring within 30 days of discontinuation of investigational product (ie, the last 
dose of AZD9291) or until disease progression, whichever is the latest, will be included in the 
AE summaries. 

Adverse events  of special interest
Adverse events of special interest (for example interstitial lung disease/pneumonitis-
like events; QTc prolongation events]) will be summarised by pre-defined categories 
described in the SAP. 
9.4.4
Interim analysis
Interim analysis of the global data will take place annually for the first three years (i.e. at 
approximately 12, 24 and 36 months from the start of recruitment) to provide annual updates 
of key study measures as specified in the SAP. Regional and country level analysis may also 
be performed at these time points if deemed appropriate.


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The final analysis will take place approximately 5 years after the start of recruitment, 
depending on the date of actual global study closure.
9.5
Determination of sample size 
OS is the primary efficacy endpoint of interest for this study. Median OS is assumed to be 
approximately 21-25 months in patients with Advanced/Metastatic Epidermal Growth Factor 
Receptor (EGFR) T790M Mutation-Positive Non-Small Cell Lung Cancer (NSCLC) who 
have received prior therapy with an EGFR Tyrosine Kinase Inhibitor (EGFR-TKI) receiving 
AZD9291. While the sample size is not known a priori illustrations of the precision with 
which OS could be calculated from this real world study are given in the table below. These 
illustrations assume a study length of 58 months with non-uniform accrual over 40 months 
and that OS is exponentially distributed.
N
21
23
25
n events
95% CI 
median OS*
n events
95% CI 
median OS*
n events
95% CI 
median OS*
500
313
18.8-23.5
297
20.5-25.8
283
22.3-28.1
1000
627
19.4-22.7
595
21.2-24.9
566
23.0-27.1
1500
941
19.7-22.4
893
21.5-24.6
800
23.3-26.8
2000
1255
19.9-22.2
1191
21.7-24.3
1133
23.6-26.5
3000
1883
20.1-22.0
1787
22.0-24.1
1700
23.8-26.2
3500
2197
20.1-21.9
2085
22.0-24.0
1983
23.9-26.1
*based on the formula in Collett 1994
Therefore if 3500 patients enter the study globally and the median OS is 25 months the 95% 
CI around this survival figure would be approximately 23.9-26.1 months. For Europe, 
assuming recruitment of 1000 patients the equivalent 95% CI would be approximately 23.0-
27.1 months.
10.
STUDY MANAGEMENT BY ASTRAZENECA 
REPRESENTATIVE
10.1
Training of site personnel
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the study protocol and related documents with the site personnel 
and also train them in any protocol-specific procedures.
The investigator will ensure that appropriate training relevant to the study is given to all 
investigational staff involved in the study.


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The investigator will also maintain a record of all individuals involved in the study (medical, 
nursing, and other staff).
10.2
Monitoring of the study
During the study, an AZ representative will have regular contacts with the study site, 
including visits, as per local regulations, to verify the conduct of the study.
The AZ representative will be available during the course of the study if the investigator or 
other staff at the site needs information and advice about the study conduct.
10.2.1
Source data
Study sites will maintain source data in accordance with Good Clinical Practice (GCP) or 
local regulations.  
10.2.2
Study agreements
The site and the investigator at each site must comply with all the terms, conditions, and 
obligations of the Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this study protocol and the Study Agreement, the terms of the 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 Study 
Agreement shall prevail.
Agreements between AstraZeneca (or its delegation) and the investigator/site must be in place 
before any study-related procedures can take place.
10.2.3
Archiving of study documents
The Investigator must follows the archiving requirements outlined in the Study Agreement. 
10.2.4
Timetable and End of Study
The study is expected to start in Q3 2015 and to end by Q2 2020.
The study will be closed in each participating country as soon as possible following national 
reimbursement of AZD9291 in that country (up to a max of 90 days post reimbursement). 
Enrolment will be closed within 6 months after market license approval in that country or at 
national reimbursement, whichever is sooner.
Patients withdrawing from the treatment prior to national reimbursement will be followed up 
as part of this study.
At national reimbursement, patients still on treatment will be transitioned to commercial 
supply as long as patient is benefitting from treatment as per investigator assessment and in 
accordance with national regulations in the countries where the study is conducted. Once the 
study is closed no further data will be collected.


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In the event that national reimbursement should not be granted following a reasonable time 
after market license approval in the country, the study will be closed in a maximum period of 
18 months after the last patient is enrolled in that country. Contingencies will be made locally 
to ensure continued drug supply for patients who are still deriving benefit from AZD9291 at 
that time.
The end of the study is defined as ‘the last visit of the last subject undergoing the study’.
AstraZeneca may also terminate the entire study prematurely if concerns for safety arise 
within this study or in any other study with AZD9291.
11.
ETHICAL AND REGULATORY REQUIREMENTS
11.1
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 Conference on Harmonization 
(ICH)/Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca 
policy on Bioethics and Human Biological Samples.
11.2
Patient data protection
The Informed Consent Form (ICF) will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
AstraZeneca or its representative will not provide patient information to patients, any 
insurance company, any employer, their family members, general physician or to any other 
third party, unless required to do so by law.
Precautions are taken to preserve confidentiality and prevent data being linked to the identity 
of the patient.  Also Regulatory authorities may require access to the relevant files.
11.3
Ethics and regulatory review
An Independent Review Board (IRB)/Ethics Committee (EC) must approve the final study 
protocol, including the final version of the ICF and any other written information and/or 
materials to be provided to the patients, as per local regulations.  The opinion of the IRB/EC 
must be given in writing.
AstraZeneca or its representative must approve any modifications to the ICF that are needed 
to meet local requirements.
If required by local regulations, the protocol must be re-approved by the IRB/EC annually.


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Before enrollment of any patient into the study, the final protocol, including the final version 
of the ICF, is to be approved by the national regulatory authority or a notification to the 
national regulatory authority is to be done, according to local regulations.
AstraZeneca or its representative will provide Regulatory Authorities, IRB/EC, and 
investigators with safety updates/reports according to local requirements.
Each investigator is responsible for providing the IRB/EC with reports of any serious and 
unexpected adverse drug reactions from any other study conducted with the IP.  AstraZeneca 
or its representative will provide this information to the investigator so that he/she can meet 
these reporting requirements.
11.4
Informed consent
The investigator at each site will:

Ensure each patient is given full and adequate oral and written information about the 
nature, purpose, possible risk, and benefit of the study.

Ensure each patient is notified that they are free to discontinue from the study at any 
time.

Ensure that each patient is given the opportunity to ask questions and allowed time to 
consider the information provided.

Ensure each patient or legally acceptable representative provides signed and dated ICF 
before conducting any procedure specifically for the study.

Ensure the original, signed ICF(s) is/are stored in the investigator’s study file.

Ensure a copy of the signed ICF is given to the patient.

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 IRB/EC.

Ensure that the Addendum to the ICF is signed and dated for the subset of patients 
tested for a T790M positive mutation via the cobasEGFR Mutation Test (or any 
other molecular testing methods if relevant) before any imaging assessments are 
collected.
11.5
Changes to the protocol and informed consent form
If there are any substantial changes to the study protocol, then these changes will be 
documented in a new version of the study protocol (Revised Study Protocol).


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The amendment in the form of a revised protocol is to be approved by the relevant IRB/EC 
and if applicable, the national regulatory authority needs also to be notified or has to provide 
approval, before implementation.  Local requirements are to be followed for revised protocols.
AstraZeneca or its representative will distribute any new versions of the protocol to each 
participating investigator.  For distribution to IRB/EC, see Section 11.3.
If a protocol amendment requires a change to a site’s ICF, AstraZeneca (or its representative) 
and the site’s IRB/EC are to approve the revised ICF before the revised form is used. 
If required by local regulations, any administrative change will be communicated to or 
approved by each IRB/EC.
11.6
Audits and inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an IRB/EC may perform 
audits or inspections at the study site, 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, 
analyzed, and accurately reported according to the protocol, GCP, ICH guidelines, and any 
applicable regulatory requirements.  The investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the study site.


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12.
LIST OF REFERENCES 
Bonomi 2010
Bonomi PD. Implications of key trials in advanced non small cell lung cancer. Cancer 
2010;116:1155-64.
Collett 1994 
Collett D. Modelling survival data in medical research Chapman & Hall/CRC 1994
Cross et al 2014
Cross D, Ashton S, Ghiorghiu S, Eberlein C, Nebhan C, Spitzler P, Orme J, et al. AZD9291, 
an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung 
cancer. Cancer Discov. 2014;4:1046-61.
Engelman et al 2008
Engelman J, Jänne P. Mechanisms of acquired resistance to epidermal growth factor receptor 
tyrosine kinase inhibitors in non-small cell lung cancer. Clin. Cancer Res. 2008;14:2895–
2899.
Fukuoka et al 2011
Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, et al. 
Biomarker analyses and final overall survival results from a phase III, randomized, open-label, 
first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with 
advanced non-small-cell lung cancer in Asia (IPASS). J.Clin.Oncol. 2011 Jul 20;29(21):2866-
2874.
GLOBOCAN 2012
Globocan 2012. Lung cancer – the most common cancer in the world. Available from: 
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx.
Goldberg et al 2012
Goldberg SB, Supko JG, Neal JW, Muzikansky A, Digumarthy S, Fidias P, et al. A phase I 
study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer. 
J.Thorac.Oncol. 2012 Oct;7(10):1602-1608. 
Gridelli et al 2012
Gridelli C, Ciardiello F, Gallo C, Feld R, Butts C, Gebbia V, et al. First-line erlotinib followed 
by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: 
the TORCH randomized trial. J.Clin.Oncol. 2012 Aug 20;30(24):3002-3011.


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Janne et al 2014
Janne PA, Ramalingam SS, Yang JCH, Ahn MJ, Kim DW, Kim SW, et al. Clinical activity of 
the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor-resistant 
non-small cell lung cancer (NSCLC). J Clin Oncol 2014; 32:5s (Suppl; abstr 8009).
Katakami et al 2013
Katakami N, Atagi S, Goto K, et al.  LUX-Lung 4: A Phase II Trial of Afatinib in Patients 
With Advanced Non-Small Cell Lung Cancer Who Progressed During Prior Treatment With 
Erlotinib, Gefitinib, or Both.  Journal of Clinical Oncology 2013; 31(27): 3335 – 3342.
Kobayashi et al 2005
Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, et al. EGFR 
mutation and resistance of non-small-cell lung cancer to gefitinib. N.Engl.J.Med. 2005 Feb 
24;352(8):786-792.
Langer et al 2012
Langer CJ, Mok T, Postmus PE. Targeted agents in the third-/fourth-line treatment of patients 
with advanced (stage III/IV) non-small cell lung cancer (NSCLC).  Cancer Treatment 
Reviews 2012.  Http://dx.doi.org/10.1016/j.ctrv.2012.05.003.
Lee et al 2013
Lee JC, Jang SH, Lee KY & Kim Y.  Treatment of non small cell lung carcinoma after failure 
of epidermal growth factor receptor tyrosine kinase inhibitor.  Cancer Res Treat. 2013; 45(2): 
79 -85.
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 
24;362(25):2380-2388.
Miller et al 2012
Miller VA, Hirsh V, Cadranel J, et al.  Afatinib versus placebo for patients with advanced, 
metastatic non-small-cell lung cancer after failure of erlotinib, gefi tinib, or both, and one or 
two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial.  Lancet Oncol. 
2012; 13: 528-538.
Mok et al 2009a
Mok TS, Wu YL, Thongprasert S, et al. (2009) Gefitinib or carboplatin-paclitaxel in 
pulmonary adenocarcinoma. N Engl J Med 361:947–957.
Mok et al 2009b
Mok T, Wu Y, Zhang L. A small step towards personalized medicine for non-small cell lung 
cancer. Discov Med. 2009;8:227-31.


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Nguyen et al 2009
Nguyen KS, Kobayashi S, Costa DB. Acquired resistance to epidermal growth factor receptor 
tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth 
factor receptor pathway. Clin Lung Cancer 2009;10:281–9.
Pao et al 2005
Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. Acquired resistance 
of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the 
EGFR kinase domain. PloS Med 2005, 2(3):e73.
Ranson et al
Ranson M., Pao W., Kim D.W., Kim S.W., Ohe Y., Felip E., et al. Preliminary results from a 
Phase I study with AZD9291: An irreversible inhibitor of epidermal growth factor receptor 
(EGFR) activating and resistance mutations in non-small cell lung cancer (NSCLC). Eur. J. 
Cancer 2013 Sep: Vol 49, Supplement 3: LBA 33.
Rosell et al 2012
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, 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;13:239-246.
Wang et al 2012
Wang M, Zhao J, Zhang LM, Li H, Yu JP, Ren XB, et al. Combined Erlotinib and Cetuximab 
overcome the acquired resistance to epidermal growth factor receptors tyrosine kinase 
inhibitor in non-small-cell lung cancer. J.Cancer Res.Clin.Oncol. 2012 Dec;138(12):2069-
2077.
Watanabe et al 2011
Watanabe S, Tanaka J, Ota T, Kondo R, Tanaka H, Kagamu H, et al. Clinical responses to 
EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who 
benefited from prior effective gefitinib therapy: a retrospective analysis. BMC Cancer 2011 
Jan 1;11:1-2407-11-1.
Wu et al 2010
Wu JY, Wu SG, Yang CH, Chang YL, Chang YC, Hsu YC, et al. Comparison of gefitinib and 
erlotinib in advanced NSCLC and the effect of EGFR mutations. Lung Cancer 2011 
May;72(2):205-212.
Yang et al 2014
Yang J-C, Kim D, Planchard D, Ohe Y, Ramalingam SS, Ahn M, Kim S, Su W, Horn L, 
Haggstrom D, Felip E, Kim J, Frewer P, Cantarini M, Ghiorghiu S, Ranson M, Janne 
PA.Updated safety and efficacy from a Phase l study of AZD9291 in patients (pts) with 
EGFR-TKI- resistant non-small cell lung cancer (NSCLC). Ann Oncol 2014; 25(Suppl 4): 
iv149, abs 449PD.


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Yu et al 2013 
Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor 
specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with 
EGFR-mutant lung cancers. Clin.Cancer Res. 2013 Apr 15;19(8):2240-2247.


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Study Code D5160C00022
Version 3
Date 20 October 2016
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Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation
Development of drug dependency or drug abuse
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.


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
Time Course. Exposure to suspect drug.  Has the subject actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug?

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?

No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.

Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.


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Appendix B
Guidance regarding Potential Interactions with Concomitant 
Medications
The use of any natural/herbal products or other “folk remedies” should be discouraged, but 
use of these products, as well as use of all vitamins, nutritional supplements, and all other 
relevant concomitant medications must be recorded in the eCRF.
Drugs inducing cyp3a4 metabolism that AstraZeneca strongly recommend are not 
combined with azd9291
AZD9291 is metabolised by CYP3A4 and CYP3A5 enzymes.
A drug-drug interaction study of AZD9291 evaluated in patients showed that there is potential 
for AZD9291 being a victim when co-administered with strong inducers of CYP3A4 
(AZD9291 concentrations are decreased when co-dosed with rifampicin).
The following potent inducers of CYP3A4 must not be used during this study for any patient 
receiving AZD9291.
Table 6
Drugs inducing CYP3A4
Contraindicated drugs
Withdrawal period prior to AZD9291 start
Carbamazepine, phenobarbital, phenytoin, 
rifampicin, rifabutin, rifapentin
St John’s Wort
3 weeks
Phenobarbitone
5 weeks
This list is not intended to be exhaustive, and a similar restriction will apply to other agents 
that are known to strongly modulate CYP3A4 activity.  Appropriate medical judgment is 
required.  Please contact AstraZeneca with any queries you have on this issue.
Medicines whose exposures may be affected by azd9291 that AstraZeneca considers may 
be allowed with caution
AZD9291 may increase the concentration of sensitive BCRP substrates (concentration of the 
sensitive BCRP substrate, rosuvastatin, is increased).
Table 7
Exposure, pharmacological action and toxicity may be increased by AZD9291
Warning of possible interaction
Advice
Rosuvastatin
Drugs are permitted but caution should be 
exercised and patients monitored closely for 
possible drug interactions.  Please refer to full 
prescribing information for all drugs prior to co-
administration with AZD9291.
Sulfasalazine
Doxorubicin
Daunorubicin
Topotecan


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Drugs that may prolong qt interval
The drugs listed in this section are taken from information provided by The Arizona Center 
for Education and Research on Therapeutics and The Critical Path Institute, Tucson, Arizona 
and Rockville, Maryland. Ref:  http://www.arizonacert.org/medical-pros/drug-
lists/drug-lists.htm.
Drugs known to prolong QT interval
The following drugs are known to prolong QT interval or induce Torsades de Pointes and 
should not be combined with AZD9291.  Recommended withdrawal periods following 
cessation of treatment with these agents are provided in the table.
Table 8
Drugs prolonging QT interval
Contraindicated drug
Withdrawal period prior to AZD9291 start
Clarithromycin, droperidol, erythromycin, 
procainamide
2 days
Cisapride, disopyramide, dofetilide, domperidone, 
ibutilide, quinidine, sotalol, sparfloxacin, 
thioridazine
7 days
Bepridil, chlorpromazine, halofantrine, 
haloperidol, mesoridazine
14 days
Levomethadyl, methadone, pimozide
4 weeks
Arsenic trioxide
6 weeks*
Pentamidine
8 weeks
Amiodarone, chloroquine
1 year
*
Estimated value as pharmacokinetics of arsenic trioxide has not been studied
Drugs that may possibly prolong QT interval
The use of the following drugs is permitted (notwithstanding other exclusions and restrictions) 
provided the patient has been stable on therapy for the periods indicated.
Table 9
Drugs that may prolong QT interval
Drug
Minimum treatment period on medication 
prior to AZD9291 start
Alfuzosin, chloral hydrate, ciprofloxacin, 
dolasetron, foscarnet, galantamine, gemifloxacin, 
isridipine, ketoconazole, levofloxacin, mexiletine, 
nicardipine, octreotide, ofloxacin, ondansetron, 
quetiapine, ranolazine, telithromycin, tizanidine, 
vardenafil, venlafaxine, ziprasidone
2 days


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Table 9
Drugs that may prolong QT interval
Drug
Minimum treatment period on medication 
prior to AZD9291 start
Amantadine, amitriptyline, amoxapine, clozapine, 
doxepin, felbamate, flecainide, fluconazole, 
fosphenytoin, gatifloxacin, granisetron, 
imipramine, indapamide, lithium, 
moexipril/HCTZ, moxifloxacin, risperidone, 
roxithromycin, sertraline, trimethoprin-sulfa, 
trimipramine, voriconazole
7 days
Azithromycin, citalopram, clomipramine, 
itraconazole, nortriptyline, paroxetine, 
solifenacin, tacrolimus
14 days
Fluoxetine 
5 weeks
Protriptyline
6 weeks
Tamoxifen
8 weeks
.


Clinical Study Protocol Appendix C
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Study Code D5160C00022
Version 3
Date 20 October 2016
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Appendix C
Actions Required in Cases of Combined Increase of 
Aminotransferase and Total Bilirubin - Hy’s Law
Introduction
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
Definitions
Potential Hy’s Law (PHL)
A Potential Hy’s Law (PHL) case is defined as a study subject with an increase in serum 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN)  together with Total Bilirubin (TBL) ≥ 2xULN irrespective of serum Alkaline 
Phosphatase (ALP), at any point during the study following the start of study medication.
Hy’s Law (HL)
A Hy’s Law (HL) case is defined as a study subject with an increase in serum AST or ALT 
≥3x ULN together with TBL ≥ 2xULN, where no other reason can be found to explain the 
combination of increases, eg, elevated serum ALP indicating cholestasis, viral hepatitis, 
another drug.
For PHL and HL to be met the elevation in transaminases must precede or be coincident with 
(ie, on the same day) the elevation in TBL, but there is no specified timeframe within which 
the elevations in transaminases and TBL must occur.
Identification of potential Hy’s law cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3xULN

AST ≥ 3xULN

TBL ≥ 2xULN.


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Version 3
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The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Determine whether the patient meets PHL criteria (see definition within this 
Appendix for definition) by reviewing laboratory reports from all previous visits
Follow-up
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
treatment in the presence of liver metastases 

Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will:

Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 

Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician

If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures
Review and Assessment of potential Hy’s law cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP.  The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.


Clinical Study Protocol Appendix C
Drug Substance AZD9291
Study Code D5160C00022
Version 3
Date 20 October 2016
55 (63)
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF

If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:

Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above

Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met.  Update the SAE report according to the 
outcome of the review.
Actions required when potential Hy’s law criteria are met before and after starting 
study treatment 
This section is applicable to patients who meet PHL criteria on study treatment (including the 
30 day follow-up period post discontinuation of study treatment) having previously met PHL 
criteria at a study visit prior to starting study treatment. 
At the first on study treatment occurrence of PHL criteria being met the Investigator will:

Determine if there has been a significant change in the patients’ condition compared 
with the last visit where PHL criteria were met

If there is no significant change no action is required


Clinical Study Protocol Appendix C
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Study Code D5160C00022
Version 3
Date 20 October 2016
56 (63)

If there is a significant change notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Potential Hy’s law criteria met of this Appendix.
A ‘significant’ change in the patient’s condition refers to a subsequent clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in 
isolation or in combination, or a clinically relevant change in associated symptoms such as 
fatigue, vomiting, rash, right upper quadrant pain, jaundice, eosinophilia.  The determination 
of whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.
Actions required for repeat episodes of potential Hy’s law
This section is applicable when a patient meets PHL criteria on study treatment (including the 
30-day follow-up period) and has already met PHL criteria at a previous on study treatment 
visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.  
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:

Was the alternative cause for the previous occurrence of PHL criteria being met 
chronic or progressing malignant disease or did the patient meet PHL criteria prior 
to starting study treatment and at their first on study treatment visit as described in 
Actions Required When Potential Hy’s Law Criteria are Met Before and After 
Starting the Study.
If No: Follow the process described in Potential Hy’s Law Criteria Met of this Appendix.
If Yes: Determine if there has been a significant change in the patient’s condition compared 
with when PHL criteria were previously met

If there is no significant change no action is required

If there is a significant change follow the process described in Potential Hy’s Law 
Criteria Met of this Appendix.
A ‘significant’ change in the patient’s condition refers to a subsequent clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in 
isolation or in combination, or a clinically relevant change in associated symptoms, such as 
fatigue, vomiting, rash, right upper quadrant pain, jaundice, eosinophilia.  The determination 
of whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.


Clinical Study Protocol Appendix C
Drug Substance AZD9291
Study Code D5160C00022
Version 3
Date 20 October 2016
57 (63)
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf 


Clinical Study Protocol Appendix C
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Study Code D5160C00022
Version 3
Date 20 October 2016
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VERSION HISTORY
Version 3.0, 20 October 2016
May be applicable for sites in Austria, Italy, Spain, Argentina, Brazil, Canada, Taiwan 
and China.
Changes to the protocol are summarised below.
Table 4 (footnote c) was amended: 
A 30 day post last dose follow up contact (visit or by telephone) should be made with the 
subject to collect new SAEs and AESI and to follow up on any ongoing SAEs and AESI-
to clarify the type of contact.
Section 5 Study Measures: was modified to introduce the collection of imaging assessments 
(CT scans or MRI) from baseline and following visits from a subset of patients where a 
T790M positive mutation was identified via the cobas® EGFR Mutation Test performed on a 
plasma or tissue specimen. 
 
The collection of imaging assessments (CT scans or MRI) from baseline and following visits 
has also been added for patients where a T790M positive mutation was identified via other 
molecular testing methods. - was also added.
Central reading of imaging assessments was added in section 5
All imaging assessments from a selected subset of patients (where available and Informed 
Consent is obtained), including unscheduled visit scans, should be collected and sent to an 
AstraZeneca appointed Clinical Research Organisation to enable independent central analyses. 
The central imaging review is required only for this selected subset of patients where a 
selected T790M positive mutation test was performed on a plasma or tissue specimen.  The 
baseline scan should ideally be performed within 28 days of the start of treatment.  The results 
of this independent review will not be communicated to investigators.  The purpose of this 
review is to assess tumour response according to RECIST 1.1 in order to evaluate the 
objective response rate in these subsets of patients with various methods of T790M molecular 
testing.  
Further details will be provided in the Statistical Analysis Plan.
Section 6.4 Overdose was modified to be in line with the AstraZeneca protocol template and 
SOP.
There is no definition of what constitutes an overdose.  In the Phase I study, 355 patients with 
advanced NSCLC were administered AZD9291 at single and multiple oral doses ranging from 
CCI


Clinical Study Protocol Appendix C
Drug Substance AZD9291
Study Code D5160C00022
Version 3
Date 20 October 2016
59 (63)
20 mg to 240 mg daily (as of data cut-off date 02 December 2014).  All doses were well 
tolerated.  Experiences of excessive doses (i.e. in excess of the optimal 80 mg indicated dose) 
in this study did not show any DLTs or acute toxicities.
There is no known antidote.  Investigators are advised that any patient, who receives a higher 
dose than intended should be monitored closely, managed with appropriate supportive care, 
and followed up expectantly.
Such overdose must be recorded in the CRF if the overdose is associated with an SAE.  
Section 11.4 Informed consent was modified and the following paragraph was added:
Ensure that the Addendum to the ICF is signed and dated for the subset of patients tested for a 
T790M positive mutation via the cobas® EGFR Mutation Test (or any other molecular testing 
methods if relevant) before any imaging assessments are collected.
Version 2.0, 23 June 2016
Is applicable to all participating countries.
Changes to the protocol are summarised below.
Section of protocol affected:
In PROTOCOL SYNOPSIS-
Study site(s) and number of patients planned.
The number of patients enrolled is reduced in Europe (from 1500 to 600) due to lower 
enrolment than initially planned. The total number of patients is more defined and with the 
participation of China, the total number of patients expected would be approximately 3500 by 
the time the study ends in Q4 2020.
Duration of IP administration
Removal of the patient registry after national reimbursement. This means that the data 
collection for ASTRIS stops at the last patient last visit.
Statistical methods
Addition of the Time to Treatment Discontinuation (TTD) in the secondary endpoints.
In the body of the protocol:
2. Study Objective
Clarification of primary and secondary objectives: The primary efficacy outcome is OS, 


Clinical Study Protocol Appendix C
Drug Substance AZD9291
Study Code D5160C00022
Version 3
Date 20 October 2016
60 (63)
with secondary efficacy outcomes including investigator assessed response rate, 
investigator assessed PFS and Time to Treatment Discontinuation (TTD).
3.2
Exclusion criteria
Clarification of exclusion criteria # 3 (with *)
Any evidence of severe or uncontrolled systemic diseases, including uncontrolled 
hypertension, active bleeding diatheses, active infection* including hepatitis B, hepatitis C 
and human immunodeficiency virus, or significantly impaired bone marrow reserve or organ 
function, including hepatic and renal impairment, which in the investigator’s opinion would 
significantly alter the risk/benefit balance. 
* active infection will include any patients receiving intravenous treatment for any 
infection and patients with hepatitis B or C surface antigen (+) – Patients receiving oral 
antiviral suppressive therapy for hepatitis B or C will be permitted to enrol in the study
Table 4
study plan
Addition in footnote (e): For subjects withdrawn from treatment but who had not progressed 
at the time of AZD9291 discontinuation. Follow up to be performed every 6 weeks (± 1 
week) relative to the date of enrolment until end of study (including survival follow-up 
period).
Addition of footnote (g) Survival status to be performed every 6 weeks (± 1 week) relative 
to the date of enrolment until end of study
Section 4.1 modified
In 3) Laboratory results for T790M meeting still needs to be available at the site but is not 
faxed anymore with the enrolment form. This is in order to avoid confidentiality issue.
Addition of: Consenting patients who do not fulfil the eligibility criteria must not be 
enrolled (dosed) into the study and will be discontinued. They will be considered 
screening failures and only demography data, reason for discontinuation will be 
recorded.  Supporting safety information can be collected in case of SAE, if applicable.
Section 4.2 modified
In 3) Removal of the restriction on CYP3A4 inhibitors as Study 12 has shown that CYP3A4 
inhibitors have no effect on AZD9291.
Section 4.3 modified
Addition of QTc interval prolongation with signs/symptoms of serious arrhythmia as a 
criteria for discontinuation to be aligned with AstraZeneca Project Specific Safety 


Clinical Study Protocol Appendix C
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Study Code D5160C00022
Version 3
Date 20 October 2016
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Requirements.
Section 4.3.1 modified
Addition: Patients may continue study treatment beyond disease progression if they are 
still receiving clinical benefit, as judged by the Investigator, and in the absence of any 
other discontinuation criteria.
Section 4.4: modified
Removal of the patient registry after national reimbursement. This means that the data 
collection for ASTRIS stops at the last patient last visit.
Section 5 modified
Disease characteristics / Disease assessment: Addition of the collection of information at entry 
and at progression, about leptomeningeal /brain metastases in the CRF. This was missed 
from the beginning.
Survival status: For patients entering in the registry, the date of death in the follow-up period 
will be used to evaluate OS.
Section 6.7   Study governance and oversight added
An Executive Steering Committee will be set up. It will involve 7 experts with the 
relevant knowledge and experience required for the study. This Executive Committee 
will have the executive oversight and supervision of the study. It will also be involved in 
the publication strategy of the study.
Section 7.2 modified
Publication or presentation of data subsets from individual institutions, regions or countries 
participating in this global multicentre studies may must not precede the primary manuscript 
with the approval of the AZ global study team.  , and when developed must always reference 
the primary publication of the entire study. The AZ global study team will determine if in 
certain instances publication of institution, regional or country-specific data by the 
participating country may precede the primary global publication.
Following a recommendation from the Executive Steering Committee.
Section 9.2 modified
Addition of the definition for Response Rate (RR): RR is defined as the percentage of 
patients with a best response of ‘responding’ by investigator assessment as recorded in 
the CRF.
Addition of Time to treatment discontinuation (TTD): 
TTD is defined as the time from the date of first dose of AZD9291 in this study until the 


Clinical Study Protocol Appendix C
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Study Code D5160C00022
Version 3
Date 20 October 2016
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date of AZD9291 discontinuation for any reason including disease progression, 
treatment toxicity, death or other reason as recorded in CRF. Subjects who are still on 
treatment at the time of analysis will be censored at the date of last dose received.
Following a recommendation from the Executive Steering Committee.
Section 9.4.2 modified
PFS and TTD will be summarized similarly to OS using KM estimates of the median times to 
progression or death, treatment discontinuation and quartiles together with their 95% CIs. 
KM estimates of the PFS or TTD rate at appropriate time points (to be defined in SAP) will 
be presented as well. A plot of the KM PFS and TTD curve will be produced.
The response rate will be summarised together with the 95% CI.
Section 9.4.4   Interim analysis added
Interim analysis of the global data will take place annually for the first three years (i.e. 
at approximately 12, 24 and 36 months from the start of recruitment) to provide annual 
updates of key study measures as specified in the SAP. Regional and country level 
analysis may also be performed at these time points if deemed appropriate.
The final analysis will take place approximately 5 years after the start of recruitment, 
depending on the date of actual global study closure.
Section 9.5 modified
The table illustrating the precision for OS was adapted with a revised patient’s distribution 
and increased study length based on the Collett formula.
Section 11.5 modified
In case of amendment to a protocol, only a revised protocol is prepared to be approved by the 
relevant IRB/EC. To comply with change in AstraZeneca SOP.
Version 1.0, 30 June 2015
Is applicable to all participating countries. Refer to the Protocol Amendment 1 for 
details.
Changes to the protocol are summarised below.
Section of protocol synopsis - Study site(s) and number of patients planned- was modified 
to include America and Asia.


Clinical Study Protocol Appendix C
Drug Substance AZD9291
Study Code D5160C00022
Version 3
Date 20 October 2016
63 (63)
Section of protocol synopsis- Duration of IP administration and Section 10.2.4 Timetable 
and End of Study were modified to add a clause about study termination in each country.  
Section of protocol synopsis - Statistical methods was amended to provide a more detailed 
and robust description of the statistical evaluations. 
Section of protocol affected: Study Plan (Table 4) was amended to provide a more detailed 
study plan in line with the CRF as well as more details about the enrolment process and 
clarification about the T790M testing and what will happen to the samples if a central 
laboratory is used.
Section of protocol affected: 4.2 Restrictions was amended to provide clarity in male
patients contraception.
Section 4.3 Discontinuation from study: a new paragraph ‘4.3.1 Procedures for 
discontinuation of a subject from study treatment’ was added to provide details about 
procedures for discontinuation from study treatment.
Section 4.4 Patient Withdrawal or Study Termination was amended to provide details 
about what will happen in case of study withdrawal and for the follow-up of overall survival.
Section 5.Study Measures was amended to provide a more detailed list of study measures 
collection in line with the CRF.
Section 6. Safety reporting and medical management was amended to provide clarity about 
SAE reporting timeframes and add instructions about follow-up of unresolved adverse events.
Section 6.6.2  QTc Prolongation (using Fredericia’s formula –QTcF–) was amended to be 
aligned with the AZD9291 Core Data Sheet:
Section 8.1 Identity and dose of investigational product – AZD9291 was modified to be 
aligned with the AZD9291 Core Data Sheet
Section 9 Statistical Analyses was rewritten to provide a more robust description of the 
statistical evaluations and sample size determination.
Original Version 22 April 2015


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Document ID: 
                                                                                   
 
Version Label: 
 
                  
 
 
 
 
 
 
 
     
            
                                          
              
 
Server Date 
(dd-MMM-yyyy HH:mm ‘GMT’Z) 
Signed By 
Meaning of Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.  
d5160c00022-csp-v2
D5160C00022 Clinical Study Protocol version 2
3.0
Approved
CURRENT
LATEST
26-Oct-2016 15:40 GMT+0100
Quality Control Approval
CCI
PPD

SAP_001.pdf: 
Protocol: D5160C00022 
Confidential - Proprietary Information 

Protocol number: D5160C00022 

Document title: Open Label, Multinational, Multicenter, Real World 
Treatment Study of Single Agent AZD9291 for Patients with 
Advanced/Metastatic Epidermal Growth Factor Receptor (EGFR) T790M 
Mutation-Positive Non-Small Cell Lung Cancer (NSCLC) Who Have 
Received Prior Therapy with an EGFR Tyrosine Kinase Inhibitor (EGFR-
TKI). 

Version numbers: SAP Version 7.0 

Date of the documents: 12 Dec 2019 

NCT number: NCT02474355 


Statistical Analysis Plan  
Study code D5160C00022 
Version 7.0 
Date 12 Dec 2019 
1
Real World Treatment Study – Statistical Analysis 
Plan (for the final analysis) 
Drug Substance 
AZD9291
Study Code 
D5160C00022 
Version Number 
7.0 
Date 
12 Dec 2019 
Open Label, Multinational, Multicenter, Real World Treatment Study of Single 
Agent AZD9291 for Patients with Advanced/Metastatic Epidermal Growth 
Factor Receptor (EGFR) T790M Mutation-Positive Non-Small Cell Lung 
Cancer (NSCLC) Who Have Received Prior Therapy with an EGFR Tyrosine 
Kinase Inhibitor (EGFR-TKI)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden


Statistical Analysis Plan  
Study code D5160C00022 
Version 7.0 
Date 12 Dec 2019 
2
SIGNATURE PAGE 
Open Label, Multinational, Multicenter, Real World Treatment Study of Single 
Agent AZD9291 for Patients with Advanced/Metastatic Epidermal Growth 
Factor Receptor (EGFR) T790M Mutation-Positive Non-Small Cell Lung 
Cancer (NSCLC) Who Have Received Prior Therapy with an EGFR Tyrosine 
Kinase Inhibitor (EGFR-TKI)
Global Product Statistician  
  
Date 
PPD


Statistical Analysis Plan  
Study code D5160C00022 
Version 7.0 
Date 12 Dec 2019 
3
SIGNATURE PAGE 
Open Label, Multinational, Multicenter, Real World Treatment Study of Single 
Agent AZD9291 for Patients with Advanced/Metastatic Epidermal Growth 
Factor Receptor (EGFR) T790M Mutation-Positive Non-Small Cell Lung 
Cancer (NSCLC) Who Have Received Prior Therapy with an EGFR Tyrosine 
Kinase Inhibitor (EGFR-TKI)
Study Statistician     
 
Date 
PPD


Statistical Analysis Plan  
Study code D5160C00022 
Version 7.0 
Date 12 Dec 2019 
4
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................ 1
SIGNATURE PAGE ................................................................................................................ 2
TITLE PAGE ............................................................................................................................ 2
SIGNATURE PAGE ................................................................................................................ 3
TITLE PAGE ............................................................................................................................ 3
TABLE OF CONTENTS ......................................................................................................... 4
LIST OF ABBREVIATIONS .................................................................................................. 6
1
STUDY DETAILS ................................................................................................... 8
1.1
Study Objectives ...................................................................................................... 8
1.2
Study Design ............................................................................................................ 8
1.3
Number of Patients .................................................................................................. 8
2
ANALYSIS SETS ................................................................................................... 9
2.1
Definition of analysis set ......................................................................................... 9
2.2
Violations and deviations ......................................................................................... 9
3
PRIMARY AND SECONDARY VARIABLES ................................................... 10
3.1
Efficacy .................................................................................................................. 10
3.1.1
Overall Survival (OS) ............................................................................................ 10
3.1.2
Progression Free Survival (PFS) ............................................................................ 10
3.1.3
Time to Treatment Discontinuation or Death (TTD) ............................................. 11
3.1.4
Response Rate (RR) ............................................................................................... 11
3.2
Safety ..................................................................................................................... 11
3.2.1
SAEs ...................................................................................................................... 11
3.2.2
AESIs ..................................................................................................................... 12
3.2.3
Hy’s Law ................................................................................................................ 12
3.2.4
Duration of exposure .............................................................................................. 12
3.2.5
Treatment Compliance ........................................................................................... 12
4
ANALYSIS METHODS ....................................................................................... 12
4.1
General principles .................................................................................................. 12
4.1.1
Handling missing data ............................................................................................ 13
4.2
Analysis Methods ................................................................................................... 13
4.2.1
Patient disposition .................................................................................................. 13
4.2.2
Protocol Deviations ................................................................................................ 14
4.2.3
Demographics and other baseline characteristics .................................................. 14
4.2.4
Medical History ..................................................................................................... 15
4.2.5
Concomitant Medication / Treatment .................................................................... 16


Statistical Analysis Plan  
Study code D5160C00022 
Version 7.0 
Date 12 Dec 2019 
5
4.2.6
Exposure and Compliance to AZD9291 ................................................................ 16
4.2.7
Efficacy .................................................................................................................. 16
4.2.8
Safety ..................................................................................................................... 20
4.2.9
Laboratory evaluations ........................................................................................... 21
4.2.10
ECG ........................................................................................................................ 21
4.2.11
Weight .................................................................................................................... 22
4.2.12
WHO performance status ....................................................................................... 22
4.2.13
Slit Lamp Test) ...................................................................................................... 22
5
INTERIM ANALYSES ......................................................................................... 22
5.1
 ........... 22
5.1.1
 ........................................................... 23
5.1.2
 ...................................................... 23
5.2
....... 24
6
CHANGES OF ANALYSIS FROM PROTOCOL ............................................... 24
7
COUNTRY SPECIFIC ANALYSES .................................................................... 24
8
REFERENCES ...................................................................................................... 25
9
APPENDICES ....................................................................................................... 26
CCI
CCI
CCI
CCI


Statistical Analysis Plan  
Study code D5160C00022 
Version 7.0 
Date 12 Dec 2019 
6
LIST OF ABBREVIATIONS  
Abbreviation or 
special term 
Explanation 
AE 
Adverse Event   
AESI 
Adverse Event of Special Interest 
BCR 
Best Clinical Response 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CT 
Computer Tomography 
CTCAE 
National Cancer Institute Common Terminology Criteria for AEs 
ECG 
Electocardiogram 
EGFR 
Epidermal Growth Factor Receptor 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose -Positron Emission Tomography 
ICH-GCP 
International Conference on Harmonisation - Good Clinical Practice 
ILD 
Interstitial Lung Disease 
IVRS/IWRS 
Interactive Voice Response System/ Interactive Web Response System 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PT 
Preferred Term 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PFS 
Progression Free Survival 
QTc 
The QT interval corrected for heart rate 


Statistical Analysis Plan  
Study code D5160C00022 
Version 7.0 
Date 12 Dec 2019 
7
Abbreviation or 
special term 
Explanation 
QTcF 
QT interval corrected per Fredericia’s formula 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RR 
Response Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS
A commercially available integrated system of software products, 
commonly used for reporting and analysis of Clinical Studies 
SOC 
System Organ Class 
TKI 
Tyrosine Kinase Inhibitor 
TTD 
Time to Treatment Discontinuation 
WHO 
World Health Organization 


Statistical Analysis Plan  
Study code D5160C00022 
Version 7.0 
Date 12 Dec 2019 
8
1
STUDY DETAILS 
1.1 Study Objectives 
The primary objective of this study is to assess the efficacy and safety of single agent 
AZD9291 in a real world setting in adult patients with advanced or metastatic, epidermal 
growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer 
(NSCLC), who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy. 
1.2 Study Design 
This is an open-label, single-arm, multinational, multicenter, real world treatment study. The 
target patient population is adult patients (fulfilling the definition of “age of majority” per 
local regulations) with locally advanced (stage IIIB) or metastatic (stage IV) NSCLC with a 
confirmed T790M mutation, who have received prior EGFR-TKI therapy.
1.3 Number of Patients 
Overall Survival (OS) is the primary efficacy endpoint for this study. Median OS is assumed 
to be approximately 21-25 months in patients with advanced or metastatic EGFR T790M 
mutation-positive NSCLC who have received prior therapy with an EGFR-TKI and are 
receiving treatment with AZD9291. While the sample size is not known a priori illustrations 
of the precision with which OS could be calculated from this real world study are given in the 
table below. These illustrations assume a study length of 58 months with non-uniform accrual 
over 40 months and that OS is exponentially distributed. 
N 
21 Months OS 
23 Months OS 
25 Months OS 
n 
events 
95% CI 
median OS*
n 
events 
95% CI 
median OS*
n 
events 
95% CI 
median OS* 
500 
313 
18.8-23.5 
297 
20.5-25.8 
283 
22.3-28.1 
1000 
627 
19.4-22.7 
595 
21.2-24.9 
566 
23.0-27.1 
1500 
941 
19.7-22.4 
893 
21.5-24.6 
800 
23.3-26.8 
2000 
1255 
19.9-22.2 
1191 
21.7-24.3 
1133 
23.6-26.5 
3000 
1883 
20.1-22.0 
1787 
22.0-24.1 
1700 
23.8-26.2 
3500 
2197 
20.1-21.9 
2085 
22.0-24.0 
1983 
23.9-26.1 
*95% CI is based on the formula in Collet 1994 (Collett, 1994) 
Therefore if 3500 patients enter the study globally and the median OS is 25 months the 95% 
confidence interval (CI) around this survival figure would be approximately 23.9-26.1 
months, assuming 1983 OS events (57% maturity). For Europe, assuming recruitment of 1000 
patients and 566 OS events, the equivalent 95% CI would be approximately 23.0-27.1 months. 


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2
ANALYSIS SETS 
As this is a real world study investigating the efficacy and safety of AZD9291, all analyses 
will be performed on the full analysis set, unless otherwise indicated.   
2.1 Definition of analysis set 
Full Analysis Set (FAS) 
The full analysis set will include all patients who received at least one dose of study treatment 
(i.e. with at least one start date in the Administration of the Study drug page in the CRF). 
2.2 Violations and deviations 
All major deviations related to the study inclusion or exclusion criteria and study conduct will 
be listed and summarised. 
The following general categories will be considered major deviations. This list is not 
exhaustive and additional important deviations may be added prior to database lock. 

Informed consent procedure deviation Missing subject’ signature from the informed 
consent document or other International Conference on Harmonisation - Good Clinical 
Practice (ICH-GCP) violation related to informed consent; laboratory or urinalysis 
samples or electocardiogram (ECG) date before informed consent date and not 
performed per standard of care but on study purpose) 

Eligibility criteria deviation (any inclusion criteria not met or exclusion criteria met) 

Prohibited medication deviation (e.g., patients received other anticancer agents, 
investigational agents, or radiotherapy while on study treatment) 

Procedures/Tests deviation (ECG or ophtalmologic assessment or WHO performance 
status not performed at screening visit) 

Investigational product administration deviation (Overdose; Screening assessment date 
not within 28 days before start of treatment; Incorrect procedure for T790M 
obtainment; New or worsening pulmonary symptoms or radiological abnormality 
suggestive of Interstitial Lung Disease (ILD) observed, but study treatment not 
interrupted; Patient experiencing grade 3 QT interval corrected per Fredericia’s 
formula (QTcF) with QTcF prolongation, but study treatment not interrupted) 

Withdrawal criteria deviation (Any withdrawal criteria met) 

Adverse Event (AE) / Serious Adverse Event (SAE) deviation (SAE / AE of special 
interest not reported in CRF within 24 hours of become aware) 
The categorization of these as major deviations is not automatic and will depend on the 
duration and the perceived effect on efficacy. 
All protocol deviations are defined in Protocol Deviation Specification document version 5.0 
where a category Programmable / Observable is assigned to each deviation. Programmable 
deviations are programmed while Observable are checked manually during monitoring visits. 
Programmable deviations are then imported, and observable deviations are entered in a 
Protocol Deviation Tool according to classification defined in the Protocol Deviation 


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Specification. All deviations are then reviewed and classified on a monthly basis as 
Major/Minor. 
A review of major protocol deviations will be performed during the data review meeting and 
prior to database lock, together with the lead medic, statistician and data manager.  
The major protocol deviations or violations assessed to have potential impact the efficacy and 
safety analyses will be summarised with the pre-specified categories (refer to Protocol 
Deviation Specification document version 5.0).  
If the number and severity of major protocol deviations which are considered to have the 
potential to impact the primary analysis during this review before Database lock, is considered 
important, sensitivity analyses may be performed. This will be decided during the data review 
meeting and before the database lock. 
3
PRIMARY AND SECONDARY VARIABLES 
3.1 Efficacy 
In this real world study tumor evaluation is per institutional standard of care, recommended to 
be at approximately 12 week intervals. The date of tumor assessment, method of evaluation 
(CT, MRI, X-ray, Ultrasound, Bone Scan, FDG-PET, Clinical examination) and the 
investigators opinion of the patient status (responding, stable disease, progressing) is captured 
in the tumor evaluation CRF.  
3.1.1
Overall Survival (OS) 
The follow-up for the patients’ survival status is to be performed every 6 weeks (± 1 week) 
relative to the date of enrolment until end of study. 
Overall survival is defined as the time from the date of first dose of AZD9291 in this study 
until the date of death due to any cause (i.e. date of death or censoring – date of first dose of 
AZD9291 in this study + 1). Any patient alive at study discontinuation will be censored at 
thestudy discontinuation date. 
3.1.2
Progression Free Survival (PFS) 
Progression Free Survival is defined as the time from the date of first dose of AZD9291 in this 
study until the date the disease is considered by the investigator to be progressing (as recorded 
in the tumour evaluation CRF and irrespective of the method of evaluation) or the date of 
death (by any cause in the absence of progression) regardless of whether the patient withdraws 
from therapy or receives another anti-cancer therapy prior to progression (i.e. date of disease 
progression or death – date of first dose of AZD9291 in this study + 1). Patients who have not 
progressed or died at study discontinuation will be censored at the time of the latest date of 
disease assessment. Patients with no post baseline disease assessment will be censored at 
Day 1.


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The PFS time will always be derived based on the date of tumour assessment or death and not 
visit dates. 
3.1.3
Time to Treatment Discontinuation or Death (TTD) 
As a supportive summary to PFS, time to treatment discontinuation or death will be assessed 
and is defined as the time from the date of the first dose of AZD9291 in the study until the 
date of AZD9291 discontinuation (as recorded on the discontinuation of study drug CRF) or 
death, regardless of the reason for discontinuation (disease progression, treatment toxicity or 
other reason as recorded in the CRF). This will be calculated as: date of AZD9291 
discontinuation or death – date of first dose of AZD9291 + 1. Patients who transitioned to 
commercial supply will be censored at the date of discontinuation of study treatment (date of 
their last dose of study treatment).  
3.1.4
Response Rate (RR) 
Response Rate is defined as the number (%) of patients with a best response (according to 
investigator assessment as recorded in the tumour evaluation CRF) of ‘responding’, regardless 
of the method of evaluation, and will be based on a subset of the FAS consisting of patients 
with at least one documented response assessment.  Data obtained up until progression, or last 
evaluable assessment in the absence of progression, will be included in the assessment of 
response rate. Patients who discontinue treatment without progression, receive a subsequent 
anti-cancer therapy and then respond will not be included as responders in the RR. 
In addition, a sensitivity analysis of RR will be performed including patients who died prior to 
any response assessment and classifying them as non-responders. 
3.2 Safety 
Specified safety endpoints (Serious Adverse Events (SAEs), Adverse Events (AEs) leading to 
dose modification, AEs of special interest (AESIs), Hy’s Law and deaths) are required to be 
included in the study database.
Other safety data, i.e. laboratory results (hematology, clinical chemistry and urinalysis), 
ECGs, and ophthalmologic assessments, are collected if performed as part of standard medical 
care but are not mandated in the protocol. 
3.2.1
SAEs 
SAEs will be collected throughout the study, from the date of first dose of AZD9291 until 30 
days after the last dose of study medication or until disease progression, whichever is the 
latest. The latest version of the Medical Dictionary for Regulatory Activities (MedDRA) will 
be used to code the SAEs. SAEs will be graded according to the National Cancer Institute 
Common Terminology Criteria for AEs (CTCAE Version 4.03). 


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3.2.2
AESIs 
The following AESIs will be collected and summarised: 

Interstitial lung disease/pneumonitis-like events,  

QTc prolongation events. 
3.2.3
Hy’s Law 
 Patients with potential Hy’s Law criteria will be collected and summarised. 
3.2.4
Duration of exposure 
Total Exposure to AZD9291 will be defined as the time (months) from the first dose to the last 
dose: 

Total exposure = (last dose date where dose > 0 mg – first dose date where dose > 
0 mg + 1)/30.4375 
Actual exposure to AZD9291 will be the time (months) from first dose to last dose, taking into 
account the number of days where no dose was taken. 

Actual exposure = (last dose date where dose > 0 mg – first dose date where dose > 0 
mg + 1 – total duration of dose interruption [i.e. number of days with dose = 0 mg]) 
/30.4375  
Note: the actual exposure calculation makes no adjustment for any dose reductions that may 
have occurred. 
3.2.5
Treatment Compliance 
Treatment compliance is defined as the number of administered doses of AZD9291 (80 mg 
and 40 mg pooled) taken as a proportion of the scheduled expected number of doses. 
4
ANALYSIS METHODS 
4.1 General principles 
The below mentioned general principles will be followed throughout the study: 

Descriptive statistics will be used for all variables, as appropriate. Continuous 
variables will be summarised by the number of observations (n), mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be summarised 
by frequency counts and percentages for each category. 

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 


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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 9.3 or higher will be used for all analyses. 

As the only population considered will be the FAS, all tables, listings and figures 
(demographics, efficacy, safety, etc.) will be provided using this population, unless 
indicated otherwise. 

For time interval analyses in months, duration in months will be calculated as total 
duration in days/30.4375 
4.1.1
Handling missing data 
In general, other than for partial dates, missing data will not be imputed and will be treated as 
missing. 
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 

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. 
4.2 Analysis Methods 
4.2.1
Patient disposition 
The total number of patients screened, enrolled and screen failed will be summarised. In 
addition, the number of patients in the FAS will also be provided. 
The number and percentage of patients who have discontinued treatment and the main reason 
for discontinuation, the number and percentage of patients who transitioned to commercial 


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drug, as well as the number and percentage of patients who have completed or withdrawn 
from the study and the main reason for completion or withdrawal will be also presented. 
4.2.2
Protocol Deviations 
All identified major protocol deviations will be listed and summarised for the FAS. All 
protocol deviations will be defined by the study team and identified and classified as major or 
minor before database lock. 
4.2.3
Demographics and other baseline characteristics 
Demographic and baseline patient characteristics defined as data prior to the first AZD9291 
dose (Demography, Receptor status, Lung cancer disease characteristics, Evaluation of 
brain/leptomeningeal metastases, which may be based on a scan taken within 28 days after the 
first dose (Please note: the delayed baseline assessment may introduce errors in the reported 
number of patients with brain/leptomeningeal metastases at baseline due to an early response 
to the treatment, or early progression in the site of brain/leptomeningeal.), Previous cancer 
therapy, Weight, WHO performance status, Electrocardiogram, Ophthalmologic assessment) 
will be summarised for the FAS. 
In addition, the number (%) of patients by country of enrolment and by race (Asian vs non-
Asian) will be summarised. 
For receptor status the number (%) of patients positive for T790M only, the number (%) of 
patients positive for T790M + 1 other mutation, the number (%) of patients positive for 
T790M + 2 other mutations, the number (%) of patients positive for T790M + 3 other 
mutations, the number (%) of patients positive for T790M + 4 other mutations and the number 
(%) of patients positive for T790M + 5 other mutations will be summarised. 
Specific mutation combinations will also be summarised. 
In addition, the following subgroups will be identified and number (%) for each subgroup will 
be summarised: 
-
T790M only  
-
Common mutations: 
T790M + Exon 19 Deletion only 
T790M +L858R only 
-
Uncommon/ Compound mutations: 
o
Uncommon mutation T790M + G719X only 
T790M + S768I only 
T790M + Exon 20 Insertion only 
o
Common compound mutations: 
T790M + 2 common mutations 
o
Uncommon compound mutations: 
T790M + 2 or more mutations including 
at least 1 uncommon mutation 
In this analysis patients classified as not detected or not done for a particular mutation will be 
regarded as not having the mutation.  
Receptor status will also be summarised by brain/leptomeningeal metastases status at 
screening (Present; Absent, Not Done), by sample type (Plasma; Tissue; Other) and by prior 


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type of therapy (TKI alone; TKI + Other anti-cancer therapy including any anti-cancer 
treatment other than a TKI, palliative radiotherapies and surgery associated with advanced 
lung cancer as defined in Appendix 6).  
Previous anti-cancer treatments will be summarised by category: TKI, Chemotherapy, 
Immunotherapy, Antiangiogenic therapy, Other anti-cancer treatment. 
Lists of possible TKIs, Chemotherapy agents, Immunotherapy agents and Antiangiogenic 
therapies are provided in Section 9. All other anti-cancer treatments that are not listed in 
Section 9 are considered in the Other therapies category.  
Previous radiotherapies and previous surgeries will also be summarised. 
Previous surgeries will be summarised by category: associated with advanced lung cancer: not 
associated with advanced lung cancer. 
List of surgeries associated with advanced lung cancer is provided in Section 9. All other 
surgeries not listed in Section 9 are considered as not associated with advanced lung cancer. 
Additionally, the following derived variables will be summarised: 

Age at study enrolment as a continuous variable  

Age at study enrolment by class ( <50; >=50 - <65; >=65 - <75; >=75 - <80,>=80 and 
<65; >=65) 

Duration from most recent receptor status assessment for T790M mutation to study 
enrolment (months) 

Duration from original lung cancer disease diagnosis to study enrolment (months) 

Duration from last TKI exposure to study enrolment (<= 6 months, > 6 months) 

Duration from last dose of prior cancer therapy  to study enrolment (months) 

Duration from scan for evaluation of brain/leptomeningeal metastases to study 
enrolment (months) 

Duration from last dose of prior anti-cancer therapy to most recent receptor status for 
T790M mutation (months) 
Enrolment date corresponds to the date enrolment ID and AZD9291 are allocated to the 
subject in Interactive Web Response System (IWRS). Enrolment date may be prior to first 
dose date of AZD9291. 
4.2.4
Medical History 
Relevant medical history (past and current) and relevant surgical history will be coded using 
the latest version of MedDRA. 
All medical history will be summarised (number and percentage of patients) for the FAS by 
system organ class (SOC) and preferred term (PT). 
All relevant surgical history will be summarised similarly. 


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4.2.5
Concomitant Medication / Treatment  
Concomitant medications are those with a stop date on or after the first dose date of study 
treatment or those that are marked as ongoing (and could have started prior to or during 
treatment). 
Concomitant medication / treatment will be summarised using frequency tables by anatomical 
therapeutic chemical classification (ATC) code. 
4.2.6
Exposure and Compliance to AZD9291 
Exposure (total and actual) to AZD9291 will be summarised in months for the FAS and for 
discontinued patients as a continuous variable and by class (<3; [3-6[; [6-12[; [12-18[; >=18 
months). 
Total Exposure Plot 
A plot giving the decreasing percentage of patients still on treatment against time (months) 
will be presented. 
Compliance 
Treatment compliance is calculated as the proportion in percentage of the scheduled expected 
number of doses, i.e. (Actual exposure/Total exposure)*100. 
Compliance will be summarised as a continuous variable for the FAS. 
4.2.7
Efficacy  
Overall Survival (OS) 
Overall survival will be summarised using Kaplan-Meier (KM) estimates of the median time 
to death or censoring and quartiles together with their 95% confidence intervals. Kaplan-
Meier estimates of the OS rate at appropriate time points (see Event rate at fixed time point) 
will be presented as well. 
A plot of the KM OS curve will be produced, including tickmarks to identify censored 
observations and numbers of patients at risk. 
The number of patients prematurely censored will be summarised. A patient would be defined 
as prematurely censored if moving to commercial supply or if their survival status was not 
defined at the date of study discontinuation and if his/her last available information in the CRF 
is more than 6 weeks prior to the study discontinuation. 
In addition, duration of follow-up will be summarised: 

In censored patients who are alive at the last assessment before study discontinuation 
only: Time from date of first dose of AZD9291 in this study to date of censoring (date 
last known to be alive).  

In prematurely censored patients: Time from date of first dose of AZD9291 in this 
study to date of censoring.  


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
In all patients: Time from date of first dose of AZD9291 in this study to the date of 
death (i.e. overall survival) or to the date of censoring for censored patients.  
Progression Free Survival (PFS)  
Progression Free Survival will be summarised similarly to OS using Kaplan-Meier (KM) 
estimates of the median time to progression or death (by any cause in the absence of 
progression) and quartiles together with their 95% confidence intervals. KM estimates of the 
PFS rate at appropriate time points (see Event rates at fixed time points) will be presented as 
well. 
Progression free survival events will be divided into 3 categories: Progression, Death due to 
disease progression, and Death due to reasons other than disease progression. Patients who 
have a progression event recorded in the tumor evaluation CRF will be summarised under 
‘Progression’. Patients with no progression event recorded in the tumor evaluation CRF but 
who have died with the cause of death assessed as due to disease progression as per list 
defined in appendix 5 will be summarised under ‘Death due to disease progression’, and 
patients who have died due to other causes will be summarised under ‘Death due to reasons 
other than disease progression’.  
Patients who have no progression or death record entered into the relevant CRF will be 
censored as described in section 3.1.2. 
A plot of the KM PFS curve will be produced, including tickmarks to identify censored 
observations and numbers of patients at risks at each specific fixed time points (see Event 
Rates at Fixed Time Points). 
The treatment status on the date of progression/death or censoring of patients will be 
summarised. 
This will include the number (%) of patients who were on treatment at the time of progression, 
the number (%) of patients who discontinued study treatment prior to progression, the number 
(%) of patients who had not progressed and were on treatment or discontinued treatment at 
time of censoring. 
Additionally, the number (%) of patients who continue on study treatment after progression 
will be summarised. 
Patients are considered as continuing treatment after progression if stop date is more than 
7 days after progression date.  
Time to Treatment Discontinuation or Death (TTD)  
As for OS, Time to Treatment Discontinuation or death will be summarised using Kaplan-
Meier (KM) estimates of the median time to treatment discontinuation or death and quartiles 
together with their 95% confidence intervals. KM estimates of the rate of patients still on 
treatment at appropriate time points (see Event Rates at Fixed Time Points) will be presented 
as well.  


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A plot of the KM estimates of TTD will be produced, including tickmarks to identify censored 
observations and numbers of patients at risks at each time point. 
Event Rates at Fixed Time Points 
For OS, PFS and TTD, event rates will be presented at specific fixed time points. 
Initially an interval of 3 months will be chosen extended to 6 months after 18 months: 3, 6, 9, 
12, 15, 18, 24, 30, 36 months, but this may be adjusted appropriately according to the 
distribution of the time-to-event variable and follow-up time. 
Response Rate 
Response rate, as defined in Section 3.1.4, will be summarised together with exact 95% 
confidence interval using the Clopper-Pearson method, based on a subset of the FAS 
consisting of patients with at least one documented response assessment.  
The Best Overall Response (responding, stable disease, progressing, not evaluated) will also 
be summarised. 
A sensitivity analysis of response rate will also be performed including patients who died 
prior to any documented response assessment and classifying them as non-responders. 
Evaluation of Brain/Leptomeningeal Metastases at Progression (regardless of site of 
progression) 
Brain/leptomeningeal metastases at progression (regardless of site of progression) 
will be summarised separately for patients with presence and absence of brain/leptomeningeal 
metastases at screening for patients who have a baseline assessment of brain/leptomeningeal 
metastases:  

For patients without brain/leptomeningeal metastases at screening, the method of 
assessment, presence of a lesion at progression and sites of lesions 
(Brain/Leptomeningeal) will be summarised. 

For patients with brain/leptomeningeal metastases at screening, the method of 
assessment and status at progression will be summarised. 
Subgroup Analyses 
Demographics, OS, PFS, TTD and RR will be analysed in the following subgroups of the 
FAS: 
Subgroup 
Demo- 
graphics
OS 
PFS 
TTD 
RR 

Sex (male ; female)
√ 
√ 
√ 
√ 
√ 

Age at enrolment 
 (<75 ; ≥75 years of age) 
√ 
Summary 
of cause 
of death
√ 
√ 
√ 

Race (White, Black, Asian, and Other).
√ 
√ 
√ 
√ 

Ethnicity (Asian, non-Asian).
√ 
√ 
√ 
√ 
√ 

Country of enrolment
√ 
√ 
√ 
√ 

WHO Performance Status (<2; =2)
√ 
√ 
√ 
√ 
√ 


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Subgroup 
Demo- 
graphics
OS 
PFS 
TTD 
RR 

Prior Lines of therapy (one line ; more 
than one line)
√ 
√ 
√ 
√ 

Mutation combinations as defined in 
section 4.2.3: 
(T790M only ;Common mutations 
Uncommon / Compound mutations)
√ 
√ 
√ 
√ 

Mutation Status (Any compound 
mutations with a sample size of at least 
50 patients (n≥50))
√ 
√ 
√ 
√ 

Sample Type for receptor status 
assessment (Plasma ; Tissue ; Other)
√ 
√ 
√ 
√ 
√ 

Type of T790M testing (Roche cobas
test on plasma ; Every other test on 
plasma with at least 50 patients ; Roche 
cobas test on tissue ; Every other test 
on tissue with at least 50 patients)
√ 
√ 
√ 
√ 

Brain/leptomeningeal metastases status 
at baseline (Present ; Absent ; Not 
Done)
√ 
√ 
√ 
√ 
√ 
o
Prior radiotherapy (Y/N) in 
Brain/leptomeningeal metastases 
subgroup
√ 
√ 
√ 

Prior Type of anti-cancer therapy (TKI 
alone[1] ; TKI + Other anti-cancer 
therapy[2]))
√ 
√ 
√ 
√ 
√ 

Prior Type of TKI (TKI first generation 
only ; TKI second generation only ; 
TKI first generation + TKI second 
generation, TKI first generation and/or 
second generation + TKI third 
generation)
√ 
√ 
√ 
√ 

Prior chemotherapy (Yes [3; No)
√ 
√ 
√ 
√ 
√ 
o
Line of Chemotherapy 
 (First line; Second line; Third line 
or more)
√ 
√ 
√ 
√ 
[1]TKI alone does not refer to monotherapy, but only ever having previously received a TKI and no other anti-
cancer treatment in the metastatic setting. 
[2] Other anti-cancer therapy includes any anti-cancer treatment other than a TKI, palliative radiotherapies and 
surgery associated with advanced lung cancer as defined in Appendix 6. 
[3] Subgroup Prior chemotherapy = Yes includes all patients previously treated by chemotherapy other than 
adjuvant or neo-adjuvant only. 


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Subgroup 
Demo- 
graphics
OS 
PFS 
TTD 
RR 

Use of TKI in patients with prior first 
or second line chemotherapy (Yes; No)
√ 
√ 
√ 
√ 
The subgroup analyses will be based on the values recorded on the CRF. 
The subgroup analyses for time-to-event endpoints will be performed only for the subgroups 
with 20 events or more. 
The summary of cause of death by age class will include disease under study, AEs not 
considered related to AZD9291, AEs considered related to AZD9291, Other. 
Deaths due to disease under study are defined as deaths due to disease progression as defined 
in the list in Appendix 5. 
A swimmer plot for PFS will be produced for the uncommon/compound mutation subgroup 
and a listing of PFS for patients with T790M + Exon 20 Insertion only will be presented. 
4.2.8
Safety 
Serious Adverse Events (SAE) 
All SAEs starting after the first dose of therapy, or within 30 days after stopping therapy, will 
be included in the summary table providing frequency (the same SAE occurring more than 
once to the same patient will be taken into account only once). 
SAEs will be presented by System Organ Class (SOC) and Preferred Term (PT). 
SAEs leading to death and SAEs leading to treatment discontinuation will be also summarised 
separately. 
Any SAEs occurring before starting treatment with AZD9291 will be included in the data 
listing but will not be included in the summary tables of SAEs.  
Adverse Events of Special Interest (AESI)  
Summaries of the AESIs will include number (%) of patients who have: 

At least one AESI  

At least one AESI related to study medication. If causality is missing, assume that the 
AESI is related. 

At least one AESI leading to dose modification (reduction/interruption) 

At least one AESI leading to discontinuation 
A summary of duration (days) of AESI will be provided for all events and this will be 
supported by summaries of events which have an end date, ongoing AESIs at death and, 
separately, at study discontinuation. All durations will be calculated. 
Duration of Ongoing AESIs will be calculated using study discontinuation date as end date. 


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Duration of fatal AESIs will be calculated using death date collected on death form as end 
date. 
Summary statistics of Time of Onset (days) from study treatment to start of AESI will also be 
provided for all AESIs. 
Summary tables of AESIs providing the number (%) of patients experiencing any of the 
specified terms by maximum CTCAE grade will be also produced. 
AEs leading to dose modification 
AEs leading to dose modification (reduction/interruption) will be presented by SOC and PT. 
AEs leading to discontinuation 
AEs leading to discontinuation will be presented by SOC and PT. 
Deaths 
A summary of deaths and cause of death will be provided and a corresponding listing will also 
be produced. 
An overall summary of AEs will be presented including: 
Number (%) of patients with at least one AE, number (%) of patients with at least one AE 
leading to dose modification, number (%) of patients with at least one AE leading to 
discontinuation, number (%) of patients with at least one AESI, number (%) of patients with at 
least one SAE. 
Subgroup analyses 
Overall summary of AEs will be analysed in the following subgroups of the FAS: 

Age at enrolment (<75 ; ≥75 years of age) 

Baseline WHO Performance Status (<2; =2) 

Sample Type (Plasma ; Tissue ; Other) 

Brain/leptomeningeal metastases status at baseline (Present ; Absent ; Not Done) 
4.2.9
Laboratory evaluations
When laboratory parameters are collected, they will be assessed by the investigator as normal, 
abnormal-not clinically significant, abnormal-clinically significant, abnormal-leading to dose 
modification or abnormal-SAE. Details about abnormality will be summarised in tables by 
parameter and visit. 
4.2.10 ECG 
QTc interval fredericia >470 ms (Yes, No), overall evaluation (Normal, Abnormal) and 
clinically significance (Yes, No) will be summarised by visit. 


Statistical Analysis Plan  
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22
4.2.11 Weight 
Weight (Kg) will be summarised by visit. 
4.2.12 WHO performance status 
WHO performance status (Normal Activity, Restricted Activity, In Bed Less Than or Equal to 
50% of the Time, In Bed More Than 50% of the Time, 100% Bedridden, Death) will be 
summarised by visit. 
4.2.13 Slit Lamp Test) 
Slit Lamp test results (Normal, Abnormal) will be summarised by left and right eyes and by 
visit. 
5
INTERIM ANALYSES 
To provide annual updates of key study measures, interim analyses of the global data will take 
place annually for the first three years (i.e. at approximately 12, 24 and 36 months from the 
start of recruitment). 
CCI


Statistical Analysis Plan  
Study code D5160C00022 
Version 7.0 
Date 12 Dec 2019 
23
CCI
CCI


Statistical Analysis Plan  
Study code D5160C00022 
Version 7.0 
Date 12 Dec 2019 
24
6
CHANGES OF ANALYSIS FROM PROTOCOL 
N.A 
7
COUNTRY SPECIFIC ANALYSES 
Regional and country level analysis may be performed at the interim analyses and final 
analysis time points if deemed appropriate. 
KM OS analysis and outputs will only be presented for countries that have enrolled a 
minimum of 150 patients and have at least 60% event maturity to ensure robustness of data for 
this endpoint. 
CCI
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Statistical Analysis Plan  
Study code D5160C00022 
Version 7.0 
Date 12 Dec 2019 
25
8
REFERENCES 
Clopper, C. J. & Pearson, E. S., 1934. The use of confidence or fiducial limits illustrated in the 
case of the binomial. Biometrika, Volume 26, pp. 404-413. 
Collett, D., 1994. Modelling Survival Data in Medical Research. s.l.:Chapman & Hall/CRC. 


Statistical Analysis Plan  
Study code D5160C00022 
Version 7.0 
Date 12 Dec 2019 
26
9
APPENDICES 
1. List of Tyrosine kinase inhibitors 
Preferred Name 
Generation 
AZD3759
1st generation
Gefitinib
1st generation
Epitinib
1st generation
Erlotinib
1st generation
Icotinib
1st generation
Afatinib
2nd generation
Dacomitinib
2nd generation
Poziotinib
2nd generation
EGF816/Nazartinib
3rd generation
Avitinib
3rd generation
Olmutinib
3rd generation
Osimertinib
3rd generation
Rociletinib
3rd generation


Statistical Analysis Plan  
Study code D5160C00022 
Version 7.0 
Date 12 Dec 2019 
27
2. List of Chemotherapies: 
Preferred Name 
Bleomycin 
Capecitabine 
Carboplatin 
Carmustine 
Cisplatin 
Cytarabine 
Docetaxel 
Doxorubicin 
Epirubicin 
Etoposide 
Fluorouracil 
Gemcitabine 
Gimeracil 
Ifosfamide 
Irinotecan 
Lobaplatin 
Nedaplatin 
Nimustine 
Olaparib 
Oteracil 
Oxaliplatin 
Paclitaxel 
Pemetrexed 
Platinum compounds 
Tegafur 
Temozolomide 
Teniposide 
Uftoral 
Vincristine 
Vinorelbine 
Vorinostat 


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Version 7.0 
Date 12 Dec 2019 
28
3. List of Immunotherapies: 
Preferred Name
Atezolizumab
Avelumab
Durvalumab
Ipilimumab
Nivolumab
Pembrolizumab
Tremelimumab
4. List of Antiangiogenic Therapies: 
Preferred Name
Anlotinib
Apatinib
Endostatin
Bevacizumab
Fruquintinib
Nintedanib
Ramucirumab
Telatinib


Statistical Analysis Plan  
Study code D5160C00022 
Version 7.0 
Date 12 Dec 2019 
29
5. Death due to disease progression coded terms: 
Coded term
Adenocarcinoma of lung  
Advanced cancer  
Brain metastases  
Cancer  
Cancer of lung  
Disease aggravation 
Disease progression  
Lung adenocarcinoma  
Lung cancer  
Lung cancer metastatic  
Lung neoplasm 
Malignant neoplasm of lower lobe, bronchus or lung, in situ 
Meningeal carcinomatosis  
Non-small cell lung cancer  
Non-small cell lung cancer metastatic 
Progression of non-small cell lung cancer 
Tumor progression  


Statistical Analysis Plan  
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Version 7.0 
Date 12 Dec 2019 
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6. Surgeries associated with advanced lung cancer: 
Preferred term
Lung lobectomy
Lymphadenectomy
Pulmonary resection
Lung neoplasm surgery
Pneumonectomy
Brain tumour operation
Pleurectomy
Hepatectomy
Adrenalectomy
Bone lesion excision
Vertebroplasty
Brain lobectomy
Internal fixation of spine
Lymphoid tissue operation
Metastases to central nervous system
Pericardial drainage
Pericardial effusion malignant
Pleural adhesion
Pleural decortication
spinal corpectomy
Spinal decompression
Tracheal resection
Tumour excision
Ventriculo-pleural shunt


Protocol: D5160C00022 
Confidential - Proprietary Information 

Protocol number: D5160C00022 

Document title: Open Label, Multinational, Multicenter, Real World 
Treatment Study of Single Agent AZD9291 for Patients with 
Advanced/Metastatic Epidermal Growth Factor Receptor (EGFR) T790M 
Mutation-Positive Non-Small Cell Lung Cancer (NSCLC) Who Have 
Received Prior Therapy with an EGFR Tyrosine Kinase Inhibitor (EGFR-
TKI). 

Version numbers: SAP Addendum Version 1.0 

Date of the documents: 03 Nov 2020 

NCT number: NCT02474355 


Statistical Analysis Plan 7.0 – Addendum 01
Study code D5160C00022
Version 1.0
Date 03 November 2020
1
Real World Treatment Study – Statistical Analysis 
Plan (for the final analysis) – Addendum 01
Drug Substance
AZD9291
Study Code
D5160C00022
Version Number
1.0
Date
03 November 2020
Open Label, Multinational, Multicenter, Real World Treatment Study of Single 
Agent AZD9291 for Patients with Advanced/Metastatic Epidermal Growth 
Factor Receptor (EGFR) T790M Mutation-Positive Non-Small Cell Lung 
Cancer (NSCLC) Who Have Received Prior Therapy with an EGFR Tyrosine 
Kinase Inhibitor (EGFR-TKI)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden


PPD
PPD


PPD
PPD


PPD
PPD


Statistical Analysis Plan 7.0 – Addendum 01
Study code D5160C00022
Version 1.0
Date 03 November 2020
5
TABLE OF CONTENTS
TITLE PAGE.......................................................................................................................1
SIGNATURE PAGE............................................................................................................2
TITLE PAGE.......................................................................................................................2
SIGNATURE PAGE............................................................................................................3
TITLE PAGE.......................................................................................................................3
TABLE OF CONTENTS.....................................................................................................5
AMENDMENT HISTORY..................................................................................................6
LIST OF ABBREVIATIONS ..............................................................................................8
1
STUDY DETAILS...............................................................................................9
2
ANALYSIS SETS ...............................................................................................9
2.1
Definition of analysis set......................................................................................9
3
PRIMARY AND SECONDARY VARIABLES...................................................9
3.1
Efficacy ...............................................................................................................9
3.1.1
Overall Survival (OS) ..........................................................................................9
3.2
Safety...................................................................................................................9
3.2.1
Serious Adverse Events (SAEs) ...........................................................................9
3.2.2
Adverse Events of Special Interest (AESIs)..........................................................9
4
ANALYSIS METHODS......................................................................................9
4.1.1
Efficacy ...............................................................................................................9
4.1.2
Safety................................................................................................................. 10
4.1.3
Potential Hy’s Law cases ................................................................................... 11
5
INTERIM ANALYSES ..................................................................................... 11
5.1
 
...................................................................................................... 11
5.1.1
...................................... 11
6
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 12
7
APPENDICES................................................................................................... 12
CCI
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Statistical Analysis Plan 7.0 – Addendum 01
Study code D5160C00022
Version 1.0
Date 03 November 2020
6
AMENDMENT HISTORY
Category:
Change refers 
to
Date
Description of change
In line 
with CSP? 
Y (version) /
N / NA
Rationale
Efficacy
16 Apr 
2020
Add OS swimmer plot for 
uncommon/compound 
mutation subgroup 
NA
Subgroup of 
interest for OS
Safety
19 Jun 
2020
Add table of AEs with 
CTCAE Grade >=3
Add Table of AESIs by 
outcome
Add Table of SAE by 
causality
Add Table of SAE by 
CTCAE grade
Update Table of Hy’s Law 
cases
Add Listing of SAEs 
Add Listing of AESIs 
Add Listing of Hy’s Law 
cases
NA
Adverse events 
analysis needs 
more details
09 Oct 
2020
Add Summary of Serious 
Adverse Events Leading to 
Dose Modification by 
System Organ Class and 
Preferred Term
NA
CCI


Statistical Analysis Plan 7.0 – Addendum 01
Study code D5160C00022
Version 1.0
Date 03 November 2020
7
Appendices
16 Apr 
2020
Recoding of Telatinib in 
antiangiogenic therapies 
NA
Dictionaries
updated
CCI


Statistical Analysis Plan 7.0 – Addendum 01
Study code D5160C00022
Version 1.0
Date 03 November 2020
8
LIST OF ABBREVIATIONS 
Abbreviation or 
special term
Explanation
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Transaminase
AST
Aspartate Transaminase
BICR
Blinded Independent Central Review
BOR
Best Objective Response
CTCAE
National Cancer Institute Common Terminology Criteria for AEs
DoR
Duration of Response
FAS
Full Analysis Set
ORR
Objective Response Rate
OS
Overall Survival
PT
Preferred Term
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SOC
System Organ Class
TBL
Total Bilirubin
ULN
Upper Limit of Normal


Statistical Analysis Plan 7.0 – Addendum 01
Study code D5160C00022
Version 1.0
Date 03 November 2020
9
1
STUDY DETAILS
This Statistical Analysis Plan (SAP) addendum outlines additional outputs and appendices 
updates after SAP final version 7.0.
2
ANALYSIS SETS
2.1
Definition of analysis set
Full Analysis Set (FAS) 
The full analysis set is defined the same way as detailed in Section 2.1 of the SAP.
3
PRIMARY AND SECONDARY VARIABLES
3.1
Efficacy
3.1.1
Overall Survival (OS)
Overall survival is defined the same way as detailed in Section 3 of the SAP.
3.2
Safety
3.2.1
Serious Adverse Events (SAEs)
SAEs are defined the same way as detailed in Section 3 of the SAP.
3.2.2
Adverse Events of Special Interest (AESIs)
AESIs are defined the same way as detailed in Section 3 of the SAP.
4
ANALYSIS METHODS
4.1.1
Efficacy 
Overall Survival (OS)
Overall survival will be summarised by mutation combination subgroup.
Analysis will include the number of exposed patients, the number of deaths, the number of 
censored patients and the number of patients prematurely censored.
In addition, duration of follow-up will be summarised as defined in Section 4.2.7 of the SAP:

In all censored patients;

In prematurely censored patients;

In all patients.
A swimmer plot for OS will be produced for the uncommon/compound mutation subgroup.
The swimmer plot will include all patients with an uncommon/compound mutation and will be 
ordered by mutation combination. Median OS and 95% confidence intervals for Full Analysis 


Statistical Analysis Plan 7.0 – Addendum 01
Study code D5160C00022
Version 1.0
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Set will be reported as reference lines. Censored patients will be identified by a cross at the 
time of censoring.
4.1.2
Safety
All the following outputs will be provided in addition to analyses described in Safety analysis 
methods section of the SAP (Section 4.2.8).
Serious Adverse Events (SAE)
The following summaries will be provided for all SAEs as defined in the SAP section 4.2.8:

number (%) of patients reporting SAEs assessed as causally related to AZD9291 by 
System Organ Class (SOC) and Preferred Term (PT). If causality is missing, assume 
that the SAE is causally related.

number (%) of patients reporting SAEs by SOC, PT and maximum CTCAE grade.

number (%) of patients reporting SAEs leading to dose modification by SOC and PT.
A listing of all SAEs will be produced. SAEs occurring before starting treatment with 
AZD9291 included in the data listing will not be included in the summary tables of SAEs.
Adverse Events of Special Interest (AESI)
Summary table of AESIs providing the number (%) of patients experiencing any of the 
specified terms by outcome will be produced.
A listing of all AESI will also be produced.
The overall summary described in SAP section 4.2.8 will be replaced by an overall summary 
of AESIs and SAEs including:

number (%) of patients with at least one AESI or SAE

number (%) of patients with at least one AESI or SAE causally related to AZD9291

number (%) of patients with at least one AE leading to dose modification

number (%) of patients with at least one AE leading to discontinuation

number (%) of patients with at least one AESI

number (%) of patients with at least one AESI causally related to AZD9291

number (%) of patients with at least one SAE.

number (%) of patients with at least one SAE causally related to AZD9291

number (%) of patients with at least one AE leading to death

number (%) of patients with at least one AE leading to death causally related to 
AZD9291
Note: If causality is missing, assume that the AE is causally related.
Subgroup analyses
Overall summary of AESIs and SAEs will be analysed in all subgroups of the FAS as defined 
in section 4.2.8 of the SAP.
A summary table of AEs with CTCAE grade ≥ 3 providing the number (%) of patients 
experiencing any of the specified terms will be also produced.


Statistical Analysis Plan 7.0 – Addendum 01
Study code D5160C00022
Version 1.0
Date 03 November 2020
11
4.1.3
Potential Hy’s Law cases
A cross tabulation of number (%) of patients who had any instance of an elevated aspartate 
transaminase / alanine transaminase (AST or ALT ≥ 3xULN) with number (%) of patients 
who had any instance of elevated total bilirubin (TBL ≥ 2xULN) will be presented in order to 
evaluate potential Hy’s Law cases.
Potential Hy’s Law cases will also be presented in a listing.
5
INTERIM ANALYSES
CCI
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Statistical Analysis Plan 7.0 – Addendum 01
Study code D5160C00022
Version 1.0
Date 03 November 2020
12
6
CHANGES OF ANALYSIS FROM PROTOCOL
NA
7
APPENDICES
1. List of Tyrosine kinase inhibitors
The following list replaces the list provided in Section 9 of the SAP.
Preferred Name
Generation
AZD3759
1st generation
Gefitinib
1st generation
Epitinib
1st generation
Erlotinib
1st generation
Icotinib
1st generation
Afatinib
2nd generation
Dacomitinib
2nd generation
Poziotinib
2nd generation
Theliatinib
2nd generation
EGF816/Nazartinib
3rd generation
Avitinib
3rd generation
Olmutinib
3rd generation
Osimertinib
3rd generation
Rociletinib
3rd generation
2. List of Chemotherapies:
Refer to Section 9 of the SAP
3. List of Immunotherapies:
Refer to Section 9 of the SAP


Statistical Analysis Plan 7.0 – Addendum 01
Study code D5160C00022
Version 1.0
Date 03 November 2020
13
4. List of Antiangiogenic Therapies:
Refer to Section 9 of the SAP
5. Death due to disease progression coded terms:
Refer to Section 9 of the SAP
6. Surgeries associated with advanced lung cancer:
Refer to Section 9 of the SAP