Conditions: Anticancer Treatment
Keywords: Advanced Non-Small Cell Lung Cancer; T790M Mutation Positive
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 421
Healthy volunteers: no

Brief summary:
A Phase III, Open Label, Randomized Study of Osimertinib versus Platinum-Based Doublet Chemotherapy for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene

Detailed description:
This is a phase III, open label, randomized study assessing Osimertinib (80 mg, orally, once daily) versus platinum-based doublet chemotherapy (standard of care) in subjects with confirmed diagnosis of Epidermal Growth Factor Receptor (EGFR) mutation positive NSCLC, who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) agent and whose tumours harbour a T790M mutation within the EGFR Gene. Subjects must be chemotherapy naive and must agree to provide a biopsy for central confirmation of T790 mutation status following confirmed disease progression on their first line EGFR-TKI treatment (e.g. erlotinib, gefitinib or afatinib). Suitable subjects will then be randomized to receive either Osimertinib (80mg orally, once daily) or platinum-based doublet chemotherapy (pemetrexed 500 mg/m2 + carboplatin area under the plasma concentration-time curve AUC 5 or pemetrexed 500 mg/m2 + cisplatin 75 mg/m2) on Day 1 of every 21-day cycle in a 2:1 (Osimertinib: platinum-based doublet chemotherapy) ratio. Once subjects on the platinum-based doublet chemotherapy arm are determined to have objective radiological progression according to RECIST 1.1 by the investigator and confirmed by independent central imaging review, they will be given the opportunity to begin treatment with Osimertinib 80mg, once daily. These subjects may continue treatment with Osimertinib even after disease progression, as long as they are continuing to show clinical benefit, as judged by the investigator. The primary objective of the study is to assess the efficacy of Osimertinib compared with platinum-based doublet chemotherapy by assessment of Progression Free Survival (PFS), using investigator assessments according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1), as well as asensitivity analysis of Progression Free Survival using Blinded Independent Central Review (BICR).

Arms:
arm 1: Osimertinib 80 mg, orally, once daily arm 2: pemetrexed 500mg/m2 + carboplatin AUC5 or pemetrexed 500mg/m2 + cisplatin 75mg/m2

Interventions: intervention 1: Chemotherapy intervention 2: Cross-over to Osimertinib
Intervention descriptions: intervention 1: Randomization to either Osimertinib or platinum-based doublet-chemotherapy on Day 1 of every 21d cycle in a 2:1 (Osimertinib:platinum-based doublet-chemotherapy) ratio intervention 2: Once subjects on the platinum-based doublet chemotherapy arm are determined to have objective radiological progression according to RECIST 1.1 by the investigator and confirmed by independent central imaging review, they will be given the opportunity to begin treatment with Osimertinib 80mg, once daily. These subjects may continue treatment with Osimertinib even after disease progression, as long as they are continuing to show clinical benefit, as judged by the investigator.

Subjects who stop platinum-based doublet chemotherapy for reasons other than objective disease progression according to RECIST 1.1 will not be eligible to cross-over to Osimertinib.

Protocol document:
Prot_000.pdf: 
1 (164)
Clinical Study Protocol 
Drug Substance
AZD9291
Study Code
D5160C00003
Version
5
Date
January 10, 2017
A Phase III, Open Label, Randomized Study of AZD9291 versus Platinum-
Based Doublet Chemotherapy for Patients with Locally Advanced or 
Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with 
Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor 
Therapy and whose Tumours harbour a T790M mutation within the 
Epidermal Growth Factor Receptor Gene (AURA3)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden


Clinical Study Protocol Synopsis
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
2 (164)
VERSION HISTORY
Version 5, January 10, 2017
The reason for this protocol amendment is to update the clinical study protocol to:

Amend the data collection and criteria for potential crossing-over post primary PFS 
analysis

Outline patient management post final OS analysis (at approximately 70% maturity)

In addition, the protocol has been updated to reflect changes in the Investigator’s 
Brochure (IB) Version 6 update (detailed in the Version History section) regarding the 
management of toxicities and pregnancy
The primary, secondary and exploratory objectives of this protocol remain unchanged, and no 
inclusion or exclusion criteria were added, changed or deleted. 
The details of the changes are summarized below:
1. Post primary PFS analysis, the data collection schedule will be reduced to key 
variables such as overall survival, patient reported outcomes and safety. Subjects still 
on the platinum-based doublet chemotherapy arm will be given the opportunity to 
begin treatment with AZD9291 80mg, once daily at the discretion of the investigator. 
2. Following the final OS analysis (at approximately 70% maturity), access to treatment 
will continue to be assured for patients still receiving AZD9291. Patients still receiving 
therapy will be permitted to continue to receive study treatment if, in the opinion of the 
investigator, they are continuing to receive benefit from treatment. Patients who 
remain on study treatment after this time point will be monitored according to routine 
clinical practice as defined by the Investigator, and will continue to report all SAE, 
overdose and pregnancy information. 
Note: Study assessments and data collection will continue at each site according to CSP 
Version 4, dated 21 March 2016 until this CSP version is approved by the health authority 
and/or IRB/IEC, in accordance with local requirements. The analysis and reporting of these 
data will be performed according to this CSP version. 
Major changes to the protocol are summarised below:
- Protocol synopsis (study design and duration of treatment) was updated to clarify the 
requirements up to the primary PFS analysis and then post primary PFS analysis. Following 
the primary PFS analysis subjects still on the platinum-based doublet chemotherapy arm will 
be given the opportunity to begin treatment with AZD9291 80 mg, once daily if it is 
considered by the Investigator to be in the patient's best interest, and if they are eligible to 


Clinical Study Protocol Synopsis
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
3 (164)
receive AZD9291 (no contraindications). 
- Section 1.3 (Rationale for study design, doses and control groups) and Section 1.5 (Study 
design) were updated to clarify the requirements up to the primary PFS analysis and then post 
primary PFS analysis. Following the primary PFS analysis subjects still on the platinum-based 
doublet chemotherapy arm will be given the opportunity to begin treatment with AZD9291 80 
mg, once daily if it is considered by the Investigator to be in the patient's best interest, and if 
they are eligible to receive AZD9291 (no contraindications).
- Section 3.7.1 (Procedures for discontinuation of a subject from study treatment): clarification 
has been added that, following the primary PFS analysis, tumour assessments will no longer 
be collected apart from patients in China. 
- Section 4 (Table 1, Table 2 and Table 3): the table title was updated to specify that the study 
plan outlined in Table 1, Table 2 and Table 3 is valid up to primary PFS analysis. 
- Section 4 (Table 4): table added to outline the study plan post primary PFS analysis until the 
final OS analysis DCO. The data collection will be reduced to key variables such as overall 
survival, patient reported outcomes and safety. The central ECG, information for PFS2 and 
health care resource use will continue until the first OS analysis DCO. 
- Section 4.2 (treatment period) and Section 4.3 (follow-up period): the sub-section titles were 
updated to specify that the study assessment and data collection are valid up to primary PFS 
analysis.
- Section 4. 3. 5 (Patient management post primary PFS analysis): section added to provide 
more detail regarding the management of patients after primary PFS analysis.
- Section 4.3.6 (Patient management post final OS analysis): section added to provide more 
detail regarding the management of patients after the final OS analysis DCO.
- Section 5.1 (efficacy assessments): section was modified to clarify that post primary PFS 
analysis, subjects still on the platinum-based doublet chemotherapy arm will be given the 
opportunity to begin treatment with AZD9291 80mg, once daily at the discretion of the 
investigator and tumour assessment will be performed in accordance with clinical practice and 
scans will no longer be centrally collected apart from patients from China.                                
- Section 5.2.4 (ECG): section was modified to clarify that post the first OS analysis DCO
ECGs will be performed according to routine clinical practice, locally and stored at the site.
ECG information (evaluation of normal/abnormal) will continue to be recorded in the eCRF.
After final OS analysis, ECGs will be performed according to routine clinical practice.               
- Section 5.2.5 (Echocardiogram/MUGA scan): section was modified to clarify that post final 
OS analysis, Echocardiogram/MUGA scan will be performed clinically indicated as necessary 
by the Investigator. 
- Section 5.3.2 (Patient reported outcomes): section was modified to clarify that the PRO data 


Clinical Study Protocol Synopsis
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
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collection will be collected until the end of study (including survival follow-up period) and at 
the time of progression, unless consent is withdrawn or patient is lost to follow up, as 
indicated in the Study Plan. 
- Section 5.3.2.5 (Healthcare resource use): section was modified to clarify that healthcare 
resource use information will continue to be collected until the first OS analysis DCO. After 
the first OS analysis DCO, this information is not required to be collected. 
- Section 5.6.2 (Collection of exploratory samples): section was modified to clarify that post 
primary PFS analysis, ctDNA samples will continue to be collected at treatment 
discontinuation and at progression.
- Section 5.8 (Post progression outcomes): section was modified to clarify PFS2 is only 
required to be collected up to the first OS analysis DCO. After the first OS analysis DCO, this
information is not required to be collected. 
- Sections 6.3.1 (Time period for collection of adverse events) and 6.4 (Reporting of serious 
adverse events): sections were modified to provide more clarity regarding the process of 
collecting SAE, overdose and pregnancy information after final OS DCO.
- Section 6.6 (Pregnancy): section was modified to reflect the Investigator’s
Brochure (IB) Version 6 update.
- Section 6.7 (Management of toxicities related to AZD9291): section was modified to reflect 
the Investigator’s Brochure (IB) Version 6 update. 
- Section 7.1 (Identity and Dose of investigational product – AZD9291) and 7.5 (Compliance): 
sections were updated to provide more clarity regarding the drug dispensing and drug 
accountability process after final OS analysis DCO.
- Section 7.8 (Post access to study treatment): section was updated to provide more clarity 
about the management of patients at the time of study completion after the final OS DCO.
Version 4, 21 March 2016
Refer to Amendment #3 document for details
Version 3, 06 May 2015
Refer to Amendment #2 document for details


Clinical Study Protocol Synopsis
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
5 (164)
Version 2, 22 Dec 2014
Refer to Amendment #1 document for details
Version 1.1, 18 July 2014
Refer to Administrative Change #1 document for details
Version 1, 6 May 2014
Initial creation
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The clinical study protocol 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.


6 (164)
PROTOCOL SYNOPSIS
A Phase III, Open Label, Randomized Study of AZD9291 versus Platinum-
Based Doublet Chemotherapy for Patients with Locally Advanced or 
Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with 
Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor 
Therapy and whose Tumours harbour a T790M mutation within the 
Epidermal Growth Factor Receptor Gene (AURA3)
International Coordinating Principal Investigators:
Professor Tony Mok
Department of Clinical Oncology
The Chinese University of Hong Kong
Prince of Wales Hospital
Shatin, N.T., Hong Kong
Professor Yilong Wu
Guangdong General Hospital
Guangdong Lung Cancer Institute
No. 106, Zhongshan Er Road, Guangzhou
Guangdong, 510030, China
Dr Vassiliki A. Papadimitrakopoulou
Department of Thoracic/HN Medical Oncology
The University of Texas 
M.D. Anderson Cancer Center
1515 Holcombe Boulevard, Unit 432
Houston, Texas 77030 USA
Study site(s) and number of subjects planned
Approximately 410 subjects will be randomized from 19 countries across approximately 160 
centres in North America, Asia and Europe.  Once 410 subjects have been randomized 
globally, recruitment will continue only in mainland China until approximately 50 Chinese 
subjects have been randomized.
Study period
Phase of development
Estimated date of first subject enrolled
Q3 2014
III
Estimated date of last subject completed
Q4 2018


Clinical Study Protocol Synopsis
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
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Study design
This is a phase III, open-label, randomized study assessing the safety and efficacy of 
AZD9291 (80 mg, orally, once daily) versus platinum-based doublet chemotherapy in patients 
with Epidermal Growth Factor Receptor Mutation and T790M Mutation Positive
(EGFRm+/T790M+), locally advanced or metastatic NSCLC who have progressed following 
treatment with an approved Epidermal Growth Factor Tyrosine Kinase Inhibitor (EGFR-TKI) 
agent. 
In order to randomize approximately 410 subjects it is expected that an estimated 1034 
subjects will be screened.  Once 410 subjects have been randomized globally, recruitment will 
continue only in mainland China until approximately 50 Chinese subjects have been 
randomized.
A biopsy will be needed for central testing of T790M mutation status following confirmed 
disease progression on first line treatment with an EGFR TKI.
Suitable subjects will then be randomized to receive either AZD9291 (80mg orally, once 
daily) or platinum-based doublet chemotherapy (pemetrexed 500 mg/m2 + carboplatin area 
under the plasma concentration–time curve AUC 5 or pemetrexed 500 mg/m2 + cisplatin 75
mg/m2) on Day 1 of every 21-day cycle in a 2:1 (AZD9291: platinum-based doublet 
chemotherapy) ratio.
Subjects should continue on investigational product AZD9291 until a treatment 
discontinuation criterion is met.  Subjects may continue to receive AZD9291 beyond RECIST 
1.1 defined progression as long as they are continuing to show clinical benefit, as judged by 
the investigator.
Subjects can receive up to 6 cycles of pemetrexed + carboplatin/cisplatin as initial treatment. 
Subjects whose disease has not progressed after four cycles of platinum-based first-line 
chemotherapy may receive pemetrexed maintenance therapy.  Subjects who progress 
according to RECIST 1.1 criteria prior to completion of initial doublet chemotherapy 
treatment or during pemetrexed maintenance monotherapy, may continue with chemotherapy 
treatment as long as they show clinical benefit, as judged by the investigator.  
Up to the primary PFS analysis, subjects must be followed until evidence of RECIST 1.1 
defined progression (regardless of reason for treatment discontinuation). It is important that 
subjects are assessed according to the intended scanning schedule to prevent the bias in 
analysis that can occur if one treatment group is assessed more or less often than the other.
Up to the primary PFS analysis, once subjects on the platinum-based doublet chemotherapy 
arm are determined to have objective radiological progression according to RECIST 1.1 by 
the investigator and confirmed by independent central imaging review, they will be given the 
opportunity to begin treatment with AZD9291 80mg, once daily.  These subjects may 
continue treatment with AZD9291, as long as they show clinical benefit, as judged by the 
investigator.  


Clinical Study Protocol Synopsis
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
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Up to the primary PFS analysis, if a subject has been deemed to have objective disease 
progression according to Investigator tumour assessment by RECIST 1.1, but is not confirmed 
by independent central imaging review, he/she is not eligible to cross-over to AZD9291 at that 
time. Should it be in the subject’s best interest, and only if further randomized chemotherapy 
is warranted, he/she may continue to receive randomized doublet chemotherapy (if initial 
doublet chemotherapy treatment has not yet been completed) or pemetrexed maintenance 
monotherapy. Sites are to submit the next scheduled tumour assessment for central imaging 
review according to Table 2. 
Following the primary PFS analysis subjects still on the platinum-based doublet chemotherapy 
arm will be given the opportunity to begin treatment with AZD9291 80mg, once daily if it is 
considered by the Investigator to be in the patient's best interest, and if they are eligible to 
receive AZD9291 (no contraindications). At least a 14 day washout period is required 
between last dose of chemotherapy and starting AZD9291 treatment.
If subjects randomised to chemotherapy are not eligible to receive AZD9291, they will enter 
into the follow-up phase of the study, and other treatment options should be discussed by the 
investigator.
Note: Throughout this document,
1. The study design and assessments required are only applicable for the period up to the 
primary PFS analysis unless indicated otherwise. 
2. The term “platinum-based doublet chemotherapy”, refers to “platinum” as both 
carboplatin and cisplatin.
Objectives
Primary Objective:
Outcome Measure:
To assess the efficacy of AZD9291 
compared with platinum-based doublet 
chemotherapy by assessment of 
Progression Free Survival (PFS).
Progression Free Survival (PFS) using 
investigator assessments according to Response 
Evaluation Criteria in Solid Tumours (RECIST 
1.1).
Sensitivity analysis of Progression Free Survival 
using Blinded Independent Central Review 
(BICR).
Secondary Objective:
Outcome Measure :


Clinical Study Protocol Synopsis
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
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To further assess the efficacy of AZD9291 
compared with platinum-based doublet 
chemotherapy in terms of:  
- Objective Response Rate (ORR)
- Duration of Response (DoR)
- Disease Control Rate (DCR)
- Tumour shrinkage
- Overall Survival (OS)
ORR, DoR, DCR and tumour shrinkage using 
investigator assessments according to Response 
Evaluation Criteria in Solid Tumours (RECIST 
1.1).
Analysis of overall survival.
To assess the effect of AZD9291 compared 
to platinum-based doublet chemotherapy 
on subjects’ disease-related symptoms and 
health related quality of life (HRQoL).
European Organization for Research and 
Treatment of Cancer Quality of Life 
Questionnaire – Core 30 items (EORTC QLQ-
C30) and European Organization for Research 
and Treatment of Cancer Quality of Life 
Questionnaire – Lung Cancer 13 items (EORTC 
QLQ-LC13).
EORTC QLQ-C30:
Questionnaire consisting of 30 items measuring 
subjects general cancer symptoms and 
functioning.
EORTC QLQ-LC13:
A complementary questionnaire measuring lung 
cancer symptoms.
To characterise the pharmacokinetics (PK) 
of AZD9291 and metabolites in subjects 
receiving AZD9291.
PK exposure parameters derived from plasma 
concentrations of AZD9291, and metabolites 
AZ5104 and AZ7550.
PK Parameters (CLss/F, Css, min and Css, max 
AUCss) will be derived using population PK 
analysis and reported separately to the CSR. Data 
from this study may form part of a pooled 
analysis with data from other studies.


Clinical Study Protocol Synopsis
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
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Safety Objective:
Outcome Measure :
To assess the safety and tolerability profile 
of AZD9291 compared with platinum-
based doublet chemotherapy.
Adverse events (graded by Common 
Terminology Criteria for Adverse Event 
(CTCAE v4)
- Clinical chemistry, haematology and urinalysis
- Vital signs (pulse and blood pressure), Physical 
Examination, Weight
- Centrally reviewed digital Electrocardiogram 
(ECG)
- Echocardiogram/ Multi Gated Acquisition Scan 
(MUGA) (for Left Ventricular Ejection Fraction) 
- World Health Organization (WHO) 
performance status
Exploratory Objectives:
Outcome Measure:
To explore the relationship between PK 
and selected endpoints (which may include 
efficacy, safety and/or Patient Reported 
Outcome [PRO]), where deemed 
appropriate.
Correlation of PK with other primary /secondary/ 
exploratory endpoints in subjects treated with 
AZD9291.
Results from such analyses will be reported 
separately from the Clinical Study Report (CSR). 
Data from this study may also form part of a 
pooled analysis with other AZD9291 studies.
To compare the effects of AZD9291 
compared with chemotherapy on post 
progression outcomes
Time from randomization to second progression 
(PFS2)
Time to subsequent treatments
Time to change in symptoms (including post 
progression assessments)
To further characterise the effects of 
AZD9291 on survival outcomes.
Assess the impact on overall survival of baseline 
potentially prognostic factors (e.g. tumour stage, 
performance status, sex, baseline lactate 
dehydrogenase [LDH])
Assess the impact on OS of subsequent 
treatments and other potential covariates (e.g. 
changes in performance status)
To compare adverse events by subject self-
reporting of specific CTCAE symptoms 
(where applicable) between AZD9291 and 
chemotherapy.
Collection of approximately 28 PRO-CTCAE 
symptoms via an electronic device solution (in 
countries where language is available).


Clinical Study Protocol Synopsis
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
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Exploratory Objectives:
Outcome Measure:
To compare AZD9291 treatment with 
chemotherapy treatment on health state 
utility.
The EQ-5D-5L health state utility index will be 
used to derive health state utility based on 
subject reported data.
To compare health resource use associated 
with AZD9291 treatment with 
chemotherapy treatment.
Health resource utilisation measures including 
hospitalization, outpatient visits, or emergency 
department visits.
To characterise the pharmacokinetics (PK) of 
AZD9291and metabolites in cerebrospinal 
fluid (CSF).
Concentration of AZD9291, AZ5104 and 
AZ7550. Ratio of metabolites to AZD9291.
Ratio of CSF to plasma concentration.
Summaries of PK concentration data.
To collect and store deoxyribonucleic acid 
(DNA) for future exploratory research into 
genes/genetic variation that may influence 
PK or response to AZD9291, platinum-
based doublet chemotherapy (ie, 
absorption, distribution, metabolism, 
excretion, safety and efficacy) and/or 
susceptibility to/development of cancers.
Correlation of polymorphisms with variation in 
Pharmacokinetics (PK), Pharmacodynamics 
(PD), safety or response observed in subjects 
treated with AZD9291 or comparator.
Data generated may be reported separately and 
may also form part of a pooled analysis with 
other AZD9291 studies.
To collect and store tumour samples and 
blood-based samples for potential for 
exploratory research into factors that may 
influence susceptibility to/development of 
NSCLC/cancer and/or response to 
AZD9291 (where response is defined 
broadly to include efficacy, tolerability or 
safety).
Analysis of key genetic and proteomic markers 
to include, but not limited to, EGFR mutations, 
Human Epidermal Growth Factor Receptor 2
(HER2) & CMET expression and/or amplication. 
Collection of plasma samples to include, but not 
be limited to, extraction of circulating tumour 
DNA (ctDNA) for investigation of blood borne 
biomarkers. The sample may be used to 
investigate the relationship between PK and 
blood-borne biomarkers.
Samples may be analysed retrospectively. Any 
biomarker data generated may be reported 
separately and may also form part of a pooled 
analysis with other AZD9291 studies.


Clinical Study Protocol Synopsis
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
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Exploratory Objectives:
Outcome Measure:
To collect and store plasma for isolation of 
ctDNA.  Extracted ctDNA will be assessed 
for the presence of genetic abberations 
including, but not limited to, EGFR 
mutations (T790M, L858R, etc).   These 
samples may be shared with a diagnostic 
partner for development of a ctDNA test 
for T790M detection.
Retrospective/real-time analysis of EGFR (and 
other) mutations in ctDNA from all study 
subjects (mandatory).
To collect and store residual CSF for 
potential exploratory research of factors 
that may influence development of 
NSCLC and/or response to AZD9291 
(where response is defined broadly to 
include efficacy, tolerability or safety).
Collection of CSF for the investigation of PK 
and/or biomarkers. Samples may be analysed 
retrospectively.
Target subject population
Male and female subjects aged 18 years and over (subjects from Japan aged at least 20 years) 
who have histologically or cytologically proven NSCLC that is locally advanced or metastatic 
and not amenable to further surgery or radiotherapy with curative intent and whose disease 
has progressed with previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor 
Therapy. 
Subjects must be eligible to receive treatment with the selected platinum–based doublet 
chemotherapy (pemetrexed + cisplatin /carboplatin) in accordance with local prescribing 
information and have documentation of EGFR Mutation (at any time since a diagnosis of 
NSCLC was made) and T790M Mutation positive tumour. Subjects must have measurable 
disease (using Computer Tomography [CT]/Magnetic Resonance Imaging [MRI]) as defined 
by RECIST 1.1 guidelines and WHO Performance Status of 0-1.
Duration of treatment
Treatment with AZD9291 80 mg, once daily, will commence following randomization. 
Subjects may continue to receive treatment with AZD9291 as long as they are continuing to 
show clinical benefit, as judged by the investigator, and in the absence of discontinuation 
criteria (see Section 3.7).
Treatment with intravenous platinum-based doublet chemotherapy (on Day 1 of every 21 day 
cycle) will commence following randomization up to a total of 6 cycles. Patients whose 
disease has not progressed after four cycles of platinum-based first-line chemotherapy may 
receive pemetrexed maintenance therapy.  
Subjects who progress according to RECIST 1.1 criteria prior to completion of initial doublet 
chemotherapy treatment or during pemetrexed maintenance monotherapy, may continue with 
treatment as long as they show clinical benefit, as judged by the investigator.  


Clinical Study Protocol Synopsis
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
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Up to the primary PFS analysis, once subjects on the platinum-based doublet chemotherapy 
arm are determined to have objective radiological progression according to RECIST 1.1 by 
the investigator and confirmed by independent central imaging review, they will be given the 
opportunity to begin treatment with AZD9291 80mg, once daily. These subjects may continue 
treatment with AZD9291 as long as they show clinical benefit, as judged by the investigator. 
If a subject has been deemed to have objective disease progression according to Investigator 
tumour assessment by RECIST 1.1, but is not confirmed by independent central imaging 
review, he/she is not eligible to cross-over to AZD9291 at that time. Should it be in the 
subject’s best interest, and only if further randomized chemotherapy is warranted, he/she may 
continue to receive randomized doublet chemotherapy (if initial doublet chemotherapy 
treatment has not yet been completed) or pemetrexed maintenance monotherapy. Sites are to 
submit the next scheduled tumour assessment for central imaging review according to Table 2. 
Following the primary PFS analysis subjects still on the platinum-based doublet chemotherapy 
arm will be given the opportunity to begin treatment with AZD9291 80mg, once daily if it is 
considered by the Investigator to be in the patient's best interest, and if they are eligible to 
receive AZD9291 (no contraindications). At least a 14 day washout period is required 
between last dose of chemotherapy and starting AZD9291 treatment.
Investigational product, 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.  A cycle of treatment is 
defined as 21 days of once daily AZD9291 treatment.
Comparator product, dosage and mode of administration
Platinum-based doublet chemotherapy will be administered intravenously on Day 1 of every 
21-day cycle of either:
-
Pemetrexed 500mg/m2 + carboplatin AUC5. 
Or 
-
Pemetrexed 500mg/m2 + cisplatin 75mg/m2.
In order to reduce the incidence and severity of skin reactions, a corticosteroid should be 
given the day prior to, on the day of, and the day after pemetrexed administration. The 
corticosteroid should be equivalent to 4mg of dexamethasone administered orally twice a day. 
To reduce toxicity, subjects treated with pemetrexed must also receive vitamin 
supplementation. Subjects must take oral folic acid or a multivitamin containing folic acid 
(350 to 1000 micrograms) on a daily basis. At least five doses of folic acid must be taken 
during the seven days preceding the first dose of pemetrexed, and dosing must continue during 
the full course of therapy and for 21 days after the last dose of pemetrexed. Subjects must also 
receive an intramuscular injection of vitamin B12 (1,000 micrograms) in the week preceding 
the first dose of pemetrexed and once every three cycles thereafter. Subsequent vitamin B12 
injections may be given on the same day as pemetrexed. Subjects may also receive other pre-


Clinical Study Protocol Synopsis
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Study Code D5160C00003
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Date January 10, 2017
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treatment / concomitant treatment as recommended by approved label for pemetrexed, 
carboplatin or cisplatin as clinically indicated by the investigator.
The wash out period between stopping the randomized chemotherapy and starting AZD9291 
80mg, once daily, in subjects eligible for cross-over is at least 14 days. Any unresolved 
toxicities from prior therapy should be controlled, and be no greater than CTCAE grade 1 
(with the exception of alopecia which may be grade 2) at the time of starting AZD9291 
treatment.
Statistical methods
Subjects will be randomized to the trial in a 2:1 ratio:
-
AZD9291 80mg will be administered orally once a day 
Or
-
Platinum-based doublet chemotherapy will be administered intravenously on Day 1 of 
every 21-day cycle of either: 
o
pemetrexed 500mg/m2 + carboplatin AUC5 
Or 
o
pemetrexed 500mg/m2 + cisplatin 75mg/m2
Subjects will be stratified at randomization based on ethnicity (Asian/Non-Asian). 
PFS is the primary endpoint for this study. Approximately 410 subjects will be randomized in 
a 2:1 ratio (AZD9291: platinum-based doublet chemotherapy) in this study. 
The primary analysis of PFS will occur when at least 221 progression events have been 
observed out of the 410 globally randomized subjects. With 221 progression events, the study 
will have at least 80% power to show a statistically significant PFS at the 5% 2-sided 
significance level if the assumed treatment effect were HR 0.67; this translates to a 3 month 
improvement on an estimated median PFS of 6 months on the control arm, assuming PFS is 
exponentially distributed. The smallest treatment difference that would be statistically 
significant is a PFS HR of 0.76 (this translates into an approximate 2 month improvement on 
an estimated median PFS of 6 months on the control arm, assuming PFS is exponentially 
distributed). Assuming 15 months non-linear recruitment, 221 PFS events are expected to 
occur approximately 20 months after the first subject is randomized in the study.
Three analyses of overall survival will be conducted. The data cut-off for the first analysis will 
be performed approximately 4 months after data cut-off for the primary analysis of PFS, and 
the second analysis will be performed when the OS data are approximately 50% mature 
(approximately 205 death events). The final (third) analysis of overall survival will be 
performed when the OS data are approximately 70% mature (approximately 287 death 
events).


Clinical Study Protocol Synopsis
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
15 (164)
PFS will be analyzed using a log rank test stratified by ethnicity (Asian, Non-Asian). The 
primary PFS analysis will be based on investigator-recorded assessment of disease 
progression by RECIST; a sensitivity analysis will also be performed using a blinded 
independent central review (BICR).
Secondary endpoints of ORR, DoR, DCR and Tumour Shrinkage will be analyzed at the time 
of the primary PFS analysis. OS will be summarised only at the time of the primary analysis 
(a summary of the frequency of deaths and primary cause of death will be provided for safety 
purposes); the analysis of OS will be performed approximately 4 months after the data cut-off 
for the primary analysis of PFS.
In order to provide strong control of the type I error rate (2-sided 5%), the primary endpoint 
(PFS) and key secondary endpoints (ORR and OS) will be tested in a sequential order. If any 
previous analysis in the sequence is not statistically significant, the alpha spending cannot be 
transferred to subsequent analyses. Since three OS analyses are planned, the Lan DeMets 
approach that approximates the O’Brien and Fleming spending function will be used to 
maintain an overall 2-sided 5% type I error across the testing of three planned analyses of OS. 
The safety and efficacy data collected for Chinese subjects from mainland China after global 
recruitment has closed will be combined with data from the Chinese subjects recruited prior to 
the end of global recruitment, and summarised and analysed separately. This China cohort will 
provide standalone safety and efficacy analyses of subjects from China and will be reported 
separately from the Clinical Study Report. These analyses may be performed at the time of the 
primary PFS analysis if at least 20 PFS events have been observed out of approximately 50 
Chinese subjects, otherwise summaries of efficacy will be provided only. Additional follow-
up of Chinese subjects if deemed appropriate may be performed when the PFS data are more 
mature (for example, 70% maturity, as consistent with the primary global PFS analysis).


Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
16 (164)
TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
VERSION HISTORY..............................................................................................2
PROTOCOL SYNOPSIS.........................................................................................6
TABLE OF CONTENTS.......................................................................................16
1.
INTRODUCTION .................................................................................................27
1.1
Non-small Cell Lung Cancer (NSCLC).................................................................27
1.2
Background and rationale for conducting this study .............................................28
1.3
Rationale for study design, doses and control groups............................................28
1.4
Benefit/risk and ethical assessment........................................................................31
1.5
Study Design..........................................................................................................32
2.
STUDY OBJECTIVES..........................................................................................34
2.1
Primary objective...................................................................................................34
2.2
Secondary objectives .............................................................................................34
2.3
Safety objectives ....................................................................................................35
2.4
Exploratory objectives ...........................................................................................35
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL......................37
3.1
Inclusion criteria ....................................................................................................37
3.2
Exclusion criteria ...................................................................................................38
3.3
Subject screening and randomization ....................................................................41
3.4
Procedures for handling incorrectly randomized subjects.....................................42
3.5
Methods for assigning treatment groups................................................................42
3.6
Restrictions ............................................................................................................43
3.7
Discontinuation from study treatment ...................................................................44
3.7.1
Procedures for discontinuation of a subject from study treatment.........................44
3.8
Criteria for withdrawal...........................................................................................45
3.8.1
Screen/enrolment failures ......................................................................................46
3.8.2
Withdrawal of the informed consent......................................................................46
3.9
Termination of the study........................................................................................46


Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
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4.
STUDY PLAN AND TIMING OF PROCEDURES.............................................47
4.1
Screening period ....................................................................................................63
4.2
Treatment period (up to primary PFS analysis).....................................................67
4.3
Post-Treatment Follow-up period..........................................................................69
4.3.1
Discontinuation visit (up to primary PFS analysis) ...............................................69
4.3.2
Twenty-eight Day follow-up (up to primary PFS analysis)...................................70
4.3.3
Progression follow-up (up to primary PFS analysis).............................................70
4.3.4
Survival follow-up (up to final OS analysis) .........................................................71
4.3.5
Patient management post primary PFS analysis and up to final OS analysis........71
4.3.6
Patient management post final (OS) analysis ........................................................72
5.
STUDY ASSESSMENTS .....................................................................................72
5.1
Efficacy assessments..............................................................................................73
5.1.1
RECIST 1.1............................................................................................................73
5.1.2
RECIST 1.1 – Blinded Independent Central Review (BICR) Assessment ...........74
5.2
Safety assessments.................................................................................................75
5.2.1
Laboratory safety assessments...............................................................................75
5.2.2
Volume of blood ....................................................................................................76
5.2.3
Physical examination .............................................................................................77
5.2.4
ECG........................................................................................................................77
5.2.5
Echocardiogram/MUGA scan................................................................................78
5.2.6
Vital signs ..............................................................................................................79
5.2.6.1
Pulse, blood pressure, weight and height...............................................................79
5.2.7
Other safety assessments........................................................................................79
5.2.7.1
Ophthalmologic exam............................................................................................79
5.3
Other assessments ..................................................................................................79
5.3.1
Baseline characteristics..........................................................................................79
5.3.2
Patient reported outcomes......................................................................................80
5.3.2.1
EORTC QLQ-C30 and QLQ-LC13.......................................................................80
5.3.2.2
EQ-5D-5L ..............................................................................................................80
5.3.2.3
PRO-CTCAE .........................................................................................................81
5.3.2.4
Administration of electronic PROs........................................................................81
5.3.2.5
Healthcare resource use .........................................................................................82
5.4
Pharmacokinetics ...................................................................................................82
5.4.1
Collection of samples for subjects randomized to AZD9291................................82
5.4.2
Determination of drug concentration.....................................................................83
5.4.3
Storage and destruction of pharmacokinetic samples............................................83
5.4.4
Collection of cerebrospinal fluid – optional ..........................................................83
5.5
Pharmacogenetics ..................................................................................................84
5.5.1
Collection of pharmacogenetic samples ................................................................84
5.5.2
Storage, re-use and destruction of pharmacogenetic samples ...............................84
5.6
Exploratory Research.............................................................................................85


Clinical Study Protocol
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Study Code D5160C00003
Version 5
Date January 10, 2017
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5.6.1
Collection of Tumour Biopsy Samples..................................................................85
5.6.1.1
Archival Tumour....................................................................................................85
5.6.1.2
Optional Tissue Collection at Screening................................................................85
5.6.1.3
Discontinuation Biopsy..........................................................................................85
5.6.2
Collection of exploratory samples – blood-borne biomarkers and ctDNA ...........86
5.7
Management of Biological Samples ......................................................................87
5.7.1
Storage, re-use and destruction of biological samples...........................................87
5.7.2
Labelling and shipment of biological samples.......................................................87
5.7.3
Chain of custody of biological samples.................................................................87
5.7.4
Withdrawal of Informed Consent for donated biological samples ........................87
5.8
Post progression outcomes.....................................................................................88
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT ..............................88
6.1
Definition of adverse events ..................................................................................88
6.2
Definitions of serious adverse event......................................................................89
6.3
Recording of adverse events ..................................................................................89
6.3.1
Time period for collection of adverse events.........................................................89
6.3.2
Follow-up of unresolved adverse events................................................................90
6.3.3
Variables ................................................................................................................90
6.3.4
Causality collection................................................................................................91
6.3.5
Adverse events based on signs and symptoms.......................................................92
6.3.6
Adverse events based on examinations and tests...................................................92
6.3.7
Hy’s Law................................................................................................................92
6.3.8
Disease progression ...............................................................................................92
6.3.9
New cancers...........................................................................................................93
6.3.10
Handling of deaths .................................................................................................93
6.4
Reporting of serious adverse events.......................................................................93
6.5
Overdose ................................................................................................................94
6.6
Pregnancy...............................................................................................................95
6.6.1
Maternal exposure..................................................................................................95
6.6.2
Paternal exposure...................................................................................................95
6.7
Management of toxicities related to AZD9291......................................................96
6.7.1
Skin reactions.........................................................................................................97
6.7.2
Diarrhoea................................................................................................................97
6.8
Management of toxicities related to Platinum-Based Doublet 
Chemotherapy........................................................................................................97
6.8.1
Dose Adjustment Recommendations for Carboplatin ...........................................98
6.8.2
Precaution for Cisplatin .........................................................................................98
6.8.3
Dose Adjustment Recommendations for Pemetrexed and Cisplatin .....................98
6.9
Study governance and oversight ..........................................................................100
6.9.1
Steering Committee .............................................................................................100


Clinical Study Protocol
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Study Code D5160C00003
Version 5
Date January 10, 2017
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7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ..................101
7.1
Identity and Dose of investigational product – AZD9291...................................101
7.2
Identity and Dose of Comparator Product – Platinum-based Doublet-
Chemotherapy......................................................................................................102
7.3
Labelling ..............................................................................................................102
7.4
Storage .................................................................................................................103
7.5
Compliance ..........................................................................................................103
7.6
Accountability......................................................................................................103
7.7
Concomitant and other treatments .......................................................................103
7.7.1
Other concomitant treatment................................................................................105
7.8
Post Study Access to Study Treatment ................................................................105
7.9
Cross-over to AZD9291.......................................................................................105
8.
STATISTICAL ANALYSES BY ASTRAZENECA..........................................106
8.1
Statistical considerations......................................................................................106
8.2
Sample size estimate............................................................................................106
8.3
Definitions of analysis sets ..................................................................................107
8.3.1
Full analysis set....................................................................................................107
8.3.2
Safety analysis set................................................................................................107
8.3.3
PK analysis set .....................................................................................................107
8.4
Outcome measures for analyses...........................................................................107
8.4.1
Calculation or derivation of efficacy variables....................................................107
8.4.2
Calculation or derivation of safety variable(s).....................................................113
8.4.3
Calculation or derivation of pharmacokinetic variables ......................................114
8.5
Methods for statistical analyses ...........................................................................114
8.5.1
Analysis of the primary variable (s).....................................................................114
8.5.2
Analysis of the secondary variable(s)..................................................................116
8.5.2.1
Analysis of ORR..................................................................................................116
8.5.2.2
Analysis of DoR...................................................................................................117
8.5.2.3
Analysis of DCR..................................................................................................117
8.5.2.4
Analysis of Tumour Shrinkage ............................................................................117
8.5.2.5
Analysis of OS .....................................................................................................117
8.5.2.6
Analysis of Time to PRO Symptom Deterioration..............................................117
8.5.2.7
Analysis of PRO Symptom Improvement Rate...................................................118
8.5.2.8
Pharmacokinetics .................................................................................................118
8.5.2.9
Patients with EGFR T790M mutation status detected in baseline plasma 
sample (ctDNA)...................................................................................................118
8.5.3
Exploratory analysis.............................................................................................118
8.6
China Cohort........................................................................................................119
8.6.1
Definition of China analysis sets .........................................................................119


Clinical Study Protocol
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Study Code D5160C00003
Version 5
Date January 10, 2017
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8.6.1.1
China-only Full Analysis Set...............................................................................119
8.6.1.2
China-only Safety Analysis Set ...........................................................................119
8.6.1.3
China-only Pharmacokinetic Analysis Set...........................................................119
8.6.2
China-only analyses.............................................................................................120
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ........................120
9.1
Training of study site personnel...........................................................................120
9.2
Monitoring of the study .......................................................................................120
9.2.1
Source data...........................................................................................................121
9.2.2
Study agreements.................................................................................................121
9.2.3
Archiving of study documents.............................................................................121
9.3
Study timetable and end of study.........................................................................121
9.4
Data management by AstraZeneca ......................................................................122
10.
ETHICAL AND REGULATORY REQUIREMENTS.......................................123
10.1
Ethical conduct of the study.................................................................................123
10.2
Subject data protection.........................................................................................123
10.3
Ethics and regulatory review................................................................................123
10.4
Informed consent .................................................................................................124
10.5
Changes to the protocol and informed consent form...........................................124
10.6
Audits and inspections .........................................................................................125
11.
LIST OF REFERENCES.....................................................................................125
LIST OF TABLES
Table 1
Study Plan for AZD9291 Subjects up to Primary PFS Analysis..............47
Table 2
Study Plan for Platinum-based Doublet-Chemotherapy Subjects 
up to Primary PFS Analysis .....................................................................52
Table 3
Study Plan for Subjects Crossing Over to AZD9291 up to Primary 
PFS Analysis ............................................................................................58
Table 4
Study Schedule Post Primary PFS Analysis and up to the Final OS 
Analysis ....................................................................................................60
Table 5
Laboratory Safety Variables.....................................................................75
Table 6                  Blood sample volumes AZD9291 subjects ..............................................76
Table 7
Blood sample volumes Platinum-based Doublet-chemotherapy 
subjects .....................................................................................................77
Table 8
PK blood sample schedule (Pre-dose, 0.5 to 1.5, and 2 to 4 hours).........82


Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
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Table 9                  Tumour biopsy samples............................................................................85
Table 10
Summary of recording and follow-up of adverse events and deaths........90
Table 11
Dose Interventions....................................................................................96
Table 12
Visit Response for HRQoL and disease-related symptoms ...................111
LIST OF FIGURES
Figure 1
Study flow chart up to primary PFS Analysis..........................................33
LIST OF APPENDICES
Appendix A
Additional Safety Information................................................................130
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document ...............................................................................132
Appendix C
Pharmacogenetics Research ...................................................................133
Appendix D
Actions Required in Cases of Combined Increase of 
Aminotransferase and Total Bilirubin - Hy’s Law.................................137
Appendix E
Guidance regarding Potential Interactions With Concomitant 
Medications ............................................................................................142
Appendix F
Patient Reported Outcomes (EOR-QLQ-C30, EOR-QLQ-LC13, 
PRO-CTCAE and EQ-5D-5L) ...............................................................145
Appendix G
Guidelines for Evaluation of Objective Tumour Response Using 
RECIST 1.1 (Response Evaluation Criteria in Solid Tumours).............157


Clinical Study Protocol
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Study Code D5160C00003
Version 5
Date January 10, 2017
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
AE
Adverse event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AnLK
Anaplastic lymphoma kinase
ANSM
Agence Nationale de Securite du Medicaments
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
ATP
Adenosine Triphosphate
AUC
Area under the curve (plasma concentration / time curve)
AUC5
Area under the plasma concentration–time curve 5 mg/ml per minute
AUC (0-24)
Area under the curve (plasma concentration / time curve from zero to 24 
hours)
AUCss
Plasma Clearance at Steady State
AZ
AstraZeneca
BCRP
Breast Cancer Resistance Protein
BICR
Blinded Independent Central Review
BoR
Best Overall Response
BP
Blood Pressure 
BSA
Body Surface Area
BUN 
Blood urea nitrogen 
CI
Confidence Interval
CK
Creatine Kinase
CLss/F
Plasma Clearance at Steady State
Cmax
Maximum plasma concentration
CMET
Proto-oncogene encoding Hepatocyte Growth Factor Receptor
CR
Complete response
CRF
Case Report Form (electronic/paper)
CRO
Clinical Research Organization


Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
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Abbreviation or 
special term
Explanation
CSA
Clinical Study Agreement
CSF
Cerebrospinal Fluid
CSR
Clinical Study Report
Css
Concentration at Study State
CT
Computer Tomography
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
Circulating tumour Deoxyribonucleic acid 
CYP
Cytochrome P450
DAE
Discontinuation of Investigational Product due to Adverse Event
DCO
Data cut off
DCR
Disease Control Rate
DLT
Dose limiting toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid 
DoR
Duration of Response
DUS
Disease under Study
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram 
EDoR
Expected Duration of Response
EGFR
Epidermal Growth Factor Receptor
EGFRm+
EGFR Mutation positive
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire – Core 30 items
EORTC QLQ LC13
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire – Lung Cancer 13 items
EU
European Union
Ex19Del
Deletions in exon 19
FDA
Food and Drug Administration
FFPE
Formalin Fixed and Paraffin Embedded
FFST
Time to First Subsequent Therapy or Death
FSH
Follicle-Stimulating Hormone
FSI
First Subject In


Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
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Abbreviation or 
special term
Explanation
G719X
An in-frame amino acid (glycine (G)) deletion at position 719 in EGFR
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GMP
Good Manufacturing Practice
HDPE
High-Density-Polyethylene
HER2
Human Epidermal Growth Factor Receptor 2
HR
Hazard Ratio
HIV
Human Immunodeficiency Virus
HRQoL
Health Related Quality of Life
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ICR
Independent Central Review
ILD
Interstitial Lung Disease
INR
International Normalized Ratio
International 
Co-ordinating 
investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally. 
IP
Investigational Product 
IUS
Intra Uterine System
iv
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
KRAS
Kirsten Rat Sarcoma Viral Oncogene Homolog
LDH
Lactate Dehydrogenase
LDL
Low-density Lipoprotein
LH
Luteinizing Hormone
LSLV
Last Subject Last Visit
LVEF
Left Ventricular Ejection Fraction
MedDRA
Medical Dictionary for Regulatory Activities
MPA
Medical Products Agency
MRI
Magnetic resonance imaging


Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
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Abbreviation or 
special term
Explanation
MUGA
Multi Gated Acquisition Scan
NCI
National Cancer Institute
NE
Not evaluable
NSCLC
Non-Small Cell Lung Cancer
NTL
Non-target Lesion
NYHA
New York Heart Association
OAE
Other Significant Adverse Event
ORR
Objective Response Rate
OS
Overall Survival
P
Probability
PD
Progression of disease
PD
Pharmacodynamics
PFS
Progression Free Survival
PFSs
Time from Randomization to Second Progression
PGx
Pharmacogenetic research
PI
Principal Investigator 
PK
Pharmacokinetics
PR
Partial Response
Pre-treatment: 
Medication used before chemotherapy, e.g., folic acid, corticosteroid and 
vitamin B12 or anti-emetic drugs according to the respective chemotherapy 
local labels (cisplatin, carboplatin and pemetrexed).
Pre-medication: 
Medication used to prevent study drug side effects, for example, to treat 
diarrhoea once it is detected, and used as long as needed. It can also be used 
prophylactically in case subjects are prone to develop a particular adverse 
event.
PRO
Patient Reported Outcome
QD
Once daily
QT
Interval on the electrocardiogram representing the duration of 
depolarization and repolarization of the heart
QTc
The QT interval corrected for heart rate
RAC
Accumulation on Multiple Dosing
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RR
Response Rate
SAE
Serious adverse event 


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Study Code D5160C00003
Version 5
Date January 10, 2017
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Abbreviation or 
special term
Explanation
SAP
Statistical Analysis Plan
SD
Stable disease
SDV
Source Data Verification
SoC
Standard of Care
SPC
EU Summary of Product Characteristics
T790M
An amino acid substitution at position 790 in EGFR, from a Threonine (T) 
to a Methionine (M)
T790M+
T790M mutation positive
TKI
Tyrosine Kinase Inhibitor
TL
Target Lesion
tmax
Time to Cmax
tss max
Time to Css max
TSST
Time to Second Subsequent Therapy or Death
ULN
Upper Limit of Normal
US
United States
WBDC
Web Based Data Capture
WHO
World Health Organization


Clinical Study Protocol
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Study Code D5160C00003
Version 5
Date January 10, 2017
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1.
INTRODUCTION
1.1
Non-small Cell Lung Cancer (NSCLC)
Lung cancer has been the most common cancer in the world for several decades, and by 2008, 
there were an estimated 1.61 million new cases, representing 12.7% of all new cancers. It was 
also the most common cause of death from cancer, with 1.38 million deaths (18.2% of the 
total) (GLOBOCAN 2008).  NSCLC represents approximately 80% to 85% of all lung 
cancers. Unfortunately, at the time of diagnosis approximately 70% of NSCLC patients 
already have advanced or metastatic disease not amenable to surgical resection. Furthermore, 
a significant percentage of early stage NSCLC patients who have undergone surgery 
subsequently develop distant recurrence and die as a result of their lung cancer (Pisters & Le 
Chevalier 2005). Patients presenting with unselected advanced NSCLC have a median overall 
survival (OS) of 10 to 12 months (Bonomi 2010).
Treatment of advanced NSCLC can be guided by the presence of certain molecular drivers 
such as EGFR, anaplastic lymphoma kinase (AnLK) and KRAS mutations. The incidence of 
Epidermal Growth Factor Receptor mutation positive (EGFRm+) NSCLC is approximately 
10-15% and 30-40% of patients in the West and Asia, respectively.
Although first- (eg, erlotinib, gefitinib) and second-generation (eg, afatinib) Epidermal 
Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR TKIs) are established therapies for 
patients with NSCLC known to have activating mutations in EGFR (EGFRm+), the 
emergence of a secondary T790M mutation in patients treated with an EGFR TKI agent has 
been described as a major route of development of resistance to this class of therapy (Pao et al 
2005, Kobayashi et al 2005) in approximately 60% of patients (Yu et al 2013).
In the advanced NSCLC post-EGFR TKI treatment failure setting, prolonged survival rates 
remain very low (median OS in the region of 1 to 2 years, Wang et al 2012, Wu et al 2010, 
Fukuoka et al 2011).  No approved therapy is currently available for patients with T790M 
mutation positive (T790M+) tumours that have acquired EGFR TKI resistance or 
refractoriness.  There is no data on response rates (RRs) with single agent chemotherapy in the 
specific subset of T790M+ patients after failure of EGFR TKI. 
Treatment guidelines for 2nd line treatment of EGFRm+ NSCLC include using platinum based 
chemotherapy doublet treatment (e.g. U.S. NCCN 2012 guidelines). Second-line platinum-
based chemotherapy post EGFR TKI for EGFRm+ NSCLC generally provides RRs 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).  Although slightly better than the RRs that can be expected with 
single-agent chemotherapy in later lines, these data together with the toxicity burden 
associated with doublet chemotherapy (that includes nausea, vomiting, bone marrow 
suppression resulting in high risk of infection and bleeding, alopecia, fatigue, and peripheral 
neuropathy) confirm the unmet medical need that exists in this patient population. 


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Study Code D5160C00003
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Date January 10, 2017
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1.2
Background and rationale for conducting this study
Activation of the EGFR tyrosine kinase triggers a cascade of intracellular downstream 
signalling events affecting cell proliferation, survival, angiogenesis and, potentially, 
metastases.  Selective inhibition of EGFR tyrosine kinase has demonstrated clinical benefit in 
approximately 70% of patients with advanced NSCLC harbouring the sensitivity mutations 
(the most common of which are L858R and deletions in exon 19 (Ex19del), described 
collectively as EGFR mutation).  The tumours initially respond to EGFR-TKIs, but 
subsequently develop resistance to therapy, with a median time to progression of nine months.  
In approximately 60% of these initially EGFR-TKI responsive patients (Yu et al 2013), 
disease progression is associated with the emergence of a secondary EGFR mutation, T790M 
in exon 20 of EGFR, which confers resistance to EGFR-TKI therapy (Pao et al 2005).  The 
T790M resistance mutation is located in the hinge region of the kinase domain of the 
adenosine triphosphate (ATP) binding pocket of the EGFR protein, where the bulky 
methionine side chain prevents binding of the EGFR-TKIs (Heuckmann et al 2012).  
AZD9291 is a potent irreversible inhibitor of both the single EGFRm+ (TKI sensitivity 
conferring mutation) and dual EGFRm+/T790M+ (TKI resistance conferring mutation) 
receptor forms of EGFR with a significant selectivity margin over wild-type EGFR.  
Therefore AZD9291 has the potential to provide clinical benefit to patients with advanced 
NSCLC harbouring both the single sensitivity mutations and the resistance mutation following 
prior therapy with an EGFR-TKI.  The clinical development programme with AZD9291 will 
initially assess the safety and efficacy of AZD9291 in patients with advanced NSCLC whose 
cancers have progressed following an EGFR-TKI regimen (with or without additional 
chemotherapy regimens), as they currently represent a major unmet medical need population.  
Importantly, preliminary data from an ongoing phase I study (D5160C00001) in this patient 
population has demonstrated good evidence of efficacy in patients who have progressed on or 
after an approved EGFR TKI only or additional therapies (> 2nd line), while treatment with 
AZD9291 has been well tolerated across a range of doses (refer to the latest edition of the 
Investigator Brochure for further details) (Ranson et al WCLC 2013).
1.3
Rationale for study design, doses and control groups
At the time this protocol was written (May 2014), no approved therapies existed to 
specifically target T790M+ acquired EGFR-TKI resistance, which represents the most 
common resistance mechanism in the majority of NSCLC patients with acquired EGFR-TKI 
resistance. The purpose of this study is to further characterise and confirm the efficacy and 
safety of AZD9291 in EGFRm+/T790M+ NSCLC patients who have acquired resistance to an 
EGFR-TKI (and who are chemotherapy naive) observed in the ongoing phase I study 
(D5160C00001).
The majority of patients with EGFRm+ NSCLC respond well initially to treatment with 
EGFR-TKIs with an Objective Response Rate (ORR) of approximately 60 to 70%, but 
eventually develop resistance with a median time to progression of around 9-11 months.  In at 


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least half of initially TKI-responsive patients, disease progression is associated with the 
emergence of a secondary EGFR mutation, called T790M mutation in exon 20 of the EGFR 
gene.  There are no current effective recommended standard of care therapies for these 
NSCLC patients with acquired EGFR-TKI resistance who are T790M+.  Treatment guidelines 
for 2nd line treatment of EGFRm+ NSCLC include using platinum based chemotherapy 
doublet treatment (e.g. NCCN 2012). 
A commonly used platinum doublet is pemetrexed in combination with cisplatin or 
carboplatin. Pemetrexed in combination with cisplatin demonstrated superior OS compared to 
Gemcitabine in combination with cisplatin in previously untreated advanced NSCLC patients 
with non-squamous histology (adenocarcinoma and large cell carcinoma) in a randomised 
phase III trial: 12.6 vs. 10.9 (with adenocarcinoma) and 10.4 vs 6.7 months (with large-cell 
carcinoma) respectively (Scagliotti et al 2008).  Pemetrexed in combination with cisplatin 
reported lower rates of grade 3 or 4 neutropenia, anaemia, thrombocytopenia, febrile 
neutropenia and alopecia, and higher rates of grade 3 or 4 nausea, compared to Gemcitabine in 
combination with cisplatin.  Pemetrexed in combination with either Cisplatin or Carboplatin is 
therefore an appropriate control arm treatment in this phase III trial. 
This patient population with a major unmet medical need is therefore appropriate to evaluate 
the efficacy and safety of AZD9291 in this study.
The study design has been discussed with the US Food and Drug Administration (FDA), 
Swedish Medical Products Agency (MPA) and French Agence Nationale de Securite du 
Medicaments (ANSM) during Scientific Advice consultations and all key aspects of the Phase 
III 2nd line study design including Progression Free Survival (PFS) as primary endpoint, dose 
rationale and patient population were supported. 
Given the unmet medical need that exists in the aforementioned patient population alongside 
the lack of well-proven treatment options, and given the good evidence of efficacy with 
AZD9291 (>50% RR in T790M+ population) and well tolerated profile reported in ongoing 
phase I study in T790M+ patient population (Ranson et al WCLC 2013), it is considered 
appropriate to assess efficacy and safety of AZD9291 in a randomised open-label phase III 
study in 2nd line NSCLC versus pemetrexed in combination with cisplatin or carboplatin.  
Once 410 subjects have been randomized globally, recruitment will continue only in mainland 
China until approximately 50 Chinese subjects have been randomized. This is to ensure 
adequate Chinese subject participation to satisfy China Regulatory Authority requirements; it 
is anticipated that this target may not be met before the global recruitment of 410 is achieved.
The primary objective of this study is PFS.  This is an appropriate primary efficacy endpoint 
in this NSCLC population and may be associated with an improvement in OS, delay to time of 
initiation of subsequent therapies, symptom control, and quality of life.  Secondary efficacy 
endpoints are those that are appropriate to this patient population and include, Duration of 
response (DoR), Disease Control Rate (DCR) [DCR: Complete response (CR) + Partial 
Response (PR) + Stable disease (SD)] and overall survival.  Characterisation of 


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pharmacokinetics (PK) as well as the safety and tolerability of AZD9291 will also be assessed 
as a secondary endpoint.
Several exploratory endpoints will be evaluated (see Section 2.4).  These include assessment 
of the effect of AZD9291 compared with chemotherapy on post progression outcomes such as 
time from randomization to second progression and time to subsequent treatments.  Additional 
exploratory endpoints will include comparisons of AZD9291 with chemotherapy on health 
state utility (using EQ-5D-5L health state utility index) and resource utilization (e.g. hospital 
visits), patient self-reporting of adverse events, the relationship between PK and selected 
endpoints, tumour samples and biomarkers (ctDNA for the assessment of biomarkers) and 
tumour biopsy for companion diagnostic development.
The collection of cerebrospinal fluid (CSF) from a select number of subjects who provide 
voluntary optional consent will enable the investigation of the ability of AZD9291, AZ5104 
and AZ7550 to cross the blood brain barrier.  Brain metastases occur in 20-30% of patients 
with advanced NSCLC, and are associated with poor prognosis (Porta et al 2011).  The first 
generation EGFR TKI agents have demonstrated only limited efficacy in treating brain 
metastases (Bai & Han 2013, Shimato et al 2006), however, preclinical data suggests that 
AZD9291 may be capable of crossing the blood brain barrier (see Investigator Brochure) and 
potentially may offer better exposures in this anatomically protected location.
Overall, the totality of primary, secondary and exploratory endpoints in this study will allow a 
robust characterisation of overall benefit / risk of AZD9291 for patients with metastatic, 
EGFR T790M+ mutation-positive, non-small cell lung cancer (NSCLC) whose
NSCLC has progressed during treatment with an FDA-approved, EGFR tyrosine kinase 
inhibitor.
The dose of 80 mg once daily was selected from a review of all available safety, tolerability, 
PK and efficacy data from study D5160C00001, in patients with advanced NSCLC who have 
progressed following prior therapy with a prior EGFR TKI agent.  At the Investigator 
Brochure (IB) data cut-off of 19 November 2013, AZD9291 had been administered as a 
capsule formulation across the dose range of 20 to 240mg once daily in this study:  20 mg 
(n=21), 40 mg (n=55), 80 mg (n=47), 160 mg (n=40) and 240 mg (n=7). No dose limiting 
toxicities (DLTs) have been reported at any dose level in the escalation cohorts during the 21-
day DLT evaluation period.  Subjects have once daily doses of AZD9291 for durations of at 
least 10 months depending on the dose level.  Emerging efficacy data has demonstrated 
durable objective responses from the starting dose level of 20 mg once daily (Ranson et al 
WCLC 2013).  The selected 80 mg dose is four fold higher than the minimum efficacious dose 
tested in study D5160C00001, whilst still being one third of the maximum dose level 
investigated (240 mg).  The 80 mg dose level is considered to have a safety and tolerability 
profile appropriate for chronic administration to subjects with advanced NSCLC.
Up to the primary PFS analysis,  once subjects on the platinum-based doublet chemotherapy 
arm are determined to have objective radiological progression according to RECIST 1.1 by 
the investigator and confirmed by independent central imaging review, they will be given the 
opportunity to begin treatment with AZD9291 80mg, once daily.  These subjects may 


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continue treatment with AZD9291 as long as they show clinical benefit, as judged by the 
investigator. If a subject has been deemed to have objective disease progression according to 
Investigator tumour assessment by RECIST 1.1, but is not confirmed by independent central 
imaging review, he/she is not eligible to cross-over to AZD9291 at that time.  Should it be in 
the subject’s best interest, and only if further randomized chemotherapy is warranted, he/she 
may continue to receive randomized doublet chemotherapy (if initial doublet chemotherapy 
treatment has not yet been completed) or pemetrexed maintenance monotherapy. Sites are to 
submit the next scheduled tumour assessment for central imaging review according to Table 2. 
Following the primary PFS analysis subjects still on the platinum-based doublet chemotherapy 
arm will be given the opportunity to begin treatment with AZD9291 80 mg, once daily if it is 
considered by the Investigator to be in the patient's best interest, and if they are eligible to 
receive AZD9291 (no contraindications). At least a 14 day washout period is required 
between last dose of chemotherapy and starting AZD9291 treatment.
If subjects are not eligible to receive AZD9291, they will enter into the follow-up phase of the 
study, and other treatment options should be discussed by the investigator.
1.4
Benefit/risk and ethical assessment
In the advanced NSCLC post-EGFR TKI treatment failure setting that has been chosen for 
initial study with AZD9291, median survival is modest (~16 months for second line therapy, 
~10 months for third line therapy) with no effective treatment options currently available. This 
population therefore represents a major unmet medical need.  Although there can be no 
certainty of clinical benefit to patients, the biological hypothesis, non-clinical and, in 
particular, the preliminary clinical efficacy and safety data with AZD9291 in the ongoing 
phase I trial (D5160C00001) support the notion that dual EGFR mutation inhibition may be a 
valid target for the treatment of EGFR T790M mutation-positive NSCLC tumours driven.  
Specifically the safety profile of AZD9291 is (in the ongoing phase I trial) modest with the 
majority of adverse events being non-clinically significant EGFR-related adverse events ie, 
diarrhoea and skin rash. All trials of AZD9291 exclude patients with clinically significant 
toxicities related to prior treatments in addition to specifically excluding patients with a 
history of interstitial lung disease (ILD) or clinically active interstitial lung disease as this is 
an uncommon but well documented EGFR related toxicity. All patients will be assessed for 
possible known EGFR-related toxicities and detailed information on the management of 
EGFR-related gastrointestinal, dermatological and ophthalmic is being provided for all 
AZD9291 studies.
It is therefore reasonable and appropriate to evaluate the oral administration of AZD9291 in 
comparison to standard platinum-based doublet chemotherapy as a second-line therapy in this 
unmet medical need post-EGFR TKI EGFR T790M mutation-positive NSCLC patient 
population, according to the proposed study design.


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1.5
Study Design 
This is a phase III, open label, randomized study to assess the safety and efficacy of AZD9291 
(80 mg, orally, once daily) versus platinum-based doublet chemotherapy in second-line 
patients with EGFR T790M mutation-positive, locally advanced or metastatic NSCLC, who 
have progressed following treatment with an approved epidermal growth factor tyrosine 
kinase inhibitor agent. 
Subjects will have to provide a mandatory biopsy sample for central testing of T790M 
mutation status following confirmed disease progression on the most recent treatment 
regimen. The T790M mutation status of the subject’s tumour must be determined by a 
designated central laboratory using the cobas® EGFR Mutation Test (Roche Molecular 
Systems). 
Up to primary PFS analysis, subjects should continue on study treatment until Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) defined progression or until a 
treatment discontinuation criterion is met. There is no maximum duration of treatment as 
subjects may continue to receive randomized treatment beyond RECIST 1.1 defined 
progression as long as they show clinical benefit, as judged by the investigator. Following the 
primary PFS analysis no further RECIST data will be collected (apart from patients in China. 
For the China cohort, RECIST data will be collected for China PFS analysis when at least 20 
PFS events have been observed out of approximately 50 Chinese subjects).
Once subjects on the platinum-based doublet chemotherapy arm are determined to have 
objective radiological progression according to RECIST 1.1 by the investigator and confirmed 
by independent central imaging review, they will be given the opportunity to begin treatment 
with AZD9291 80 mg, once daily. These subjects may continue treatment with AZD9291 as 
long as they show clinical benefit, as judged by the investigator.
If a subject has been deemed to have objective disease progression according to Investigator 
tumour assessment by RECIST 1.1, but is not confirmed by independent central imaging 
review, he/she is not eligible to cross-over to AZD9291 at that time. Should it be in the 
subject’s best interest, and only if further randomized chemotherapy is warranted, he/she may 
continue to receive randomized doublet chemotherapy (if initial doublet chemotherapy 
treatment has not yet been completed) or pemetrexed maintenance monotherapy. Sites are to 
submit the next scheduled tumour assessment for central imaging review according to Table 2. 
Following the primary PFS analysis, subjects still on the platinum-based doublet 
chemotherapy arm will be given the opportunity to begin treatment with AZD9291 80 mg, 
once daily if it is considered by the Investigator to be in the patient's best interest, and if they 
are eligible to receive AZD9291 (no contraindications). At least a 14 day washout period is 
required between last dose of chemotherapy and starting AZD9291 treatment.


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Figure 1
Study flow chart up to primary PFS Analysis


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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To assess the efficacy of AZD9291 
compared with platinum-based doublet 
chemotherapy by assessment of 
Progression Free Survival (PFS).
PFS using investigator assessments according to 
Response Evaluation Criteria in Solid Tumours 
(RECIST 1.1).
Sensitivity analysis of PFS using Blinded 
Independent Central Review (BICR).
2.2
Secondary objectives
Secondary Objective:
Outcome Measure :
To further assess the efficacy of AZD9291 
compared with platinum-based doublet 
chemotherapy in terms of:  
- Objective Response Rate (ORR)
- Duration of Response (DoR)
- Disease Control Rate (DCR)
- Tumour shrinkage 
- Overall Survival (OS)
ORR, DoR, DCR and tumour shrinkage using 
investigator assessments according to Response 
Evaluation Criteria in Solid Tumours (RECIST 
1.1).
Analysis of overall survival.
To assess the effect of AZD9291 compared 
to platinum-based doublet chemotherapy 
on subjects’ disease-related symptoms and 
health related quality of life (HRQoL).
EORTC QLQ-C30 and EORTC QLQ-LC13.
EORTC QLQ-C30:
Questionnaire consisting of 30 items measuring 
subjects general cancer symptoms and 
functioning.
EORTC QLQ-LC13:
A complementary questionnaire measuring lung 
cancer symptoms.
To characterise the pharmacokinetics (PK) 
of AZD9291 and metabolites in subjects 
receiving AZD9291.
PK exposure parameters derived from plasma 
concentrations of AZD9291, and metabolites 
AZ5104 and AZ7550.
PK Parameters (CLss/F, Css, min and Css, max 
AUCss) will be derived using population PK 
analysis and reported separately to the CSR. Data 
from this study may form part of a pooled 
analysis with data from other studies


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2.3
Safety objectives
Safety Objective:
Outcome Measure :
To assess the safety and tolerability profile 
of AZD9291 compared with platinum-
based doublet chemotherapy.
Adverse events (graded by CTCAE v4)
- Clinical chemistry, haematology and urinalysis
- Vital signs (pulse and BP), Physical 
Examination, Weight
- Central Digital ECG
- Echocardiogram/MUGA (for LVEF) 
- WHO performance status)
2.4
Exploratory objectives  
Results from such analyses outlined below may be reported separately from the Clinical Study 
Report (CSR).
Exploratory Objective:
Outcome Measure :
To explore the relationship between PK 
and selected endpoints (which may include 
efficacy, safety and/or PRO), where 
deemed appropriate.
Correlation of PK with other primary /secondary/ 
exploratory endpoints in subjects treated with 
AZD9291.
Results from such analyses will be reported 
separately from the Clinical Study Report (CSR). 
Data from this study may also form part of a 
pooled analysis with other AZD9291 studies.
To compare the effects of AZD9291 
compared with platinum-based 
chemotherapy on post progression 
outcomes
Time from randomization to second progression 
(PFS2)
Time to subsequent treatments
Time to change in symptoms (including post 
progression assessments)
To further characterise the effects of 
AZD9291 on survival outcomes.
Assess the impact on overall survival of baseline 
potentially prognostic factors (e.g. tumour stage, 
performance status, sex, baseline LDH)
Assess the impact on overall survival of 
subsequent treatments and other potential 
covariates (e.g. changes in performance status)
To compare adverse events by subject self-
reporting of specific CTCAE symptoms 
(where applicable) between AZD9291 and 
chemotherapy.
Collection of approximately 28 PRO-CTCAE 
symptoms via an electronic device solution (in 
countries where language is available).


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To compare AZD9291 treatment with 
platinum-based chemotherapy treatment on 
health state utility.
The EQ-5D-5L health state utility index will be 
used to derive health state utility based on 
subject reported data.
To compare health resource use associated 
with AZD9291 treatment with platinum-
based chemotherapy treatment.
Health resource utilisation measures including
hospitalization, outpatient visits, or emergency 
department visits.
To characterise the pharmacokinetics (PK) 
of AZD9291 and metabolites in 
cerebrospinal fluid (CSF).
Concentration of AZD9291, AZ5104 and 
AZ7550. Ratio of metabolites to AZD9291.
Ratio of CSF to plasma concentration.
Summaries of PK concentration data.
To collect and store deoxyribonucleic acid 
(DNA) for future exploratory research into 
genes/genetic variation that may influence 
PK or response to AZD9291, platinum-
based doublet chemotherapy (ie, 
absorption, distribution, metabolism, 
excretion, safety and efficacy) and/or 
susceptibility to/development of cancers.
Correlation of polymorphisms with variation in 
PK, PD, safety or response observed in subjects 
treated with AZD9291 or comparator.
Data generated may be reported separately and 
may also form part of a pooled analysis with 
other AZD9291 studies.
To collect and store tumour samples and 
blood-based samples for potential for 
exploratory research into factors that may 
influence susceptibility to/development of 
NSCLC/cancer and/or response to 
AZD9291(where response is defined 
broadly to include efficacy, tolerability or 
safety).
Analysis of key genetic and proteomic markers 
to include, but not limited to, EGFR mutations, 
HER2 & CMET expression and/or amplication. 
Collection of plasma samples to include, but not 
be limited to, extraction of circulating tumour 
DNA (ctDNA) for investigation of blood borne 
biomarkers. The sample may be used to 
investigate the relationship between PK and 
blood-borne biomarkers.
Samples may be analysed retrospectively. Any 
biomarker data generated may be reported 
separately and may also form part of a pooled 
analysis with other AZD9291 studies.
To collect and store plasma for isolation of 
ctDNA.  Extracted ctDNA will be assessed 
for the presence of genetic abberations 
including, but not limited to, EGFR 
mutations (T790M, L858R, etc).   These 
samples may be shared with a diagnostic 
partner for development of a ctDNA test 
for T790M detection.
Retrospective/real-time analysis of EGFR (and 
other) mutations in ctDNA from all study 
subjects (mandatory).


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To collect and store residual CSF for 
potential exploratory research of factors 
that may influence development of 
NSCLC and/or response to AZD9291 
(where response is defined broadly to 
include efficacy, tolerability or safety).
Collection of CSF for the investigation of PK 
and/or biomarkers. Samples may be analysed 
retrospectively.
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
For inclusion in the study subjects should fulfil the following criteria:
1. Provision of signed and dated, written informed consent prior to any study specific 
procedures, sampling and analyses. If a subject declines to participate in any voluntary 
exploratory research and/or genetic component of the study, there will be no penalty or 
loss of benefit to the subject and he/she will not be excluded from other aspects of the 
study.
2. Female and male subjects aged at least 18 years. Subjects from Japan aged at least 20 
years.
3. Subjects with histologically- or cytologically-documented NSCLC.
4. Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy 
5. Evidence of radiological disease progression following 1st line EGFR TKI (ie, 1st line 
treatment for advanced/metastatic disease) without any further treatment. 
6. Subjects must have a diagnosis of “Nonsquamous Non-Small Cell Lung Cancer” in order 
to be eligible to receive treatment with pemetrexed platinum-based doublet chemotherapy 
in accordance with local prescribing information.
7. Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to 
be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, 
L861Q).
8. Subjects must have central confirmation of tumour T790M+ mutation status from a tissue 
biopsy sample taken after documented disease progression on first line treatment with an 
approved, EGFR tyrosine kinase inhibitor.
9. WHO performance status 0-1 with no deterioration over the previous 2 weeks and a 
minimum life expectancy of 12 weeks.
10. At least one lesion, not previously irradiated and not chosen for biopsy during the study 
screening period, that can be accurately measured at baseline as ≥ 10mm in the longest 


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diameter (except lymph nodes which must have short axis ≥ 15mm) with computerised 
tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate 
repeated measurements.  If only one measurable lesion exists, it is acceptable to be used as 
long as it has not been previously irradiated and baseline tumour assessment scans are 
done at least 14 days after the screening biopsy is performed.
11. Females should be using adequate contraceptive measures, should not be breast feeding 
and must have a negative pregnancy test prior to start of dosing if of child-bearing 
potential or must have evidence of non-child-bearing potential by fulfilling one of the 
following criteria at screening:
-
Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 
months following cessation of all exogenous hormonal treatments
-
Women under 50 years old would be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and with Luteinizing Hormone (LH) and Follicle-Stimulating Hormone 
(FSH) levels in the post-menopausal range for the institution
-
Documentation of irreversible surgical sterilisation by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation.
12. Male subjects should be willing to use barrier contraception ie, condoms.
13. For inclusion in optional genetic research, subject must provide informed consent for 
genetic research.
If a subject declines to participate in any voluntary exploratory research and/or genetic 
component of the study, there will be no penalty or loss of benefit to the subject and 
he/she will not be excluded from other aspects of the study.
3.2
Exclusion criteria
Subjects should not enter the study if any of the following exclusion criteria are fulfilled:
1. Treatment with any of the following:

Treatment with more than one prior line of treatment for advanced NSCLC

Treatment with an EGFR-TKI (e.g., erlotinib, gefitinib or afatinib) within 8 days or 
approximately 5x half-life, whichever is the longer, of the first dose of study 
treatment.  (If sufficient washout time has not occurred due to schedule or PK 
properties, an alternative appropriate washout time based on known duration and 
time to reversibility of drug related adverse events could be agreed upon by 
AstraZeneca and the Investigator) 

Any investigational agents or other anticancer drugs from a previous treatment 
regimen or clinical study within 14 days of randomization


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
Previous treatment with AZD9291, or a 3rd generation EGFR TKI

Prior neo-adjuvant or adjuvant chemotherapy treatment within 6 months of starting 
1st EGFR TKI treatment

Major surgery (excluding placement of vascular access) within 4 weeks of 
randomization

Radiotherapy treatment to more than 30% of the bone marrow or with a wide field 
of radiation within 4 weeks of randomization

Subjects currently receiving (or unable to stop use at least 1 week prior to 
receiving the first dose of AZD9291) medications or herbal supplements known to 
be potent inhibitors or inducers of CYP3A4 (Appendix E)

Treatment with an investigational drug within five half-lives of the compound
2. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 (with the 
exception of alopecia grade 2) at the time of starting study treatment.
3. Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring 
steroids for at least 4 weeks prior to start of study treatment.
4. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled 
hypertension and active bleeding diatheses, which in the investigator’s opinion makes it 
undesirable for the subject to participate in the trial or which would jeopardise compliance 
with the protocol, or active infection including hepatitis B, hepatitis C and human 
immunodeficiency virus (HIV).  Screening for chronic conditions is not required.
5. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the 
formulated product or previous significant bowel resection that would preclude adequate 
absorption of AZD9291.
6. Any of the following cardiac criteria:

Mean resting corrected QT interval (QTc) > 470 msec, obtained from 3 
electrocardiograms (ECGs)

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, PR interval >250msec

Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalaemia, congenital long QT syndrome, family history of 
long QT syndrome or unexplained sudden death under 40 years of age in first degree 
relatives or any concomitant medication known to prolong the QT interval. 


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7. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required 
steroid treatment, or any evidence of clinically active interstitial lung disease.
8. Inadequate bone marrow reserve or organ function as demonstrated by any of the following 
laboratory values:

Absolute neutrophil count < 1.5 x 109/L 

Platelet count < 100 x 109/L

Haemoglobin < 90 g/L

Alanine aminotransferase (ALT) > 2.5 times the upper limit of normal (ULN) if no
demonstrable liver metastases or > 5 times ULN in the presence of liver metastases

Aspartate aminotransferase (AST) > 2.5 times ULN if no demonstrable liver metastases 
or > 5 times ULN in the presence of liver metastases

Total bilirubin > 1.5 times ULN if no liver metastases or > 3 times ULN in the presence 
of documented Gilbert’s Syndrome (unconjugated hyperbilirubinaemia) or liver 
metastases

Creatinine >1.5 times ULN concurrent with creatinine clearance < 50 ml/min 
(measured or calculated by Cockcroft and Gault equation); confirmation of creatinine 
clearance is only required when creatinine is > 1.5 times ULN.
9. History of hypersensitivity of AZD9291 (or drugs with a similar chemical structure or class 
to AZD9291) or carboplatin or pemetrexed or cisplatin, or any exipients of these agents.
10. Women who are breast-feeding. 
11. Males and females of reproductive potential who are not using and effective method of 
birth control and females who are pregnant or breastfeeding or have a positive (urine or 
serum) pregnancy test prior to study entry.
12. Contraindication for pemetrexed and cisplatin/carboplatin (e.g. predominantly squamous 
cell histology).
13. Involvement in the planning and conduct of the study (applies to AstraZeneca staff or staff 
at the study site).
14. Judgment by the investigator that the subject should not participate in the study if the 
subject is unlikely to comply with study procedures, restrictions and requirements.
In addition, the following is considered a criterion for exclusion from the exploratory genetic
research:


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15. Previous allogenic bone marrow transplant.
16. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic 
sample collection.
Procedures for withdrawal of incorrectly randomized subjects see Section 3.4. 
3.3
Subject screening and randomization
Investigator(s) should keep a subject pre-screening log of subjects considered for the study.
The Investigator(s) will:
1. Obtain signed informed consent from the potential subject, or their guardian or legal 
representative before any study specific procedures are performed.
2. Determine subject eligibility. See Section 3.1 and 3.2.
3. Obtain a unique 7-digit enrolment number (E-code) 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 AURA3 study.
At Visit 2, once the subject is deemed eligible, the Principal Investigator or suitably trained 
delegate will:
4. Obtain a unique randomization number via IVRS/IWRS.
Randomization codes will be assigned as subjects become eligible for randomization. 
If a subject is re-screened, always a new E-code will be assigned. Any repeated tests and/or 
procedures will be performed as per documented local standards. Subjects will reconfirm their 
consent to participate in the study by resigning and dating their original consent form(s), next 
to their initial signature and date. A subject with a valid negative T790M result cannot be re-
screened. 
The following assessments need to be repeated for subjects who are re-screened and where 
>28 days will have lapsed since their last screening period to the date of proposed 
randomization:

Demography & baseline characteristics

Medical/surgical history

Inclusion/exclusion criteria

Physical examination, including weight

WHO performance status


Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
42 (164)

Pregnancy test (if applicable)

Vital signs (pulse and BP)

Clinical chemistry/haematology/urinalysis

Digital ECG

Echocardiogram/MUGA (if clinically needed)

Tumour assessments (RECIST 1.1)

Concomitant medications & procedures

Adverse events

Anti-cancer treatment
A subject randomized to platinum-based doublet chemotherapy who crosses over to AZD9291 
will be managed via IVRS/IWRS. 
If a subject withdraws from participation in the study, then his/her enrolment/randomization 
code cannot be reused.
Note: Section 4.1 describes the procedures to be carried out during screening/enrolment 
period. Section 4.2 describes procedures to be carried out during randomization period.
3.4
Procedures for handling incorrectly randomized subjects
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive study medication.  There can be no exceptions to this rule.  Subjects 
who are randomized, but subsequently found not to meet all the eligibility criteria must not be 
initiated on treatment, and must be withdrawn from the study. 
Where a subject does not meet all the eligibility criteria but is started on treatment in error, the 
Investigator should inform the AstraZeneca study physician immediately, and a discussion 
should occur between the AstraZeneca study physician and the investigator regarding whether 
to continue or discontinue the subject from treatment. The AstraZeneca study physician must 
ensure all decisions are appropriately documented.
3.5
Methods for assigning treatment groups
Suitable subjects will be centrally randomized to receive either AZD9291 80mg QD p.o. or 
platinum-based doublet chemotherapy (pemetrexed 500mg/m2 + carboplatin AUC5 or 
pemetrexed 500mg/m2 + cisplatin 75mg/m2) on Day 1 of every 21d cycle in a 2:1 (AZD9291:
platinum-based doublet chemotherapy) ratio using the IVRS/IWRS system. The 
investigational site must declare (in IVRS/IWRS), prior to randomization, their choice of 
chemotherapy for that subject.
Subjects will be stratified at randomization based on ethnicity (Asian/Non-Asian).


Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
43 (164)
Investigators will have the option to provide AZD9291 80mg, once daily, to subjects 
randomized to platinum-based doublet chemotherapy, who are determined by them to have 
objective radiological progression according to RECIST 1.1, and who have objective disease 
progression confirmed by the independent central imaging review.
3.6
Restrictions
The following restrictions apply while the subject is receiving AZD9291 and for the specified 
times before and after:
1.
Females of child-bearing potential should use reliable methods of contraception 
from the time of screening until 6 weeks after discontinuing study 
treatment. Acceptable methods of contraception include total and true sexual
abstinence, tubal ligation, hormonal contraceptives that are not prone to drug-drug 
interactions (IUS Levonorgestrel Intra Uterine System (Mirena), 
Medroxyprogesterone injections (Depo-Provera)), copper-banded intra-uterine 
devices and vasectomised partner. All hormonal methods of contraception should 
be used in combination with the use of a condom by their male sexual partner for 
intercourse. For subjects receiving platinum-based doublet-chemotherapy, the 
reliable methods of contraception chosen should be in accordance with the local 
prescribing label.
2.
Male subjects should be asked to use barrier contraceptives (ie, by use of condoms) 
during sex with all partners during the trial and for a washout period of 4 months.  
Subjects should avoid procreation for 6 months after completion of trial treatment.
Subjects should refrain from donating sperm from the start of dosing until 6 months 
after discontinuing study treatment.  If male subjects wish to father children they 
should be advised to arrange for freezing of sperm samples prior to the start of 
study treatment. For subjects receiving platinum-based doublet chemotherapy, 
above recommendations should be in accordance with the local prescribing label.
3.
Once enrolled, all subjects must try to avoid concomitant use of medications, herbal 
supplements and/or ingestion of foods that are known potent inducers of CYP3A4 
whenever feasible, but subjects may receive any medication that is clinically 
indicated for treatment of adverse events. Such drugs must have been discontinued 
for an appropriate period before they enter screening and for a period of 3 months 
after the last dose of AZD9291. All concomitant medications should be captured on 
the eCRF. Guidance on medicines to avoid, medications that require close 
monitoring and on washout periods is provided (see Appendix E).
4.
If medically feasible, subjects taking regular medication, with the exception of 
potent inducers of CYP3A4 (see above), should be maintained on it throughout the 
study period. Subjects randomized to AZD9291 taking concomitant medications 
whose disposition is dependent upon Breast cancer resistance protein (BCRP) 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 


Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
44 (164)
whilst receiving AZD9291. Guidance on medications to avoid, medications that 
require close monitoring and on washout periods is provided (see Appendix E).
Patients taking rosuvastatin should have creatine phosphokinase levels monitored 
(due to BCRP mediated increase in exposure.) If the subject experiences any 
potentially relevant adverse events suggestive of muscle toxicity including 
unexplained muscle pain, tenderness, or weakness, particularly if accompanied by 
malaise or fever, rosuvastatin must be stopped, and any appropriate further 
management should be taken.
Subjects taking warfarin should be monitored regularly for changes in prothrombin 
time or international normalized ratio (INR).
5.
Subjects 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 subject 
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.  Subjects must 
not use any eye drops or ointment for treatment of eye symptoms, unless agreed by 
a study doctor, at any time during the study until 1 week after AZD9291 has been 
permanently discontinued.  Subject should consult the clinic promptly if they have 
any concerns. 
3.7
Discontinuation from study treatment
Subjects may be discontinued from study treatment in the following situations:

Subject decision.  The subject is at any time free to discontinue treatment, without 
prejudice to further treatment

Adverse Event

Pregnancy

Severe non-compliance with the study protocol as judged by the investigator and/or 
AstraZeneca

Subject incorrectly initiated on study treatment

Objective disease progression or subject is no longer receiving clinical benefit

Lost to follow up. 
3.7.1
Procedures for discontinuation of a subject from study treatment 
The Principal Investigator/Investigator will perform the best possible observation(s), test(s) 
and evaluation(s) as well as give appropriate medication and all possible measures for the 
safety of the subject. They will also immediately inform AstraZeneca of the withdrawal. 
Adverse events will be followed up (See Section 6); electronic questionnaire devices (e.g., for 


Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
45 (164)
patient reported outcomes) and all unused study drug should be returned by the subject or 
representative (e.g. caretaker, family member). 
Any subject who discontinues study treatment for reasons other than objective disease 
progression should have tumour assessments performed as scheduled in the protocol (see 
Table 1 or Table 2) until objective disease progression is documented or death occurs, unless 
consent is withdrawn.  (Note: following the primary PFS analysis tumour assessments will no 
longer be collected apart from patients in China. For the China cohort, RECIST data will be 
collected for China PFS analysis when at least 20 PFS events have been observed out of 
approximately 50 Chinese subjects. Following China PFS analysis, tumour assessments will 
no longer be collected for China cohort). Study procedures related to PROs, SAEs and anti-
cancer treatment must be captured until permanent withdrawal from the study.
If a subject is withdrawn from study, see Section 3.8.
3.8
Criteria for withdrawal
At any time, subjects are free to discontinue study treatment or withdraw from the study (ie, 
study treatment and assessments), without prejudice to further treatment.  A subject that 
decides to discontinue investigational product will always be asked about the reason(s) and the 
presence of any adverse events.  If possible, they will be seen and assessed by an 
Investigator(s).  Adverse events will be followed up (See Section 6); electronic questionnaire 
devices (ePRO) and all investigational products should be returned by the subject or 
representative. The term withdrawal from the study refers to both discontinuation from study 
treatment and study assessments.
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 clinical study database (eCRF). 
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.


Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
46 (164)
Withdrawn subjects will not be replaced.
3.8.1
Screen/enrolment failures
Screen/enrolment failures are subjects who do not fulfil the eligibility criteria for the study, 
and therefore must not receive AZD9291.  These subjects should have the reason for study 
withdrawal recorded as “Eligibility Criteria not fulfilled” (ie, subject does not meet the 
required inclusion/exclusion criteria).  This reason for study withdrawal is only valid for 
screen/enrolment failures (not subjects who have received investigational product).
3.8.2
Withdrawal of the informed consent
Subjects are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE).  The Investigator will follow up AEs outside of the clinical study. 
The subject or representative will return the ePRO device and unused AZD9291 tablets.  
If a subject withdraws from participation in the study, then his/her enrolment/randomization 
code cannot be reused. 
3.9
Termination of the study
The study may be stopped if, in the judgment of AstraZeneca, trial subjects are placed at 
undue risk because of clinically significant findings that:
-
meet individual stopping criteria or are otherwise considered significant 
-
are assessed as causally related to investigational product
-
are not considered to be consistent with continuation of the study.
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the eCRF. All reasons for discontinuation of 
treatment must be documented.
In the case of terminating the study, the Sponsor will ensure that adequate consideration is 
given to the protection of the subject’s interest.


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
47 (164)
4.
STUDY PLAN AND TIMING OF PROCEDURES 
Table 1
Study Plan for AZD9291 Subjects up to Primary PFS Analysis
Visit
Screening/ 
Enrolment
Treatment Period (further treatment
cycles as per Cycle 7)
Follow-up Period
For details see Protocol Section
1
2
3
4
5
6
7-9
10+
Treatment 
Discontinuation
28-day
follow-up
Progression 
follow-up
Survival
follow-up
Cyclea/ Day
C1  
D1
C1  
D8
C1     
D15
C2    
D1
C3    
D1
C4-6     
D1
C7b+     
D1
NA
NA
NA
NA
Day
-28 
to 1
1
8
15
22
43
64-106
127+
NA
NA
NA
NA
Window (days)y
NA
0
+2
+2
+7
+7
+7
+7
0
+7
+ 7
+ 7
SECTION:
Informed consentc
X
3.3, 4.1, 4.2, 4.3
Submit tumour tissue sample 
for mutation analysisd
X
4.1 & 5.6
Collect/submit optional 
tumour biopsy for 
exploratory research & 
diagnostic development
X
Xu
Xu
4.1 & 5.6
Archival tumour tissuee
X
5.6
Demography & baseline 
characteristics
X
4.1
Medical/surgical history
X
4.1
Inclusion/exclusion criteria
X
3
Physical examination, 
including weightm
X
Xf
X
X
X
X
X
Xw
5.2.3, 5.2.6.1


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
48 (164)
Table 1
Study Plan for AZD9291 Subjects up to Primary PFS Analysis
Visit
Screening/ 
Enrolment
Treatment Period (further treatment
cycles as per Cycle 7)
Follow-up Period
For details see Protocol Section
1
2
3
4
5
6
7-9
10+
Treatment 
Discontinuation
28-day
follow-up
Progression 
follow-up
Survival
follow-up
Cyclea/ Day
C1  
D1
C1  
D8
C1     
D15
C2    
D1
C3    
D1
C4-6     
D1
C7b+     
D1
NA
NA
NA
NA
Day
-28 
to 1
1
8
15
22
43
64-106
127+
NA
NA
NA
NA
Window (days)y
NA
0
+2
+2
+7
+7
+7
+7
0
+7
+ 7
+ 7
SECTION:
Height
X
5.2.6.1
WHO Performance statusm
X
X
X
X
X
X
X
X
X
4.1
Pregnancy test (pre-
menaopausal females only)
X
5.2.1
Ophthalmologic assessment
X
as clinically indicated
5.2.7.1
Plasma sample for ctDNAm
and blood borne biomarkers
Xh
X
X
X
X
X
X
every 6 weeks in line with
RECIST assessmentsi
5.6.2
Vital signs (pulse and BP)m
X
X
X
X
X
X
X
X
X
Xw
5.2.6
Clinical chemistry/ 
Haematology/Urinalysism
X
X
X
X
X
X
X
X
X
Xw
5.2.1
PK blood sample (including 
metabolites)
X
X
X
C5 only
Xv
5.4
Digital ECGg
X
X
X
X
X
X
X
X
X
Xw
5.2.4
Echocardiogram/MUGA (for 
LVEF)
X
every 12 weeks (± 1 week) relative to randomization
Xw
5.2.5
Optional genetic consent and 
sample
Xj
5.5


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
49 (164)
Table 1
Study Plan for AZD9291 Subjects up to Primary PFS Analysis
Visit
Screening/ 
Enrolment
Treatment Period (further treatment
cycles as per Cycle 7)
Follow-up Period
For details see Protocol Section
1
2
3
4
5
6
7-9
10+
Treatment 
Discontinuation
28-day
follow-up
Progression 
follow-up
Survival
follow-up
Cyclea/ Day
C1  
D1
C1  
D8
C1     
D15
C2    
D1
C3    
D1
C4-6     
D1
C7b+     
D1
NA
NA
NA
NA
Day
-28 
to 1
1
8
15
22
43
64-106
127+
NA
NA
NA
NA
Window (days)y
NA
0
+2
+2
+7
+7
+7
+7
0
+7
+ 7
+ 7
SECTION:
Optional CSF sample
X (once only)k
5.4.4
Tumour assessments l
(RECIST v1.1)
X
every 6 weeks (± 1 week) relative to randomization until disease progression
4.1, 4.2, 4.3.3, 5.1.1, 5.1.2
EORTC QLQ-C30 and
EQ-5D-5L (by e-device)x
Xm
every 6 weeks (± 1 week) relative to randomization
X
Xn
Xn
5.3.2
EORTC QLQ LC13 (by e-
device)x
Xm
weekly (± 2 days)
relative to 
randomization
every 3 weeks (± 3 days)
relative to randomization
X
Xo
Xo
5.3.2
PRO-CTCAE (by e-
device)p, x
Xm
weekly (± 2 days) for first 18 weeks 
from randomization
Xq
X
Xo
Xo
5.3.2
Healthcare Resource Use
asked for at every visit
5.3.2.5
IVRS/IWRS
X
X
X
X
X
Xb
X
3.3, 3.5
Dispense study medication
X
X
X
X
Xb
3.3
Dose with AZD9291
Daily dosing
7.1
Concomitant medication & 
procedures
7.7
Adverse events
Xr
6.3 & 6.4


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
50 (164)
Table 1
Study Plan for AZD9291 Subjects up to Primary PFS Analysis
Visit
Screening/ 
Enrolment
Treatment Period (further treatment
cycles as per Cycle 7)
Follow-up Period
For details see Protocol Section
1
2
3
4
5
6
7-9
10+
Treatment 
Discontinuation
28-day
follow-up
Progression 
follow-up
Survival
follow-up
Cyclea/ Day
C1  
D1
C1  
D8
C1     
D15
C2    
D1
C3    
D1
C4-6     
D1
C7b+     
D1
NA
NA
NA
NA
Day
-28 
to 1
1
8
15
22
43
64-106
127+
NA
NA
NA
NA
Window (days)y
NA
0
+2
+2
+7
+7
+7
+7
0
+7
+ 7
+ 7
SECTION:
Survival Status
Xs
4.3.4
Anti-cancer treatment
X
X
Xs
4.2
Subsequent response/ 
progression data
Xt
5.8
a
A cycle is defined as 21-day treatment period.
b
Visit schedule changes after Cycle 7 Day 1 from every 21 days (3 weeks) to every 42 days (6 weeks).
c
Consent may be taken prior to the 28-day window if required. The screening period will then start with first study-related assessment, excluding the collection of the 
tumour tissue sample for central mutation analysis.
d
Taken following progression on the latest line of therapy. The collection of this tumour tissue sample for central mutation analysis is not included in the 28-day 
screening period.
e
Archival tumour sample only to be submitted after T790M positive status confirmed by central testing.  Not required for T790M negative patients.
f
If  assessments are not done at Visit 2, but have been done at Visit 1 and within 14 day window prior to staring study treatment, with no change in condition and no 
clinical indication to do so, they do not have to be repeated on Visit 2  (except for fasting glucose).
g
There is a potential to move from centrally reviewed to locally reviewed ECGs upon review of QT data of approximately 100 subjects. 
h
To be taken prior to receiving the central T790M mutation result.  All screening plasma samples are required by AstraZeneca, regardless of the outcome of the 
mutation screening.
i
Collect every 6 weeks up to and including progression (corresponding with the RECIST assessments – and continuing after treatment discontinuation in absence of 
disease progression). If patient discontinues from study, please collect a sample at treatment discontinuation and at Progression follow-up.


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
51 (164)
j
If for any reason the sample is not drawn prior to randomization it may be taken at any visit until the last study visit.
k
To be obtained at one time point at any time from Cycle 2 Day 1 onwards.
l
At least one lesion, not previously irradiated that can be accurately measured.  
m
To be completed pre-dose.
n
Assess every 6 weeks (± 1 week) relative to the date of randomization until end of study (including survival follow-up period) and at the time of progression.
o
Assess every 3 weeks (± 3 days) relative to the date of randomization until end of study (including survival follow-up period) and at the time of progression.
p
PRO-CTCAE will only be administered in those languages where a linguistically validated version exists.
q
Assessed at Cycle 7 Day 1 then every 3 weeks (± 3 days) relative to the date of randomization thereafter until end of study (including survival follow-up period) and 
at the time of progression.
r
Following AZD9291 discontinuation, SAEs considered related to study procedures should continue to be collected until disease progression.
s
Survival status including anti-cancer treatment to be performed every 6 weeks (relative to randomization) following disease progression or withdrawal from 
treatment. [Note: Additional survival calls will be made in the 2 weeks following the date of the data cut-off for each OS analysis.]
t
Record subsequent response/progression data every 6 weeks until first confirmed disease progression on a subsequent treatment.
u
Discontinuation biopsy can be taken at discontinuation or progression, whichever comes first.
v
After Cycle 7, every other cycle up to and including Cycle 13.
w
A 28-day follow-up assessment will be required if on treatment assessment was abnormal at treatment discontinuation.
x
ePRO LogPads must be assigned to subjects only on the day of randomization; baseline ePROs should be completed by subjects prior to dosing, when they are still 
in the clinic on the day of randomization, to ensure these are done properly.
y
Visit windows are always calculated in relation to Cycle 1, Day 1.


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
52 (164)
Table 2
Study Plan for Platinum-based Doublet-Chemotherapy Subjects up to Primary PFS Analysis 
Visit
Screening/ 
Enrolment
Randomization
Treatment Period (further treatment
cycles as per Cycle 7)
Follow-up Period
For details see Protocol 
Section
1
2
3
4
5
6
7-9
10+
Treatment 
Discontinuation
28-day
follow-up
Progression 
follow-up
Survival
follow-up
Cyclea/ Day
C1  
D1f
C1  
D8
C1      
D15
C2     
D1
C3      
D1
C4-6     D1
C7b
+      NA
NA
NA
NA
Day
-28 
to 1
-7 to 1
1
8
15
22
43
64-106
127
+
NA
NA
NA
NA
Window 
(days)y
NA
-7
0
+2
+2
+7
+7
+7
+7
0
+7
+ 7
+ 7
SECTION:
Informed consentc
X
3.3, 4.1, 4.2, 4.3
Submit tumour tissue 
sample for mutation 
analysisd
X
4.1 & 5.6
Collect and submit
optional tumour 
biopsy for exploratory 
research and 
diagnostic 
development
X
Xu
Xu
4.1 & 5.6
Archival tumour 
tissuee
X
5.6
Demography & 
baseline characteristics
X
4.1
Medical/surgical 
history
X
4.1
Inclusion/exclusion 
criteria
X
3


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
53 (164)
Table 2
Study Plan for Platinum-based Doublet-Chemotherapy Subjects up to Primary PFS Analysis 
Visit
Screening/ 
Enrolment
Randomization
Treatment Period (further treatment
cycles as per Cycle 7)
Follow-up Period
For details see Protocol 
Section
1
2
3
4
5
6
7-9
10+
Treatment 
Discontinuation
28-day
follow-up
Progression 
follow-up
Survival
follow-up
Cyclea/ Day
C1  
D1f
C1  
D8
C1      
D15
C2     
D1
C3      
D1
C4-6     D1
C7b
+      NA
NA
NA
NA
Day
-28 
to 1
-7 to 1
1
8
15
22
43
64-106
127
+
NA
NA
NA
NA
Window 
(days)y
NA
-7
0
+2
+2
+7
+7
+7
+7
0
+7
+ 7
+ 7
SECTION:
Physical examination, 
including weightm
X
Xg
X
X
X
Xv
X
Xv
5.2.3, 5.2.6.1
Height
X
5.2.6.1
WHO Performance 
status m
X
X
X
X
X
X
X
X
X
4.1
Pregnancy test (pre-
menaopausal females 
only)
X
5.2.1
Ophthalmologic 
assessment
X
as clinically indicated
5.2.7.1
Vital signs (pulse and 
BP) m
X
X
X
X
X
X
X
X
X
Xv
5.2.6
Clinical chemistry/ 
Haematology/
Urinalysism
X
Xg
X
X
X
X
X
Xv
X
Xv
5.2.1


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
54 (164)
Table 2
Study Plan for Platinum-based Doublet-Chemotherapy Subjects up to Primary PFS Analysis 
Visit
Screening/ 
Enrolment
Randomization
Treatment Period (further treatment
cycles as per Cycle 7)
Follow-up Period
For details see Protocol 
Section
1
2
3
4
5
6
7-9
10+
Treatment 
Discontinuation
28-day
follow-up
Progression 
follow-up
Survival
follow-up
Cyclea/ Day
C1  
D1f
C1  
D8
C1      
D15
C2     
D1
C3      
D1
C4-6     D1
C7b
+      NA
NA
NA
NA
Day
-28 
to 1
-7 to 1
1
8
15
22
43
64-106
127
+
NA
NA
NA
NA
Window 
(days)y
NA
-7
0
+2
+2
+7
+7
+7
+7
0
+7
+ 7
+ 7
SECTION:
Plasma sample for 
ctDNAm and blood 
borne biomarkers
Xh
X
X
X
X
X
X
every 6 weeks in line with
RECIST assessments
5.6.2
Digital ECGk
X
X
X
X
X
X
X
Xv
X
Xv
5.2.4
Echocardiogram/MUG
A (for LVEF)
X
every 12 weeks (± 1 week) relative to randomization
Xv
5.2.5
Optional genetic 
consent and sample
Xj
5.5
Tumour assessments
(RECIST v1.1)l
X
every 6 weeks (± 1 week) relative to randomization until disease progression
4.1, 4.2, 4.3.3, 5.1.1, 5.1.2
EORTC QLQ-C30 and
EQ-5D-5L 
(by e-device)w
X
every 6 weeks (± 1 week) relative to randomization
X
Xn
Xn
5.3.2
EORTC QLQ LC13 
(by e-device)w
X
weekly(± 2 days) relative to 
randomization
every 3 weeks (± 3 days) relative
to randomization
X
Xo
Xo
5.3.2
PRO-CTCAE                  
(by e-device)p, w
X
weekly (± 2 days) for first 18 weeks from randomization
Xq
X
Xo
Xo
5.3.2


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
55 (164)
Table 2
Study Plan for Platinum-based Doublet-Chemotherapy Subjects up to Primary PFS Analysis 
Visit
Screening/ 
Enrolment
Randomization
Treatment Period (further treatment
cycles as per Cycle 7)
Follow-up Period
For details see Protocol 
Section
1
2
3
4
5
6
7-9
10+
Treatment 
Discontinuation
28-day
follow-up
Progression 
follow-up
Survival
follow-up
Cyclea/ Day
C1  
D1f
C1  
D8
C1      
D15
C2     
D1
C3      
D1
C4-6     D1
C7b
+      NA
NA
NA
NA
Day
-28 
to 1
-7 to 1
1
8
15
22
43
64-106
127
+
NA
NA
NA
NA
Window 
(days)y
NA
-7
0
+2
+2
+7
+7
+7
+7
0
+7
+ 7
+ 7
SECTION:
Healthcare Resource 
Use
asked for at every visit
5.3.2.5
IVRS/IWRS
X
X
X
3.3, 3.5, 7.2
Folic Acid 
administration 
(pre-treatment)
5-7d prior to 1st infusion; daily during treatment period
4.2
Vitamin B12 
(pre-treatment)
Within 7d prior to 1st infusion; every 9 weeks during treatment period
4.2
Corticosteroid 
administration 
(pre-treatment)
On the day prior to, on the day, and on the day after infusion
4.2
Platinum-based 
Doublet 
Chemotherapyx
X
X
X
X
3.3, 7.2
Concomitant 
medication & 
procedures
7.7
Adverse events
Xr
6.3 & 6.4


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
56 (164)
Table 2
Study Plan for Platinum-based Doublet-Chemotherapy Subjects up to Primary PFS Analysis 
Visit
Screening/ 
Enrolment
Randomization
Treatment Period (further treatment
cycles as per Cycle 7)
Follow-up Period
For details see Protocol 
Section
1
2
3
4
5
6
7-9
10+
Treatment 
Discontinuation
28-day
follow-up
Progression 
follow-up
Survival
follow-up
Cyclea/ Day
C1  
D1f
C1  
D8
C1      
D15
C2     
D1
C3      
D1
C4-6     D1
C7b
+      NA
NA
NA
NA
Day
-28 
to 1
-7 to 1
1
8
15
22
43
64-106
127
+
NA
NA
NA
NA
Window 
(days)y
NA
-7
0
+2
+2
+7
+7
+7
+7
0
+7
+ 7
+ 7
SECTION:
Survival Status
Xs
4.3.4
Anti-cancer treatment
X
X
Xs
4.2
Subsequent response/ 
progression data
Xt
5.8
a
A cycle is defined as 21-day treatment period.
b
Visit schedule changes after Cycle 7 Day 1 from every 21 days (3 weeks) to every 42 days (6 weeks). Platinum-based doublet chemotherapy will be administrated 
every 21 days from previous cycle’s day 1. Subjects can continue to receive platinum-based doublet-chemotherapy until meeting discontinuation criteria (see Section 
3.9) or up to a total of 6 cycles or until progression (whichever occurs first). Each cycle treatment may be interrupted for a maximum of 21 days. If cycle treatment is 
delayed by more than 21 days, subject will be permanently discontinued from doublet-chemotherapy. If appropriate, and according to the approved label use or local 
practice guidelines, pemetrexed may be continued as maintenance treatment. In case of treatment interruption, other assessments are to be done as originally planned.  
Subjects whose disease has not progressed after four cycles of platinum-based doublet chemotherapy may receive pemetrexed maintenance therapy. 
c
Consent may be taken prior to the 28-day window if required. The screening period will then start with first study-related assessment, excluding the collection of the 
tumour tissue sample for central mutation analysis.
d
Taken following progression on the latest line of therapy. The collection of this tumour tissue sample for central mutation analysis is not included in the 28-day 
screening period.
e
Archival tumour sample only to be submitted after T790M positive status confirmed by central testing.  Not required for T790M negative patients.


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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f
Chemotherapy may start within 1 week after randomization to allow Vitamin B12, Folic acid and corticosteroid treatment, as well as any other assessments for this 
visit, with the exception of the ePROs, which must be assigned to the subject on the date of randomization.
g
If  assessments are not done at Visit 2, but have been done at Visit 1 and  within 14 day window prior to starting study treatment, with no change in condition and no 
clinical indication to do so, they do not have to be repeated on Visit 2 (Except for fasting glucose).
h
To be taken prior to receiving the central T790M mutation result.  All screening plasma sample are required by AstraZeneca, regardless of the outcome of the 
mutation screening.
i
Collect every 6 weeks up to and including progression (corresponding with the RECIST assessments – and continuing after treatment discontinuation in absence of 
disease progression). If patient discontinues from study, please collect a sample at treatment discontinuation and at Progression follow-up.
j
If for any reason the sample is not drawn prior to randomization it may be taken at any visit until the last study visit.
k
There is a potential to move from centrally reviewed to locally reviewed ECGs upon review of QT data of approximately 100 subjects.
l
At least one lesion, not previously irradiated, that can be accurately measured.  Subjects randomized to the platinum-based doublet chemotherapy arm with objective 
radiological progression according to RECIST 1.1 confirmed by the Investigator and by independent central imaging review will be given the opportunity to cross-
over and begin treatment with AZD9291 80mg, once daily.  For subjects under consideration for cross-over to AZD9291, scheduled tumour assessments will continue 
until confirmation of objective radiological disease progression by independent central imaging review.
m
To be completed pre-dose for all cycles.
n
Assess every 6 weeks (± 1 week) relative to the date of randomization until end of study (including survival follow-up period) and at the time of progression.
o
Assess every 3 weeks (± 3 days) relative to the date of randomization until end of study (including survival follow-up period) and at the time of progression.
p
PRO-CTCAE will only be administered in those languages where a linguistically validated version exists.
q
Assessed at Cycle 7 Day 1 then every 3 weeks (± 3 days) relative to the date of randomization thereafter until end of study (including survival follow-up period) and 
at the time of progression.
r
Following chemotherapy discontinuation, SAEs considered related to study procedures should continue to be collected until disease progression.
s
Survival status including anti-cancer treatment to be performed every 6 weeks (relative to randomization) following disease progression or withdrawal from treatment. 
Additional survival calls will be made in the 2 weeks following the date of the data cut-off for each OS analysis.
t
Record subsequent response/progression data every 6 weeks until first confirmed disease progression on a subsequent treatment.
u
Discontinuation biopsy can be taken at discontinuation or progression, whichever comes first.
v
A 28-day follow-up assessment will be required if on treatment assessment was abnormal at treatment discontinuation.
w
ePRO LogPads must be assigned to subjects only on the day of randomization; baseline ePROs should be completed prior to dosing, by subjects when they are still in 
the clinic on the day of randomization, to ensure these are done properly.
x
Platinum-based doublet chemotherapy must be administered no less than every 21 days from previous cycle Day 1
y
Visit windows are always calculated in relation to Cycle 1 Day 1.


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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Table 3
Study Plan for Subjects Crossing Over to AZD9291 up to Primary PFS Analysis
Visit
Cross-over AZD9291 
Treatment Visit
AZD9291 
Treatment 
Discontinuation
Survival follow-up
For details see 
Protocol Section
Cyclea/ Day
Each cycle
NA
NA
Day
1
NA
NA
Window (days)j
+ 7
0
+ 7
SECTION:
Cross-over
Informed Consent
X
3.3, 4.1, 4.2, 4.3
Physical examination, 
including weight h
X
X
5.2.3, 5.2.6.1
WHO Performance 
status h
X
X
X
4.1
Vital signs (pulse and 
BP)h
X
X
5.2.6
Clinical chemistry/ 
Haematology/Urinalysis
h
X
X
5.2.1
Digital ECGh
X
X
5.2.4
EORTC QLQ-C30 and
EQ-5D-5L (by e-device)
Xc
X
Xc
5.3.2
EORTC QLQ LC13 (by 
e-device)
Xd
X
Xd
5.3.2
PRO-CTCAE (by e-
device)e
Xd
X
Xd
5.3.2
IVRS/IWRS
X
X
3.3, 3.5
Dose with AZD9291i
X 
7.1
Concomitant medication 
& procedures
X
6.7
Adverse events
Xf
6.3 & 6.4
Survival Status
Xg
4.3.4
Anti-cancer treatment
X
Xg
4.3


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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a
A cycle for subjects crossing over to AZD9291 is defined as 42-day treatment period.
b
Cross-over consent must be given prior to cross-over from platinum doublet-chemotherapy to AZD9291 treatment.
c
Assess every 6 weeks (± 1 week) relative to the date of randomization until end of study (including survival follow-up period)
d
Assess every 3 weeks (± 3 days) relative to the date of randomization until end of study (including survival follow-up period)
e
PRO-CTCAE will only be administered in those languages where a linguistically validated version exists.
f
Following platinum-based doublet chemotherapy discontinuation, SAEs considered related to study procedures should 
continue to be collected until resolution.
g
Survival status including anti-cancer treatment to be performed every 6 weeks (relative to the date of randomization) 
following subsequent disease progression with cross-over AZD9291 treatment, or withdrawal from treatment. [Note: 
Additional survival calls will be made in the 2 weeks following the date of the data cut-off for each OS analysis.]
h
To be completed pre-dose on each cross-over AZD9291 treatment visit day
i
AZD9291 will be dispensed every 42 days.
j
Cross-over visit windows are always calculated in relation to Cycle 1 Day 1 of cross-over AZD9291 treatment.


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Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
60 (164)
Table 4
Study Schedule Post Primary PFS Analysis and up to the Final OS Analysis 
Visit
Treatment post 
primary PFS 
analysis every 84 
days (12 weeks )
Follow-up Period
For details see Protocol 
Section
Treatment 
Discontinuation
28-day 
follow-up
Progression 
follow-up
Survival
follow-up
Cyclea/ Day
C7+ 
D1
NA
NA
NA
NA
Window (days)
+7
NA
+ 7
+ 7
+ 7
Collect and submit optional 
tumour biopsy for exploratory 
research and diagnostic 
development
Xb
Xb
4.1 & 5.6
Physical examination, including 
weightd
X
X
Xc
5.2.3 & 5.2.6.1
WHO Performance statusd
X
X
X
X
4.1
Pregnancy test (pre-menopausal
females only)
as clinically indicated
5.2.1
Ophthalmolgic assessment
as clinically indicated
5.2.7.1
Plasma sample for ctDNA and 
blood borne biomarkers
X
Xd
5.6.2
Vital signs (pulse and BP)d
X
X
Xc
5.2.6
Clinical chemistry/ 
Haematology/Urinalysisd
X
X
Xc
5.2.1
Local ECG assessmente
X
X
Xc
5.2.4
Echocardiogram/MUGA
X 
Xc
5.2.5


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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Visit
Treatment post 
primary PFS 
analysis every 84 
days (12 weeks )
Follow-up Period
For details see Protocol 
Section
Treatment 
Discontinuation
28-day 
follow-up
Progression 
follow-up
Survival
follow-up
Cyclea/ Day
C7+ 
D1
NA
NA
NA
NA
Window (days)
+7
NA
+ 7
+ 7
+ 7
Optional genetic consent and 
sample
Xf
5.5
Optional CSF sample
X (once only)g
5.4.4
Tumour assessments
As per routine clinical practice 
4.2 & 5.1.1
EORTC QLQ-C30 and
EQ-5D-5L (by e-device)h
X
X
X
X
5.3.2
EORTC QLQ LC13 (by e-
device)i
X
X
X
X
5.3.2
PRO-CTCAE (by e-device)i
X
X
X
X
5.3.2
IVRS/IWRS
X
X
3.3, 3.5
Dispense study medication
X
3.3
Concomitant medication & 
procedures
7.7
Adverse events
Xj
6.3 & 6.4
Survival Status
Xk
4.3.4
Anti-cancer treatment
X
Xk
4.2
Subsequent response/
progression data
Xlm
5.8


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
62 (164)
Visit
Treatment post 
primary PFS 
analysis every 84 
days (12 weeks )
Follow-up Period
For details see Protocol 
Section
Treatment 
Discontinuation
28-day 
follow-up
Progression 
follow-up
Survival
follow-up
Cyclea/ Day
C7+ 
D1
NA
NA
NA
NA
Window (days)
+7
NA
+ 7
+ 7
+ 7
Healthcare Resource Usem
X
X
X
5.3.2.5
a  A cycle is defined as 21-day treatment period.
b  Discontinuation biopsy can be taken at discontinuation or progression, whichever comes first.
c  A 28-day follow-up assessment will be required if on treatment assessment was abnormal at treatment discontinuation.
d  To be taken at the time of progression.
e Central ECG is required up to the first OS analysis DCO. Post the first OS analysis DCO, ECGs will be collected locally and stored at the site. 
f If for any reason the sample is not drawn prior to randomization it may be taken at any visit until the last study visit.
g  To be obtained at one time point at any time from Cycle 2 Day 1 onwards.
h Assess every 6 weeks (± 1 week) relative to the date of randomization until end of study (including survival follow-up period) and at the time of progression.
i Assess every 3 weeks (± 1 week) relative to the date of randomization until end of study (including survival follow-up period) and at the time of progression.
j  Following treatment discontinuation, SAEs considered related to study procedures should continue to be collected as outlines in Table 10
k  Survival status including anti-cancer treatment to be performed every 6 weeks (relative to randomization) following disease progression or withdrawal from treatment.
[Note: Additional survival calls will be made in the 2 weeks following the date of the data cut-off for each OS analysis.] 
l Record subsequent response/progression data every 6 weeks until first confirmed disease progression on a subsequent treatment. 
m The information is required up to the first OS analysis DCO. Post the first OS analysis DCO, the information is not to be collected.  


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Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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4.1
Screening period
It is recommended the screening assessments be performed in a stepwise process beginning 
with the confirmation of T790M mutation status as determined by the designated central 
laboratory.  However, certain screening assessments must be done in parallel to the T790M 
mutation assessment, as appropriate (e.g. Baseline ctDNA and blood borne biomarkers plasma 
samples must be taken before central T790M status result is known).    Procedures will be 
performed according to the Study Plan (Table 1 or Table 2). Tumour assessments and other 
clinical data obtained as standard of care prior to consent may be used for the study, provided 
the assessments fall within the protocol specified period prior to randomization.
At screening, consenting subjects are assessed to ensure that they meet eligibility criteria. 
Subjects who do not meet these criteria must not be randomized into the study. Demographic
data and other characteristics will be recorded and will include date of birth or age, gender, 
smoking history, race and/or ethnicity according to local regulations.
Subjects will be considered in screening/enrolment period until all Visit 1 assessments are 
completed and eligibility is confirmed. Subjects will be considered randomized and in the 
treatment period once study treatment has been initiated.
Written informed consent/Assignment of subject enrolment/randomization number:

Each potential subject will provide written informed consent prior to starting any study 
specific procedures (see Section 10.4).

All subjects will be required to provide consent to supply a tumour biopsy sample taken 
during the screening period for entry into this study.  This consent is included in the main 
subject informed consent form.  Please note that subjects are asked to provide separate 
consent for provision of optional tumour biopsy samples, if willing (see Section 5.6).

Additionally, subjects will be given the option to consent to the host pharmacogenetics 
research component and the CSF analysis of the study in separate Informed Consent 
Forms (ICF). 

As per standard, enrolment number (E-code) is assigned to the subject and Principal 
Investigator or delegate should perform screening/enrolment call (see Section 3.3). During 
the randomization visit (Visit 2), subject will receive randomization number and 
randomized arm information via IVRS/IWRS.  For chemotherapy, administration may 
occur approximately 7 days after randomization due to pre-treatment requirements.


Revised Clinical Study Protocol
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Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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Mandatory screening tumour biopsy sample for mutation analysis:
Tumour sample must be formalin fixed and paraffin embedded (FFPE) and must be biopsied 
following progression on the latest line of therapy.  Samples may be collected from primary or 
metastatic tumour deposits.  Bone samples (including soft tissue tumoral masses emerging 
from the bone) cannot be accepted for testing.  Sites should ship the FFPE tumour sample to 
the testing laboratory as soon as it is available. Tissue should be less than 60 days old from 
date of sectioning to date of testing.  Blocks must be provided wherever possible. If this is not 
possible, a minimum of 6 slides of freshly prepared unstained 5-micron sections from this 
screening tumour block may be provided. See Section 5.6.
The mandatory screening tumour biopsy must not be taken from a previously irradiated lesion 
(please refer to Inclusion criterion # 10 for details). This biopsy sample is not subject to the 
28-day screening window; if tissue is already available from a biopsy taken since 
documentation of disease progression on the most recent treatment regimen then there is no 
need for a further biopsy as this sample can be submitted for T790M mutation status. If the 
first biopsy is not confirmed as T790M mutation positive due to test failure (i.e. an invalid 
result or invalid run occurred), testing will be repeated and an additional biopsy sample may 
be requested. If the T790M mutation is not detected in the first biopsy (and the cobas® EGFR 
Mutation Test indicates a valid result), no additional testing for the subject will be performed 
for this study and an additional biopsy sample WILL NOT be accepted.
Optional second tissue sample for diagnostic development:
The optional second tissue sample (FFPE) may be provided to facilitate diagnostic 
development and pre-market approval of the diagnostic test. This should be obtained at the 
same time and as part of the same procedure as the mandatory screening biopsy. Optional 
tumour biopsy tissue may also be used for companion diagnostic development.
The following will be collected at screening:
Demography:
Demographic data and other characteristics will be recorded and will include date of birth or 
age, gender, smoking history, race and/or ethnicity according to local regulations.
Medical/surgical history:
A standard medical and surgical history will be obtained.
Physical examination including vital signs (pulse and BP), height, weight:
Physical examination includes an assessment of the following: general appearance, 
respiratory, cardiovascular, skin, head and neck (including ears, eyes, nose and throat), 
abdomen, lymph nodes, thyroid, musculo-skeletal (including spine and extremities) and 
neurological systems.


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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Ophthalmologic assessment:
Measurements of best-corrected visual acuity, intraocular pressure and slit-lamp fundoscopy 
should be obtained. 
Eligibility criteria:
Subjects must not be randomized unless all eligibility criteria have been fully met. 
World Health Organization (WHO) Performance Status:
Performance status will be assessed at the visits indicated in the Study Plan (see Table 1, 
Table 2, Table 3 and Table 4) according to WHO criteria as follows:
0 = 
Fully active, able to carry out all pre-disease activities without restrictions
1 = Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature e.g., light housework, office work
2 = 
Ambulatory and capable of self-care, but unable to carry out any work activities.  Up 
and about more than 50% of waking hours
3 = 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours
4 = 
Completely disabled, cannot carry on self-care, totally confined to bed or chair.
Pregnancy test:
Pregnancy test (blood or urine tests are acceptable based on the site’s standard clinical 
practice) for women of childbearing potential only. 
Archival tumour sample (if available):
All subjects will be asked to provide consent to supply a sample of their archival tumour 
blocks if a sample taken at the time of diagnosis is available.  Any archival biopsy samples 
taken following previous lines of therapy will also be requested, if available.  In each case the 
previous subject treatment must be clearly indicated for each sample provided. 
Tumour samples will preferably be in the form of a formalin fixed paraffin embedded block 
(sample derived from the diagnostic tumour or a metastatic site).  If this is not possible, 10-20 
slides of freshly prepared unstained 5 micron sections from the archival tumour block may be 
provided.
Laboratory safety assessments:
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
should be taken.  See Section 5.2.1.
If clinical chemistry, haematology and urinalysis assessments have been performed within 14 
days pre-randomization they do not have to be repeated prior to commencing treatment on 
visit 2 Day 1 if the subject's condition has not changed (no new treatment during this period of 
time, no new complication or aggravation).


Revised Clinical Study Protocol
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Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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Plasma for ctDNA and blood borne biomarkers: 
All subjects are required to provide two baseline plasma samples prior to receiving the result 
of their T790M mutation status result.  These baseline samples are not required to be taken 
again, if the subject is re-screened. All screening plasma samples should be sent to the 
AstraZeneca (AZ) appointed Clinical Research Organisation (CRO) for retrospective analysis.  
See Section 5.6.2.
Pharmacogenetics (optional):
Optional genetic blood sample should be taken from consenting subjects at screening.  If for 
any reason the sample is not drawn prior to dosing it may be taken at any visit until the last 
study visit.  See Section 5.5.
Tumour Assessments (RECIST 1.1):
The imaging modalities used for RECIST 1.1 assessments will be CT or MRI scans of chest 
and abdomen (including liver and adrenal glands). Any other sites where disease is suspected 
or known at baseline must be also imaged. Baseline assessments should be performed as close 
as possible to the start of treatment (and prior to randomization). See Section 5.1.1.  All 
imaging assessments including unscheduled visit scans should be collected on an ongoing 
basis and sent to the AZ appointed CRO to enable central analyses if required. 
According to the therapy area standards, base-line assessment should be within 28days of the 
study treatment start and follow-up assessments will be relative to the date of randomization. 
Subjects with known or suspected brain metastases at screening should have a CT/MRI of the 
brain prior to starting study treatment. These subjects should be followed up on study with 
repeated CT/MRI assessment, using the same frequency as RECIST assessments. The same 
modality for CT/MRI should be used for a subject throughout the study. Brain metastases will 
be assessed as non-target lesions. See Section 5.1.1.
Anti-cancer treatment:
All prior anti-cancer therapy will be collected at screening and end of the study and recorded 
in the eCRF.  
Concomitant medication use:
Information on any treatment in the 4 weeks prior to starting study treatment and all 
concomitant treatments given during the study, with reasons for the treatment, will be 
recorded in the Case Report Form (CRF). See Section 7.7. 
Digital ECG:
Three 12-lead ECG should be performed. See Section 5.2.4.


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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Echocardiogram/ MUGA:
An Echocardiogram or MUGA scan to assess LVEF will be performed at screening (prior to 
study medication). The modality of the cardiac function assessments must be consistent within 
a subject ie, if echocardiogram is used for the screening assessment then echocardiogram 
should also be used for subsequent scans. The subjects should also be examined using the 
same machine and operator whenever possible.
4.2
Treatment period (up to primary PFS analysis)
For subjects receiving AZD9291: 
A cycle of treatment is defined as 21 days of once daily AZD9291 treatment.  After Cycle 7 
Day 1, the duration between study visits will change from every 21 days (3 weeks) to every 42 
days (6 weeks). 
If a subject continues to receive treatment with AZD9291 beyond RECIST 1.1 defined 
progression they must continue to follow the treatment visit schedule and assessments 
excluding study specific RECIST 1.1 assessments.  
For subjects randomized to AZD9291, please follow the study schedule described in Table 1. 
For subjects receiving platinum-based doublet-chemotherapy:
Folic acid will be administered 5-7 days prior to the 1st dose, then daily during the treatment 
period until 21 days post the last dose. Vitamin B12 will be administered within 7 days of first 
infusion and every 9 weeks during the treatment period. Corticosteroid will be adminstered on 
the day prior to, on the day, and on the day after infusion. Subjects may also receive other pre-
treatment/ concomitant treatment as recommended by approved label for pemetrexed, 
carboplatin or cisplatin as clinically indicated by the investigator.
Platinum-based doublet chemotherapy will be administered every 21 days from previous cycle 
Day 1. Subjects can continue to receive platinum-based doublet-chemotherapy until matching 
discontinuation criteria (see Section 3.9) or up to a total of 6 cycles. Each cycle treatment can 
be interrupted maximum of 21 days. If cycle treatment is delayed by more than 21 days, 
subject will be permanently discontinued from doublet-chemotherapy.  If appropriate, and 
according to the approved label use or local practice guidelines, pemetrexed may be continued 
as maintenance treatment.
Subjects who progress according to RECIST 1.1 criteria prior to completion of initial doublet 
chemotherapy treatment or during pemetrexed maintenance monotherapy may continue with 
chemotherapy treatment as long as they show clinical benefit, as judged by the investigator. 
For subjects receiving platinum-based doublet-chemotherapy, please follow the study 
schedule in Table 2.


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Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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For subjects who cross-over to AZD9291: 
Once subjects on the platinum-based doublet chemotherapy arm are determined to have 
objective radiological progression according to RECIST 1.1 by the investigator and confirmed 
by independent central imaging review, they will be eligible to receive AZD9291 80mg, once 
daily and will follow the assessments as per Table 3.
If a subject has been deemed to have objective disease progression according to Investigator 
tumour assessment by RECIST 1.1, but is not confirmed by independent central imaging 
review, he/she is not eligible to cross-over to AZD9291 at that time.  Should it be in the 
subject’s best interest, and only if further randomized chemotherapy is warranted, he/she may 
continue to receive randomized doublet chemotherapy (if initial doublet chemotherapy 
treatment has not yet been completed) or pemetrexed maintenance monotherapy. Sites are to 
submit the next scheduled tumour assessment for central imaging review according to Table 2. 
The following criteria must be met for a subject to cross-over to AZD9291:

No intervening systemic anti-cancer therapy following discontinuation of randomized 
chemotherapy treatment.

At least a 14 day washout period between last dose of randomized chemotherapy and 
starting cross-over AZD9291 treatment.

Any unresolved toxicities from prior therapy should be controlled, and be no greater than 
CTCAE grade 1 (with the exception of alopecia which may be grade 2) at the time of 
starting AZD9291 treatment.
These subjects may continue treatment with AZD9291 as long as they show clinical benefit, 
as judged by the investigator.
While RECIST 1.1 assessments are not required to be reported in the RAVE eCRF following 
confirmation of progression by Independent Central Review, tumour assessments should be 
done in accordance to local clinical practices.
If subjects are not eligible to cross-over to AZD9291, they will enter into the follow-up phase 
of the study, and other treatment options should be discussed by the investigator.
The following will be collected during the Treatment Period (described mainly what is not 
already mentioned under Screening Period, Section 4.1):
Ophthalmologic examination:
To be performed as clinically indicated. A 28-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.


Revised Clinical Study Protocol
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Study Code D5160C00003
Edition Number 5
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Echocardiogram/MUGA:
To be performed every 12 weeks and as clinically indicated. A 28-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.
Physical examination, including vital signs (pulse and blood pressure), laboratory 
parameters, ECG: 
A 28-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.
Plasma for ctDNA and blood borne biomarkers:
All subjects will be requested to provide one plasma sample prior to dosing, at each treatment 
period study visit.
PK Blood Samples (including metabolites):
For subjects randomized to AZD9291, blood samples (plasma) will be taken to determine 
concentrations of AZD9291, AZ5104 and AZ7550.
EORTC QLQ-C30, EQ-5D-5L, EORTC QLQ-LC13 and PRO-CTCAE:
Patient reported outcomes will be collected for all subjects throughout the study period via a 
hand-held electronic device.
Healthcare Resource Use:
Healthcare resource use assessment will be completed by the Investigational Site for any such 
healthcare resource use between visits.
Concomitant Medication Use:
For subjects randomized to doublet-chemotherapy, Folic acid, Vitamin B12 and 
Corticosteroid administration will be initiated prior to the start of study treatment.
Descriptions of the procedures for this treatment period are included in Table 1, Table 2 and 
Table 3.
4.3
Post-Treatment Follow-up period
4.3.1
Discontinuation visit (up to primary PFS analysis)
A Discontinuation Visit will be performed at the time randomized treatment is permanently 
stopped.  A second Discontinuation Visit will be performed for those subjects that stop 
AZD9291 in the Cross-over Treatment Phase.  
For subjects randomized to the platinum-based doublet-chemotherapy, the discontinuation 
visit should be done after central confirmation of disease progression. The Chemotherapy 
discontinuation visit and Cross-Over visit can be done on the same day, as long as all other 
parameters are met.


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Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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Refer to Table 1, Table 2 or Table 3 for details. 
4.3.2
Twenty-eight Day follow-up (up to primary PFS analysis)
As a minimum, telephone contact should be made with the subject 28(+7) days following the 
discontinuation of investigational product to collect new AEs and follow up on any ongoing 
AEs and concomitant medications (including any subsequent cancer therapy).  Refer to 
Section 6.3 for full details on AE recordings during follow-up.  
4.3.3
Progression follow-up (up to primary PFS analysis)
Subjects who discontinue study medication for reasons other than objective disease 
progression will continue RECIST 1.1 assessments every 6 weeks (relative to date of 
randomization) for objective progression. 
If a subject has been deemed to have objective disease progression according to Investigator 
tumour assessment by RECIST 1.1, but is not confirmed by independent central imaging 
review, he/she is not eligible to cross-over to AZD9291 at that time.  Should it be in the 
subject’s best interest, and only if further randomized chemotherapy is warranted, he/she may 
continue to receive randomized doublet chemotherapy (if initial doublet chemotherapy 
treatment has not yet been completed) or pemetrexed maintenance monotherapy. Sites are to 
submit the next scheduled tumour assessment for central imaging review according to Table 2.  
In addition to RECIST 1.1 assessments, the following assessments are also required during 
this follow-up period as detailed in the Study Plan Table 1, Table 2 or Table 3.

EORTC QLQ-C30 and EQ-5D-5L every 6 weeks and at the time of progression.

EORTC QLQ LC13 and PRO-CTCAE every 3 weeks and at the time of progression.

Plasma for ctDNA collected every 6 weeks up to and including progression 
(corresponding with the RECIST assessments – and continuing after treatment 
discontinuation if this is in absence of progression)

Adverse event collection detailed in Section 6.3

Anti-cancer therapy and surgery collected every 6 weeks

WHO performance status should also be collected at other site visits that the subject 
attends, if appropriate site staff are available to collect such information. In addition, 
where possible, please provide WHO performance status when information on subsequent 
anticancer therapy is provided.

Once subjects on the platinum-based doublet chemotherapy arm are determined to have 
objective radiological progression according to RECIST 1.1 by the investigator and 
confirmed by independent central imaging review, they will receive AZD9291 80mg, once 
daily and will follow the assessments as per Table 3.  These subjects may continue 
treatment with AZD9291 as long as they show clinical benefit, as judged by the 
investigator.


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Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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
Subjects who are not be eligible to cross-over to AZD9291will enter into the follow-up 
phase of the study, and other treatment options should be discussed by the investigator.
4.3.4
Survival follow-up (up to final OS analysis)
Assessments for survival should be made every 6 weeks following objective disease 
progression. Survival information may be obtained via telephone contact with the subject, the 
subject’s family or caretaker or by contact with the subject’s current physician. In addition to 
the survival status, the following assessments are also required post progression as detailed in 
the study plan (see Table 1, Table 2, Table 3 or Table 4):

EORTC QLQ-C30 and EQ-5D-5L every 6 weeks.

EORTC QLQ LC13 and PRO-CTCAE every 3 weeks.

Anti-cancer therapy and surgery collected every 6 weeks.

Subsequent response/progression data every 6 weeks until the first confirmed disease 
progression on a subsequent treatment (to inform PFS2 endpoint). PFS2 is only required 
for primary PFS analysis and the first OS analysis. Post the first OS analysis DCO, the 
information is not required to be collected. 

WHO performance status should also be collected at other site visits that the subject 
attends, if appropriate site staff are available to collect such information. In addition, 
where possible, please provide WHO performance status when information on subsequent 
anticancer therapy is provided.
Survival data will be collected up to the time of the final OS analysis.  Subjects should be 
contacted in the week following the data cut-off for the final survival analyses to provide 
complete survival data.
The status of ongoing, withdrawn (from the study) and “lost to follow-up” subjects at the time 
of an OS 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.
4.3.5
Patient management post primary PFS analysis and up to final OS analysis
The primary PFS analysis will occur when at least 221 progression events have been observed 
out of the 410 globally randomized subjects.
Following the primary PFS analysis subjects still on AZD9291 may continue treatment with 
AZD9291 as long as they show clinical benefit, as judged by the investigator.
Following the primary PFS analysis subjects still on the platinum-based doublet chemotherapy 
arm will be given the opportunity to begin treatment with AZD9291 80mg, once daily if it is 
considered in the patients best interest by the Investigator and they are eligible to receive 


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Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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AZD9291 (no contraindications). These subjects may continue treatment with AZD9291 as 
long as they show clinical benefit, as judged by the investigator. If subjects are not given 
AZD9291 at the discretion of the investigator, they will enter into the follow-up phase of the 
study, and other treatment options should be discussed by the investigator.
Patients on study treatment will be followed for survival, PRO and core safety assessments 
(haematology, clinical chemistry, AEs/SAEs and concomitant medications (including any 
subsequent cancer therapy), study treatment dosing details as per Table 4. 
Post the first OS DCO, the duration between study visits will change to every 84 days (12 
weeks).
All patients (both patients still on study treatment and patients withdrawn from study 
treatment) will be followed for survival, subsequent therapy and PRO outcomes unless 
consent is withdrawn or patient is lost to follow up.
4.3.6
Patient management post final (OS) analysis
The final (third) analysis of overall survival will be performed when the OS data are 
approximately 70% mature (approximately 287 death events). At this time point, the clinical 
study database will close to new data. Patients are, however, permitted to continue to receive 
study treatment (AZD9291) beyond the closure of the database if, in the opinion of the 
investigator, they are continuing to receive benefit from treatment. Dispensing of study 
treatment post final OS analysis DCO will be done outside of IWRS. Patients who remain on 
study treatment after this time point will be monitored according to routine clinical practice as 
defined by the Investigator. At routine clinic visits, patients will return used and unused 
medication, and a thorough drug accountability assessment will be performed at the site. 
For patients who do continue to receive treatment beyond the time of this data cut off, 
investigators will continue to report all SAEs, overdoses and pregnancies to AstraZeneca via 
paper and emailed (preferably) or faxed directly to TCS (also known as AZ DES) in 
accordance with Section 6.4 6.5 6.6. If an investigator learns of any SAEs, including death, at 
any time after a patient has completed the study, and he/she considers there is a reasonable 
possibility that the event is causally related to the IP, the investigator should notify 
AstraZeneca (see Section 6.4). Additionally, as stated in Section 6.3, any SAE or non-serious 
AE that is ongoing at the time of this DCO, must be followed up to resolution unless the event 
is considered by the investigator to be unlikely to resolve, or the patient is lost to follow up.
5.
STUDY ASSESSMENTS
The RAVE Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.  The investigator will ensure that data are recorded on the electronic Case 
Report Forms as specified in the study protocol and in accordance with the instructions 
provided.


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Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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The investigator ensures the accuracy, completeness and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
Investigator will sign the completed electronic Case Report Forms. A copy of the completed 
electronic Case Report Forms will be archived at the study site.
For details of data and study management see Section 9.4 of Clinical Study Protocol.
5.1
Efficacy assessments
5.1.1
RECIST 1.1
All imaging assessments including unscheduled visit scans should be collected on an ongoing 
basis and sent to an AstraZeneca (AZ) appointed Clinical Research Organisation (CRO) to 
enable independent central analyses.
For both investigator and Blinded Independent Central Review (BICR) RECIST 1.1 criteria 
will be used to assess each subject's tumour response to treatment and allow calculation of 
PFS, ORR, DCR, DoR and assess tumour shrinkage. The RECIST 1.1 guidelines for 
measurable, non-measurable, target and non-target lesions and the objective tumour response 
criteria [CR (complete response), PR (partial response), SD (stable disease) or PD 
(progression of disease)] are presented in Appendix G. For ORR, a visit response of CR or PR 
must be confirmed by a later scan conducted at least 4 weeks after the initial response is 
observed. See Section 4 for considerations related to RECIST 1.1 assessments.
The methods used at baseline for assessment of tumour burden [CT or MRI scans of chest and 
abdomen (including liver and adrenal glands)] must be used at each subsequent follow-up 
assessment. Any other areas of disease involvement should be additionally investigated based 
on the signs and symptoms of individual subjects. The baseline assessment should be 
performed within 28 days of the start of randomized treatment. Up to the primary PFS 
analysis, subsequent assessments are to be performed every 6 weeks relative to randomization 
until objective disease progression. It is important to follow the assessment schedule as 
closely as possible. If scans are performed outside of the scheduled visit (± 1 week window 
interval) and the subject has not progressed, every attempt should be made to perform the 
subsequent scans at their scheduled time points. Any other sites at which new disease is 
suspected should also be appropriately imaged. For subjects under consideration for cross-
over to AZD9291, scheduled tumour assessments will continue until confirmation of objective 
radiological disease progression by independent central imaging review according to RECIST 
1.1, if even after investigator has deemed objective disease progression. 
Following the primary PFS analysis, subjects still on the platinum-based doublet 
chemotherapy arm will be given the opportunity to begin treatment with AZD9291 80 mg, 
once daily if it is considered by the Investigator to be in the patient's best interest, and if they 
are eligible to receive AZD9291 (no contraindications). At least a 14 day washout period is 
required between last dose of chemotherapy and starting AZD9291 treatment.
For subjects not or no longer under consideration, or ineligible to cross-over to AZD9291 (e.g. 
subjects randomized to the chemotherapy arm, but not meeting criteria to cross-over to 


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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AZD9291; subjects originally randomized to the AZD9291 arm; or subjects who already 
crossed-over to AZD9291), no subsequent tumour assessments are expected to be sent for 
independent central imaging analysis after the investigator confirms objective disease 
progression.
Post the primary PFS analysis, tumour assessment will be performed in accordance with 
clinical practice and scans will no longer be centrally collected apart from subjects included in 
the China cohort. For China cohort, tumours assessment will be continued up to PFS analysis 
for China cohort until at least 20 PFS events have been observed out of approximately 50 
Chinese subjects. After the China PFS analysis, tumour assessment will be performed in 
accordance with clinical practice and scans will no longer be centrally collected. 
Subjects with known or suspected brain metastases at screening should have a CT/MRI of the 
brain prior to starting study treatment. These subjects should be followed up on study with 
repeated CT/MRI assessment, using the same frequency as RECIST assessments. The same 
modality for CT/MRI should be used for a subject throughout the study. Brain metastases will 
be assessed as non-target lesions.
If the investigator is in doubt as to whether progression has occurred, particularly with 
response to non-target lesions (NTLs) or the appearance of a new lesion, it is advisable to 
continue treatment until the next scheduled assessment or sooner if clinically indicated and 
reassess the subject’s status. If repeat scans confirm progression, then the date of the initial 
scan should be declared as the date of progression.
To achieve “unequivocal progression” on the basis of non-target disease, there must be an 
overall substantial worsening in non-target disease such that, even in the presence of SD or PR 
in target disease, the overall tumour burden has increased sufficiently to merit discontinuation 
of therapy. A modest “increase” in size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status. 
Categorisation of objective tumour response assessment at each visit will be based on the
RECIST 1.1 criteria of response: CR, PR, SD and PD. Target lesion (TL) progression will be 
calculated in comparison to when the tumour burden was at a minimum (ie, smallest sum of 
diameters previously recorded on study). In the absence of progression, tumour response (CR, 
PR, SD) will be calculated in comparison to the baseline tumour measurements obtained 
before starting treatment.
The primary PFS analysis for this study will be based on the tumour assessments using 
investigator site assessments according to RECIST 1.1.
5.1.2
RECIST 1.1 – Blinded Independent Central Review (BICR) Assessment
All imaging assessments including unscheduled visit scans will be collected on an ongoing 
basis and sent to an AstraZeneca appointed CRO to enable central analysis. The central review 
will provide confirmation of progression for patients on platinum-based doublet chemotherapy 
who have progressed, as assessed by the investigator, at the request of the investigational site 
for confirmation of progression prior to starting AZD9291.  Otherwise, the results of this 


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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independent central review will not be communicated to the investigational site, and the 
management of subjects will be based on the result of RECIST 1.1 assessments conducted by 
the investigator.  Up to the primary PFS analysis, since confirmation by central imaging 
review is required for subjects to cross-over to AZD9291, no subjects will be permitted to 
cross-over without the aforementioned confirmation. A sensitivity analysis will be conducted 
to identify any potential biases in the investigator assessments compared with BICR according 
to RECIST 1.1 (see Section 8.5.1).
After the primary PFS analysis, any imaging for tumour assessments will not be required to be 
submitted for BICR, apart from subjects included in the China cohort. For China cohort, 
imaging assessment will be continued up to PFS analysis for China cohort until at least 20 
PFS events have been observed out of approximately 50 Chinese subjects. After the China 
PFS analysis, any imaging for tumour assessments will not be required to be submitted for 
BICR for China cohort. 
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, haematology and urinalysis 
will be taken at the times indicated in the Study Plan (Table 1, Table 2, Table 3 or Table 4).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF.
The clinical chemistry, haematology and urinalysis will be performed at a local laboratory at 
or near to the Investigator site.  Sample tubes and sample sizes may vary depending on 
laboratory method used and routine practice at the site.  The number of samples/blood 
volumes is therefore subject to site-specific change.
The following laboratory variables will be measured:
Table 5
Laboratory Safety Variables 
Clinical chemistry
Haematology
Serum (S)/Plasma (P)-Albumin
Blood (B)-Haemoglobin
S/P-ALT
B-Leukocyte
S/P-AST
B-Haematocrit
S/P-Alkaline phosphatase
B-Red blood cell (RBC) count
S/P-Bilirubin, total
B-Absolute leukocyte differential count:
S/P-Calcium, total
          Neutrophils
S/P-Creatinine
          Lymphocytes


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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Table 5
Laboratory Safety Variables 
Clinical chemistry
Haematology
S/P-Glucose (fasting, on PK days only) 1
S/P-Lactate dehydrogenase (LDH) 2
          Monocytes
S/P-HbA1C
          Basophils
S/P-Magnesium
          Eosinophils
S/P-Potassium
B-Platelet count
S/P-Sodium
B-Reticulocytes
S/P-Urea nitrogen/Blood urea nitrogen (BUN)
Urinalysis
U-Glucose
U-Protein
U-Blood
1 Patients in AZD9291 cohort will be required to fast (water only) for at least 8 hours prior to the collection of a fasting glucose sample 
required   on PK days.  Random glucose sample will be collected on non-PK days.  Fasting is not required for patients in chemo cohort.  
2 LDH is an additional variable collected at Visit 1 only.
Additionally, at the Screening Visit, a pregnancy test (blood or urine tests are acceptable 
based on the site’s standard clinical practice) will be collected from all females of child 
bearing potential only.
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at 
centre as source data for laboratory variables.  For information on how Adverse Events (AEs) 
based on laboratory tests should be recorded and reported, see Section 6.3.
NB. In case a subject shows an AST or ALT ≥3xULN and total bilirubin ≥ 2xULN please 
refer to Appendix D ‘Actions required in cases of combined increase of Aminotransferase and 
Total Bilirubin – Hy’s Law’, for further instructions (Section 6.3.7 and Appendix D).
5.2.2
Volume of blood
Total mandatory blood volume for AZD9291 subjects in first 9 weeks is 172 mL (Table 6).  
Table 6 Blood sample volumes AZD9291 subjects


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Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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Visit
Safety (mL)1
PK Analysis (mL)
Plasma (mL)
PGx (mL)
Screening
15
20
10 (optional)
Cycle 1
45
6
30
Cycle 2
15
NA
10
Cycle 3 
15
6 
10
SUBTOTAL 
(mandatory)
90
12
70
1For safety, assumes 6 mL clinical chemistry and 9 mL haematology per visit
Total mandatory blood volume for Platinum-based Doublet-chemotherapy subjects in first 9 
weeks is 160 mL (Table 7).
Table 7
Blood sample volumes Platinum-based Doublet-chemotherapy subjects
Visit
Safety (mL)1
PK Analysis (mL)
Plasma (mL)
PGx (mL)
Screening
15
20
10 (optional)
Cycle 1
45
NA
30
Cycle 2
15
NA
10
Cycle 3 (onwards)
15
NA
10
TOTAL 
(mandatory)
90
70
1 For safety, assumes 6 mL clinical chemistry and 9 mL haematology per visit
5.2.3
Physical examination
All subjects will have a physical examination performed at the time points indicated in the 
Study Plan (Table 1, Table 2, Table 3 or Table 4), which includes an assessment of the 
following: general appearance, skin, head and neck (including ears, eyes, nose and throat), 
respiratory, cardiovascular, abdomen, lymph nodes, thyroid, musculo-skeletal (including spine 
and extremities), and neurological systems.
5.2.4
ECG
All subjects will have three 12-lead ECG performed at the time points indicated in Study Plan 
(Table 1, Table 2, Table 3 or Table 4). A twelve-lead ECG will be obtained after the subject 
has been resting semi-supine for at least 10 minutes prior to times indicated and should be 
recorded at 25 mm/sec. All ECGs should be recorded with the subject in the same physical 
position. For each time point three ECG recordings should be taken at approximately 5 minute 
intervals. A standardised ECG machine should be used and the patient should be examined 
using the same machine throughout the study if possible. Prior to first OS analysis DCO, 


Revised Clinical Study Protocol
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digital ECG recordings will be collected, analysed and stored by a central ECG vendor. Post 
first OS analysis DCO, ECGs will be collected locally and stored at the site. 
After paper ECGs have been recorded, the investigator or designated physician will review 
each of the ECGs and may refer to a local cardiologist if appropriate.  A paper copy should be 
filed in the patient’s medical records.  If an abnormal ECG finding at screening or baseline is 
considered to be clinically significant by the investigator, it should be reported as a concurrent 
condition.  For all ECGs details of rhythm, ECG intervals and an overall evaluation will be 
recorded.
ECG data will be collected digitally and will be transferred electronically for central analysis 
as described in the study specific ECG manual.
Heart rate, PR, R-R, QRS and QT intervals will be determined and reviewed by an external 
cardiologist. 
If there is a clinically significant abnormal ECG finding during the Treatment period, this 
should be recorded on the AE eCRF, according to standard adverse events collection and 
reporting processes. A 28-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.
Patients who experience a QTcF interval greater than 500 msec on at least 2 separate ECGs 
must have AZD9291 treatment interrupted until the QTcF interval is less than 481 msec or 
recovery to baseline if baseline QTcF is greater than or equal to 481 msec, then restart at a 
reduced dose (40 mg).
Patients experiencing QTcF interval prolongation with signs/symptoms of serious arrhythmia
will not be permitted to restart study treatment.
After the first OS analysis DCO, ECG assessments will be performed locally (triplicate 12-
lead ECG, with paper printouts of 10 seconds for Investigator review) and a paper copy will 
be stored in the patient’s medical records. ECG information (evaluation of normal/abnormal) 
will continue to be recorded in the eCRF. If there is a clinically significant abnormal ECG 
findings during this period, this should be recorded on the AE eCRF, according to standard 
adverse events collection and reporting processes. After final OS analysis, ECG assessments 
will be performed according to routine clinical practice as defined by the Investigator. 
5.2.5
Echocardiogram/MUGA scan
An Echocardiogram or MUGA scan to assess LVEF will be performed at screening (prior to 
study medication) and every 12 weeks (± 1 week window interval) relative to randomization. 
The modality of the cardiac function assessments must be consistent within a patient ie, if 
echocardiogram is used for the screening assessment then echocardiogram should also be used 
for subsequent scans. The subjects should also be examined using the same machine and 
operator whenever possible. A 28-day follow-up assessment will be required if an on 
treatment assessment was abnormal at the time of discontinuation of study therapy, to confirm 


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Date January 10, 2017
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reversibility of the abnormality. After final OS analysis, the assessment will be performed as 
clinically indicated necessary by the Investigator. 
5.2.6
Vital signs
5.2.6.1
Pulse, blood pressure, weight and height
Supine blood pressure and pulse rate will be measured after 10 minutes rest.  Assessments will 
be performed at the visits as shown in the Study Plan (see Table 1, Table 2, Table 3 or Table 
4).  Additionally at the discretion of the investigator if clinically indicated.
Weight will be performed at screening and then Day 1 of each cycle and at the discontinuation 
visit. Weight will be documented in kilogram (e.g. 68.5 kg) in eCRF.
Height will be assessed at screening only and will be documented in centimeters (e.g. 168 cm) 
in eCRF.
Any changes in vital signs (pulse and BP) should be recorded as an AE if applicable.
5.2.7
Other safety assessments
5.2.7.1
Ophthalmologic exam
At screening, a full ophthalmic assessment (measurements of best-corrected visual acuity, 
intraocular pressure and slit-lamp fundoscopy) should be obtained.  For any subject who 
experiences visual symptoms (including blurring of vision), additional tests may be conducted 
throughout the study period, if clinically indicated (see Table 1, Table 2 or Table 4). 
Any clinically significant findings, including those confirmed by the ophthalmologist must be 
reported as an AE. Photographs should be performed to record any clinically significant 
findings. These photographs should be available for central review by AstraZeneca and 
AstraZeneca representatives if necessary. 
Subjects experiencing corneal ulceration will not be permitted to restart study treatment.
Ophthalmologic exams to be performed as clinically indicated. A 28-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. 
Ophthalmology examination results should be collected in the eCRF.
5.3
Other assessments
5.3.1
Baseline characteristics
Baseline demographics, disease history, previous treatments and EGFR mutation information 
will be collected.


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Study Code D5160C00003
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Date January 10, 2017
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5.3.2
Patient reported outcomes
Patient reported outcomes (PROs), an umbrella term referring to all outcomes and symptoms, 
are directly reported by the subject. PROs have become a significant endpoint when 
evaluating effectiveness of treatments in clinical trials. The following PROs will be 
administered: EORTC QLQ C-30, QLQ-LC13, EQ-5D-5L and PRO CTCAE (see 
Appendix F). PROs will be collected until end of study (including survival follow-up period) 
and at the time of progression  unless consent is withdrawn or patient is lost to follow up as 
indicated in the Study Plan (Table 1, Table 2, Table 3 or Table 4).
5.3.2.1
EORTC QLQ-C30 and QLQ-LC13
The EORTC QLQ-C30 was developed by the EORTC Quality of Life Group 1993. It consists 
of 30 items and measures cancer patients’ functioning (HRQoL) and symptoms (Aaronson et 
al 1993) for all cancer types. Questions can be grouped into 5 multi-item functional scales 
(physical, role, emotional, cognitive and social); 3 multi-item symptom scales (fatigue, pain, 
nausea and vomiting); a 2-item global HRQoL scale; 5 single items assessing additional 
symptoms commonly reported by cancer patients (dyspnoea, loss of appetite, insomnia, 
constipation, diarrhoea) and 1 item on the financial impact of the disease.
The QLQ LC13 is a well-validated complementary module measuring lung cancer associated 
symptoms and side effects from conventional chemotherapy and radiotherapy (Bergman et al 
1994).  Refer to Appendix F. The QLQ LC13 includes questions assessing cough, 
haemoptysis, dyspnoea and site specific pain (symptoms), sore mouth, dysphagia, peripheral 
neuropathy and alopecia (treatment-related side effects) and pain medication.
5.3.2.2
EQ-5D-5L
The EQ-5D is a standardised measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal 
(EuroQol Group 1990).  Applicable to a wide range of health conditions and treatments, it 
provides a simple descriptive profile and a single index value for health status that can be used 
in the clinical and economic evaluation of health care as well as in population health surveys.
The questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort 
and anxiety/depression.  Each dimension has 5 response options (no problems, slight 
problems, moderate problems, severe problems, and extreme problems) that reflect increasing 
levels of difficulty (EuroQol Group 2013). 
Since 2009, the EuroQol group has been developing a more sensitive version of the EQ-5D 
(the EQ-5D-5L), which expands the range of responses to each dimension from 3 to 5 levels 
of increasing severity (Herdman et al 2011).  Preliminary studies indicate that the 5L version 
improves upon the properties of the 3L measure in terms of reduced ceiling effect, increased 
reliability and an improved ability to differentiate between different levels of health (Pickard 
et al 2007, Janssen et al 2008, Janssen et al 2008b).
The subject will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions.  The questionnaire also includes a visual 


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Edition Number 5
Date January 10, 2017
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analogue scale, where the subject will be asked to rate current health status on a scale of zero 
to 100, with zero being the worst imaginable health state (see Appendix F).
5.3.2.3
PRO-CTCAE
The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse 
Events (PRO-CTCAE) system has been developed by the National Cancer Institute (NCI).  
The PRO-CTCAE will only be administered in those countries where a linguistically validated 
version exists, currently English, Japanese, German and Spanish.  PRO-CTCAE is an item-
bank of symptoms experienced by patients while undergoing treatment of their cancer. It was
developed in recognition that collecting symptom data directly from patients using PRO tools 
can improve the accuracy and efficiency of symptomatic AE data collection. This was based 
on findings from multiple studies demonstrating that physicians and nurses underestimate 
symptom onset, frequency, and severity in comparison with patient ratings (Sprangers et al 
1992; Litwin et al 1988-1992; Basch et al 2009). To date, 81 symptoms of the CTCAE 
(version 4) have been identified to be amenable to patient reporting. These symptoms have 
been converted to patient terms (e.g., CTCAE term “myalgia” converted to “aching muscles”). 
For several symptoms, like fatigue and pain, additional questions are asked about symptom 
frequency, severity, and interference with usual activities. For other symptoms like rash, 
additional questions focus on the presence on the body. The items included in the PRO-
CTCAE have undergone extensive qualitative review among experts and patients. Using 
cognitive testing methods, these items and the additional questions for some of the symptoms 
have been extensively evaluated by cancer patients, so that symptoms of interest are clear, 
comprehendible and measurable. Not all items are administered in any one clinical trial. The 
intention is to only ask patients to complete those items, which are considered relevant for the 
trial, site of cancer, and cancer treatment (see Appendix F).
5.3.2.4
Administration of electronic PROs
Subjects will complete the PRO assessments by using a handheld electronic device (ePRO). 
The following best practise guidelines should be followed when collecting PRO data via an 
electronic device:

Site staff to explain the value and relevance of participation to subjects that we are asking 
these questions because we are interested in hearing directly from them how they feel. The 
research nurse or appointed site staff should also stress that the information is confidential. 
Therefore, if the subject has any medical problems he/she should discuss them with the 
doctor or research nurse separately from the ePRO assessment

Remind subjects that there are no right or wrong answers, avoid bias by not clarifying 
items

Train the subject on how to use the ePRO device using the materials and training provided 
by the ePRO vendor. Also provide guidance on whom to call if there are problems with 
the device by providing the patient information pamphlet provided by the ePRO vendor.
In order to minimize missing data, compliance must be checked frequently to identify 
problems early. If compliance drops below 85%, a check-in call from the site to ask the 
subject if he/she has any difficulties is highly recommended. Up to primary PFS analysis, the 


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Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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assessment will be performed as shown in the Study Plan (see Table 1, Table 2 and Table 3). 
After primary PFS analysis and up to the final OS analysis DCO, the assessment will be
performed as shown in Table 4. After final OS analysis, all PRO data will no longer be 
collected.
5.3.2.5
Healthcare resource use
The site will ask subjects for any healthcare resource use between visits (ie, excluding routine 
follow up clinic visits associated with the clinical trial but including both planned and 
unplanned admissions) during the treatment period and at the 28-day follow-up.
For the purposes of economic evaluation it is necessary to capture healthcare resource use 
related to the treatment and the underlying disease.  Within the study the following resource 
use will be captured:

Hospital episodes including the type of contact (hospitalisations, outpatient, day case), 
reason, length of stay (including intensive care unit) and concomitant medications and 
procedures

Treatment related to Adverse Events (including the method of delivery of the treatment)

Treatment not related to the study.
The above resource use data will mainly come from the subject’s medical record and will be 
captured by site staff using WBDC. After primary PFS analysis, healthcare resource use 
information will continue to be collected until the first OS analysis DCO. After the first OS 
analysis DCO, the information will not be collected. 
5.4
Pharmacokinetics
5.4.1
Collection of samples for subjects randomized to AZD9291
Three venous blood samples per visit in time windows Pre-dose, 0.5 to 1.5, and 2 to 4 hours 
for determination of total concentrations of AZD9291 and metabolites (AZ5104 and AZ7550) 
in plasma will be taken at the times presented in Table 8.
The date and time of collection of each sample and the date and time of dose (on PK sampling 
day and for previous dose) will be recorded.
Table 8
PK blood sample schedule (Pre-dose, 0.5 to 1.5, and 2 to 4 hours)
Time 
relative 
to dose
Cycle 1 -Visit 2
Cycle 3 -Visit 6
Cycle 5 -Visit 8
Cycle 7 -Visit 10
and every other cycle up 
to and including Cycle 13 
mL
6 (2 mL x 3)
6 (2 mL x 3)
6 (2 mL x 3)
6 (2 mL x 3)
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual. 
No PK blood samples will be collected in subjects crossed-over from chemotherapy treatment. 


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Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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5.4.2
Determination of drug concentration
Samples for determination of AZD9291 (and metabolite) concentrations in plasma and 
cerebrospinal fluid (CSF) will be collected and analysed by Covance on behalf of 
AstraZeneca, using an appropriate bioanalytical method. Full details of the analytical method 
used will be described in a separate bioanalytical report.  All samples still within the known 
stability of the analytes of interest (ie, AZD9291, AZ5104 and AZ7550) at the time of receipt 
by the bioanalytical laboratory will be analysed.
In addition, the pharmacokinetic samples may be subjected to further analyses by AstraZeneca 
in order to further investigate the presence and/or identity of additional drug metabolites. Any 
results from such analyses will be reported separately from the Clinical Study Report.
Details on sample processing, handling, shipment and storage are provided in the Laboratory 
Manual.
Full details of the analytical method used will be described in a separate bioanalytical report.
5.4.3
Storage and destruction of pharmacokinetic samples
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or six 
months after issuance of the draft Bioanalytical Report (whichever is earlier), unless requested 
for future analyses. 
Pharmacokinetic samples may be disposed of or destroyed and anonymised by 
pooling. Additional analyses may be conducted on the anonymised, pooled pharmacokinetic 
samples to further evaluate and validate the analytical method. Any results from such 
analyses may be reported separately from the CSR.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the Clinical Study 
Report but separately in a Bioanalytical Report.
Any residual back-up PK samples may be used for future exploratory biomarker research (in 
this case, residual back-up PK samples will be shipped to the AZ Biobank or it’s designee; see 
details in the Laboratory Manual).
5.4.4
Collection of cerebrospinal fluid – optional
For subjects randomized to AZD9291: If the subject agrees, and upon signature of optional 
ICF, a sample of CSF will be obtained at one time point taken at any time from Cycle 2 Day 1 
onwards. Samples will be collected, labelled and stored and shipped as detailed in the 
laboratory manual.
Any residual CSF after PK analysis may be used for exploratory research into factors that may 
influence development of NSCLC and/or response to AZD9291. If possible, the CSF sample 
should be taken on the same day as planned PK samples.


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Study Code D5160C00003
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5.5
Pharmacogenetics
If a subject agrees to participate in the host pharmacogenetics research component of the study 
a blood sample will be collected. 
AstraZeneca intends to perform genetic research in the AZD9291 clinical development 
programme to explore how genetic variations may affect the clinical parameters associated 
with AZD9291.
The benefits of being able to explore associations between genes and clinical outcomes within 
the AZD9291 programme are potentially many and include:
-
analysis of genes that may affect efficacy, safety and tolerability (for example, but not 
limited to, drug metabolising enzymes and drug transporters)
-
genetic research into genes that my contribute to the risk of NSCLC (for example, but 
not limited to, mutations in the gene encoding EGFR)
The results of this pharmacogenetic research will be reported separately and will not form part 
of the Clinical Study Report.
5.5.1
Collection of pharmacogenetic samples
The subject’s consent to participate in the pharmacogenetic research components of the study 
is optional.  
The single blood sample (10 mL) for genetic research will be obtained from the subjects 
immediately prior to the first administration of AZD9291 in the study. Although genotype is a 
stable parameter, early sample collection is preferred to avoid introducing bias through 
excluding subjects who may withdraw due to an adverse event. Such subjects would be 
important to include in any genetic analysis. If for any reason the sample is not drawn prior to 
dosing it may be taken at any visit until the last study visit. Only one sample should be 
collected per subject for genetics during the study. 
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual.
5.5.2
Storage, re-use and destruction of pharmacogenetic samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality.  Samples will be stored for a maximum of 15 
years from the date of the Last Subject’s Last Visit, after which they will be destroyed.  DNA 
is a finite resource that may be used up during analyses.  The results of any further analyses 
will be reported either in the Clinical Study Report itself or as an addendum, or separately in a 
scientific report or publication.  Samples will be stored and used until no further analyses are 
possible or the maximum storage time has been reached.
Refer to Appendix C for details of the optional (DNA) genetic research.


Revised Clinical Study Protocol
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Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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5.6
Exploratory Research
If a subject agrees to participate in the exploratory biomarker research component of the study 
biological samples (e.g., plasma, serum, archived and study-obtained tumour, etc.) will be 
collected and may be analysed for exploratory biomarkers to assess correlations with disease 
activity, effects of investigational product and clinical outcomes.
The results of this exploratory biomarker research will be reported separately and will not 
form part of the Clinical Study Report.
The results of this exploratory biomarker research may be pooled with biomarker data from 
other studies with the investigational product to generate hypotheses to be tested in future 
studies.
5.6.1
Collection of Tumour Biopsy Samples
5.6.1.1
Archival Tumour
All subjects eligible for the study will be asked to provide consent to supply a sample of their 
archival tumour blocks if a sample taken at the time of diagnosis is available (blocks 
preferred, slides acceptable). 
Only submit samples for subjects who have a centrally confirmed T790M+ mutation.  Any 
archival biopsy samples taken following previous lines of therapy will also be requested, if 
available. In each case the previous patient treatment must be clearly indicated for each 
sample provided. This sample will be used to support exploratory biomarker analyses (see 
Section 5.6).
5.6.1.2
Optional Tissue Collection at Screening
Subjects will be asked to consent to provide additional tumour tissue at screening, which can 
be collected at the same time as the mandatory screening tumour biopsy (see Section 4.1), 
where appropriate to do so. This biopsy will be used to support the development of the 
diagnostic test for pre-market approval by FDA (US) and/or for exploratory biomarker 
analyses (see Section 5.6). 
5.6.1.3
Discontinuation Biopsy
Subjects will also be asked to consent to a further optional biopsy, to be collected at 
discontinuation of study treatment. This sample will be used to support exploratory biomarker 
analyses (see Section 5.6).
For timings of tumour biopsies see Table 9.
Table 9 Tumour biopsy samples


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Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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Time relative to dose
Requirement
Archival
M*
Screening 
M + O2
Discontinuation or progression1
O
1 To be taken at discontinuation or progression, whichever occurs first
2 Only block tissue sample will accepted
M = Mandatory
     O = Optional
M* = mandatory if available
Tumour samples should be provided in the form of a formalin fixed paraffin embedded block 
(tissue derived from the diagnostic tumour or a metastatic site). If this is not possible, the 
following may be provided:
-
12-20 slides of freshly prepared unstained 5-micron sections from the mandatory 
screening FFPE tumour block may be provided
-
10-20 slides of freshly prepared unstained 5-micron sections from the archival tumour 
block may be provided. 
Further details on sample processing, handling and shipment are provided in the Laboratory 
Manual.
5.6.2
Collection of exploratory samples – blood-borne biomarkers and ctDNA
Up to primary PFS analysis, all subjects will be requested to provide a series of blood samples 
to generate plasma samples. These samples will be used for the extraction and analysis of 
ctDNA. The ctDNA may be used to further investigate the relationship between PK and 
blood-borne biomarkers.  The ctDNA samples will be used to further explore EGFR (and 
other gene) mutation status and may be used to develop a plasma-based diagnostic test.
Plasma samples will be taken at the following times (pre-dose):

Screening

Cycle 1 - Day 1, Day 8 & 15; Cycle 2, 3, 4, 5, 6 – Day 1; thereafter

Every 6 weeks up to and including progression (corresponding with the RECIST 
assessments)

Discontinuation of study drug (if subject continues after progression on AZD9291)
The samples will be analysed for a range of oncology biomarkers, which may correlate with 
drug response. Post primary PFS analysis, ctDNA samples will continue to be collected at 
treatment discontinuation and at progression.
Details on sample processing, handling, shipment and storage are provided in the Laboratory 
Manual.


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Edition Number 5
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5.7
Management of Biological Samples
5.7.1
Storage, re-use and destruction of biological samples
Biological samples for future research will be retained at AstraZeneca or it’s designee for a 
maximum of 15 years following the finalisation of the Clinical Study Report, after which they 
will be destroyed.  The results of this biomarker research will be reported either in the Clinical 
Study Report itself or as an addendum, or separately in a scientific report or publication. The 
results of this biomarker research may be pooled with biomarker data from other studies with 
the investigational product to generate hypotheses to be tested in future research.
5.7.2
Labelling and shipment of biological samples
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix B ‘IATA 6.2 Guidance Document’.
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the subject unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved.
All tumour samples should be shipped at ambient temperature as per the Laboratory Manual 
to the AstraZeneca designated central Contract Research Organisation.
5.7.3
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator at each centre keeps full traceability of collected biological samples 
from the subjects while in storage at the centre until shipment or disposal (where appropriate) 
and keeps documentation of receipt of arrival.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the AstraZeneca assigned Biobank system 
during the entire life cycle.
5.7.4
Withdrawal of Informed Consent for donated biological samples 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.


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As collection of the biological samples is an optional part of the study, then the subject may 
continue in the study.
The Principal Investigator:

Ensures subjects’ withdrawal of informed consent to the use of donated samples is notified 
immediately to AstraZeneca

Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented 
and the signed document returned to the study site

Ensures that the subject and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
AstraZeneca ensures that biological samples are destroyed at the end of a specified period as 
described in the informed consent.
5.8
Post progression outcomes
The date of second progression (PFS2) will be recorded by the Investigator and defined 
according to local standard clinical practice and may involve any of the following: objective 
radiological evidence (preferred), symptomatic progression or death. Second progression 
status will be reviewed every 6 weeks following the progression event used for the primary 
variable PFS (the first progression) and status recorded. 
PFS2 is only required for primary PFS analysis and the first OS analysis. Post the first OS 
analysis DCO, the information is not required to be collected. 
The start and stop date, and details of the type of all subsequent anticancer treatments will be 
recorded.
PRO data and WHO performance status will be collected post progression (see Section 4).
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of adverse events
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 


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whether or not considered causally related to the product.  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).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
For cases where it could be suspected that a tissue-derived medicine has been contaminated by 
a pathogen, information about any of the above conditions (including infection) should be 
collected.  Any deterioration of the disease targeted in the study and associated symptoms 
should not be regarded as an adverse event.
6.2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability/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 jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse Events will be collected from time of signature of informed consent throughout the 
treatment period and including the safety follow-up period.  The follow-up period is defined 
as 28 days after study treatment is discontinued. SAEs occurring in the follow-up period 
should be reported to AstraZeneca in the usual manner (see Section 6.4). 
Following discontinuation of study treatment, SAEs considered related to study procedures 
should continue to be collected while subjects are followed up for disease progression as 
outlined in Table 10.
After the final OS database lock, there may be some subjects remaining on study treatment. 
For these subjects who are continuing to receive AZD9291 AstraZeneca will collect 
information (during the treatment period and for 28 (+ 7) days after last dose) on SAEs, 


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overdose and pregnancy via paper and emailed (preferably) or faxed directly to TCS (also 
known as AZ DES). Drug accountability information will be recorded in the patient notes.
For each subject who discontinues study treatment for a reason other than disease progression:
-
Follow-up information on all ongoing AEs should continue to be collected to the survival 
follow-up
-
SAEs considered related to study procedures must continue to be collected and reported to 
AstraZeneca using standard SAE timelines and process until the end of progression follow 
up (ie, disease progression) 
-
All deaths must continue to be collected after progression and during the survival follow-
up
Table 10
Summary of recording and follow-up of adverse events and deaths
From ICF 
to 
Treatment 
Period 
(Screening 
Period)
Until 28-day 
Follow-up 
Visit (safety 
follow-up 
period)
Post 28-day 
Follow-up visit 
but prior to 
progression (if 
applicable)
Post 28-day 
Follow-up visit 
and post 
progression 
(survival follow-
up period)
Collect all new AEs in CRF
Yes
Yes
No
No
Collect all ongoing AEs in 
CRF
Yes
Yes
Yes
Yes
Collect all study procedure-
related SAEs in CRF
Yes
Yes*
Yes*
Yes*
Death due to AE, or 
unknown cause1
Yes
Yes*
No
No
1
for example, death not due to disease progression or related to study procedure - refer to Section 6.3.10
* Post final OS analysis DCO, recording and follow up of SAEs will be done via paper
6.3.2
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.
6.3.3
Variables 
The following variables will be collect for each AE:

AE (verbatim)

The date when the AE started and stopped


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
Changes in CTCAE grade (for skin reactions and diarrhoea only); maximum CTCAE 
grade for all other AEs

Whether the AE is serious or not

Investigator causality rating against the Investigational Product (yes or no)

Action taken with regard to investigational product

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date Investigator became aware of serious AE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to Study procedure(s)

Description of AE.
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2.
6.3.4
Causality collection
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix A to the Clinical 
Study Protocol.


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6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or care provider or reported in response to the 
open question from the study personnel: ‘Have you/the child had any health problems since 
the previous visit/you were last asked?’ or revealed by observation will be collected and 
recorded in the CRF. When collecting AEs, the recording of diagnoses is preferred (when 
possible) to recording a list of signs and symptoms.  However, if a diagnosis is known and 
there are other signs or symptoms that are not generally part of the diagnosis, the diagnosis 
and each sign or symptom will be recorded separately.
6.3.6
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs (pulse and BP) will be 
summarised in the clinical study report.  Deterioration as compared to baseline in protocol-
mandated parameters should therefore only be reported as AEs if they fulfil any of the SAE 
criteria or are the reason for discontinuation of treatment with the investigational product 
unless clearly due to progression of disease under study (see Section 6.3.8).
If deterioration in a laboratory value, vital sign, ECG, or other safety assessment is associated 
with clinical signs and symptoms, the sign or symptom will be reported as an AE and the 
associated laboratory result or other finding will be considered as additional information.  
Wherever possible the reporting Investigator uses the clinical, rather than the laboratory term 
(e.g., anaemia versus low haemoglobin value). In the absence of clinical signs or symptoms, 
clinically relevant deteriorations in non-mandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
6.3.7
Hy’s Law
Cases where a subject shows an AST or ALT ≥3xULN and total bilirubin ≥2xULN may need 
to be reported as SAEs.  Prompt reporting of cases meeting Hy’s law criteria (via the SAE 
expedited reporting system) is required for compliance with regulatory guidelines.  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 D.
6.3.8
Disease progression
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease.  The 
development of new, or progression of existing metastasis to the primary cancer under study 
should be considered as disease progression and not an AE.  


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Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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Progression of the malignancy under study, including signs and symptoms progression, should 
not be reported as a serious adverse event. Hospitalization due to signs and symptoms of 
disease progression should not be reported as serious adverse event. 
6.3.9
New cancers
The development of a new cancer should be regarded as an AE and will generally meet at 
least one of the serious criteria. New cancers are those that are not the primary reason for the 
administration of the study treatment and have been identified after the subject’s inclusion in 
this study. They do not include metastases of the original cancer.
6.3.10
Handling of deaths
All deaths that occur during the study, or within the follow-up period after the administration 
of the last dose of investigational product, should be reported as follows:

Death, which is unequivocally due to disease progression, should be communicated to the 
study monitor at the next monitoring visit and should be documented in the CRF module, 
but should not be reported as a SAE during the study

Where death is not clearly due to disease progression of the disease under study the AE 
causing the death should be reported to the study monitor as an SAE within 24 hours. The 
report should contain a comment regarding the co-involvement of progression of disease, 
if appropriate, and should assign a single primary cause of death together with any 
contributory causes

Deaths with an unknown cause should always be reported as a 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 (with 
translation of important parts into English) should be reported in an expedited fashion to 
an AstraZeneca representative within the usual timeframes.
If an investigator learns of any SAEs, including death, at any time and he/she considers there 
is a reasonable possibility that the event is related to AZD9291, the investigator should notify 
AstraZeneca. Such cases should be regarded for expedited reporting purposes as though they 
were study reports. Therefore, a causality assessment are needed for a decision on whether or 
not expedited reporting is required.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the CRF.
Note that at the time of study completion (i.e. after the final DBL), the WBDC system will be 
decommissioned and SAE data will be collected via paper and emailed (preferably) or faxed 
directly to TCS (also known as AZ DES), which will be responsible for processing all SAEs 
onto the AZ global safety database. Drug accountability information will be stored in the 
patient notes at site.


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Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 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.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day ie, immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed. 
The reference document for definition of expectedness is the IB for the AstraZeneca drug 
AZD9291 and the EU Summary of Product Characteristics (SPC) for the active comparator 
product (including any AstraZeneca comparator). 
6.5
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.
There is no known antidote. Investigators will be advised that any patient who receives a 
higher dose than that intended should be monitored closely, managed with appropriate 
supportive care and followed up expectantly. Such overdoses should be recorded as follows:
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module
An overdose without associated symptoms is only reported on the Overdose CRF module
If an overdose 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.


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca during the 
course of the study and within 6 weeks of the last dose of AZD9291 (for female subjects) or 
within 4 months of the last dose for female partners of male subjects (see section 6.6.2 for 
more details)
6.6.1
Maternal exposure
If a subject becomes pregnant during the course of the study, study treatment should be 
discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the subject was discontinued from the study.
If any pregnancy occurs in the course of the study or within 6 weeks of the final dose of the 
investigational product then the Investigator or other site personnel informs the appropriate 
AstraZeneca representatives within 1day ie, immediately but no later than 24 hours of when 
he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
6.6.2
Paternal exposure 
Pregnancy of the subject’s partners is not considered to be an adverse event. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should if possible be followed up and documented.   
To capture information about a pregnancy from the partner of a male subject, the male 
subject’s partner consent must be obtained to collect information related to the pregnancy and 
outcome; the male subject 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 six months after dosing should be followed up and documented.


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Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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6.7
Management of toxicities related to AZD9291
If a subject experiences a CTCAE grade 3 and/or unacceptable toxicity not attributable to the 
disease or disease-related processes under investigation, dosing will be interrupted and 
supportive therapy administered as required in accordance with local practice/guidelines.
Patients with QTcF prolongation to >500 msec should have study treatment interrupted and 
regular ECGs performed until resolution to <481 msec or recovery to baseline (if baseline 
QTcF is >481 msec), and then restarted at a reduced dose of 40mg. If the QTcF does not 
resolve to < 481 msec or baseline within 21 days the patient will be permanently withdrawn 
from study treatment.
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) or a lower dose (40 mg) using the rules 
below for dose modifications (Table 11) and with discussion and agreement with the 
AstraZeneca Study Team Physician as needed. There will be no individual modifications to 
dosing schedule in response to toxicity, only potential dose reduction or dose interruption. 
If the toxicity does not resolve to ≤CTCAE grade 2 after 3 weeks, then the subject should be 
withdrawn from the study and observed until resolution of the toxicity.
Table 11
Dose Interventions
Intervention
AZD9291 Dose
Starting Dose
80 mg
Reduced Dose
40 mg
On resolution of toxicity within 3 weeks:
If an AE subsequently requires dose interruption, AZD9291 may restart at the same dose or 
the reduced dose, on resolution/improvement of the AE at the discretion of the Investigator.
If new or worsening pulmonary symptoms (e.g., dyspnoea) or radiological abnormality 
suggestive of interstitial lung disease is observed, an interruption in study treatment dosing is 
recommended, and the AstraZeneca study team must be informed.  The results of the full 
diagnostic workup (including high-resolution computed tomography (HRCT), blood and 
sputum culture, haematological parameters) will be captured in the RAVE eCRF. All image 
data should also be provided to AstraZeneca.  It is strongly recommended to perform a full 
diagnostic workup, to exclude alternative causes such as lymphangitic carcinomatosis, 
infection, allergy, cardiogenic edema, or pulmonary hemorrhage.  In the presence of 
confirmatory HRCT scans where other causes of respiratory symptoms have been excluded, a 
diagnosis of interstitial lung disease should be considered and study treatment must be 
permanently discontinued.  
In the absence of a diagnosis of interstitial lung disease study treatment may be restarted 
following consultation with the AstraZeneca Study Team Physician.


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Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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Subjects experiencing any of the following will not be permitted to restart study treatment:

Corneal ulceration

Interstitial Lung Disease (ILD) 

QTc interval prolongation with signs/symptoms of serious arrhythmia
6.7.1
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 investigators.
Skin reactions are to be reported as AEs in the CRF, with additional details captured in the 
"SKNREAC" CRF:
Changes in the characteristics of skin reactions will be collected in the "SKNREAC" CRF. 
Changes in the CTCAE grade of skin reactions will be collected in the AE CRF.
Photographs of skin reactions may be collected and these photographs should be available for 
central review by AstraZeneca and for external expert dermatological review if required.  
Skin biopsies of skin reactions may be taken as per investigator discretion, as per the standard 
local medical practice.  Skin biopsies should ideally be taken in subjects with clinically 
significant or grade ≥ 3 skin reaction. 
6.7.2
Diarrhoea
Recommendations for appropriate management of diarrhoea, including dose-adjustments for 
adverse events 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 investigators. Changes in CTCAE grade of diarrhoea will be captured in the 
AE eCRF. 
For further guidance on skin reactions and diarrhoea, please refer to “Guidance for the 
Management of Adverse Events in Studies using 80mg AZD9291”.
6.8
Management of toxicities related to Platinum-Based Doublet 
Chemotherapy
Detailed here, as guidance, are the US (FDA) approved toxicity management guidelines for 
pemetrexed, carboplatin and cisplatin (US Prescribing Information). 
For toxicity management please adhere to these guidelines or, where appropriate, to local 
approved or clinical practice guidelines. A discussion with AZ study physician would be 
indicated in case of using local clinical practice guidelines. 


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Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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6.8.1
Dose Adjustment Recommendations for Carboplatin 
Pretreatment platelet count and performance status are important prognostic factors for 
severity of myelosuppression in previously treated patients. 
The suggested dose adjustments for single agent or combination therapy shown in the table 
below are modified from controlled trials in previously treated and untreated patients with 
ovarian carcinoma. Blood counts were done weekly, and the recommendations are based on 
the lowest post-treatment platelet or neutrophil value. 
Platelets 
Neutrophils 
Adjusted Dose* (From Prior Course) 
>100 000 
>2 000 
125% 
50-100 000 
500-2 000 
No Adjustment 
<50 000 
<500 
75% 
* Percentages apply to carboplatin for Injection, USP as a single-agent or to both carboplatin and
cyclophosphamide in combination. In the controlled studies, dosages were also adjusted at a lower level (50% to
60%) for severe myelosuppression. Escalations above 125% were not recommended for these studies.
Carboplatin is usually administered by an infusion lasting 15 minutes or longer. No pre- or 
post-treatment hydration or forced diuresis is required.
Patients with Impaired Kidney Function:
Baseline Creatinine Clearance 
Recommended Dose on Day 1 
41 mL/min - 59 mL/min 
250 mg/m2
16 mL/min - 40 mL/min 
200 mg/m2
Patients with creatinine clearance values below 60 mL/min are at increased risk of severe 
bone marrow suppression.  In renally impaired patients who received single-agent carboplatin   
therapy, the   incidence   of   severe   leukopenia, neutropenia, or thrombocytopenia has been
about 25% when the dosage modifications in the table below have been used.
The data available for patients with severely impaired kidney function (creatinine clearance
below 15 mL/min) are too limited to permit a recommendation for treatment.
These dosing recommendations apply to the initial course of treatment. Subsequent 
dosages should be adjusted according to the patient’s tolerance based on the degree of 
bone marrow suppression.
6.8.2
Precaution for Cisplatin 
Peripheral blood counts should be monitored weekly. Liver function should be monitored 
periodically. Neurologic examination should also be performed regularly.
6.8.3
Dose Adjustment Recommendations for Pemetrexed and Cisplatin 
Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic 
counts or maximum non-hematologic toxicity from the preceding cycle of therapy. Treatment 


Revised Clinical Study Protocol
Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
99 (164)
may be delayed to allow sufficient time for recovery. Upon recovery, patients should be 
retreated using the guidelines in below Tables, which are suitable for using pemetrexed as a 
single-agent or in combination with cisplatin. Please follow this recommendation for 
pemetrexed when dosed together with carboplatin
Dose Reduction for Pemetrexed (single-agent or in combination) and Cisplatin -
Hematologic Toxicities:
Nadir ANC <500/mm3 and nadir platelets 
≥50000/mm3
75% of previous dose (pemetrexed and cisplatin). 
Nadir platelets <50 000/mm3 without 
bleeding regardless of nadir ANC
75% of previous dose (pemetrexed and cisplatin). 
Nadir platelets <50 000/mm3 with 
bleeding, regardless of nadir ANC 
50% of previous dose (pemetrexed and cisplatin). 
If patients develop non-hematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment 
should be withheld until resolution to less than or equal to the patient’s pre-therapy value. 
Treatment should be resumed according to guidelines in below Table.
Dose Reduction for Pemetrexed (single-agent or in combination) and Cisplatin –
Non-hematologic Toxicitiesa,b
Dose of Pemetrexed 
(mg/m2) 
Dose of Cisplatin (mg/m2) 
Any Grade 3 or 4 toxicities except 
mucositis 
75% of previous dose 
75% of previous dose 
Any diarrhea requiring hospitalization 
(irrespective of Grade) or Grade 3 or 4 
diarrhea 
75% of previous dose 
75% of previous dose 
Grade 3 or 4 mucositis 
50% of previous dose 
100% of previous dose 
a NCI Common Toxicity Criteria (CTC) 
b excluding neurotoxicity (see Table below).
In the event of neurotoxicity, the recommended dose adjustments for pemetrexed and cisplatin 
are described in below Table. Patients should discontinue therapy if Grade 3 or 4 
neurotoxicity is experienced.
Dose Reduction for Pemetrexed (single-agent or in combination) and Cisplatin –
Neurotoxicity:
CTC Grade 
Dose of Pemetrexed (mg/m2) 
Dose of Cisplatin (mg/m2) 
0-1 
100% of previous dose 
100% of previous dose 


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Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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2 
100% of previous dose 
50% of previous dose 
Discontinuation Recommendation: Pemetrexed therapy should be discontinued if patient 
experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after two dose 
reductions or immediately if Grade 3 or 4 neurotoxicity is observed.
Renally Impaired Patients: In clinical studies, patients with creatinine clearance ≥45 mL/min 
required no dose adjustments other than those recommended for all patients. Insufficient 
numbers of patients with creatinine clearance below 45 mL/min have been treated to make 
dosage recommendations for this group of patients. Therefore, pemetrexed should not be 
administered to patients whose creatinine clearance is <45 mL/min using the standard 
Cockcroft and Gault formula (below) or GFR measured by Tc99m-DTPA serum clearance 
method:
Males: 
[140 - Age in years] × Actual Body Weight (kg)  
_____________________________________              = mL/min
           72 × Serum Creatinine (mg/dL)
Females: 
Estimated creatinine clearance for males × 0.85
Caution should be exercised when administering Pemetrexed concurrently with NSAIDs to 
patients whose creatinine clearance is <80 mL/min.
6.9
Study governance and oversight
6.9.1
Steering Committee
A Steering Committee comprising of the principal investigators for study D5160C00003, in 
addition to principal investigators from the other AZD9291 pivotal studies will provide advice 
on any aspect of the study design or conduct based on requests from the sponsor and assure 
consistency across the entire AZD9291 pivotal programme. 


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Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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No Data Monitoring Committee (DMC) is planned, as the safety profile of AZD9291 from the 
ongoing phase I trial in a similar NSCLC patient population is modest, predictable with no 
reported life-threatening adverse events. There is therefore no requirement for pre-planned 
specified expert independent safety reviews in this study.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity and Dose of investigational product – AZD9291
Investigational product
Dosage form and strength
AZD9291
40mg Tablets
80mg Tablets
AstraZeneca will supply AZD9291 as tablets for oral administration as a single daily dose of 
80 mg.  Tablets can be taken whole with approximately 240 mL water, with or without regard 
to food. Subjects will be required to fast (water only) for at least 8 hours prior to the collection 
of a fasting glucose sample as per the study plan (Table 1) and Section 5.2.1.
At each dispensing visit, sufficient AZD9291 for 21, 42, or 84 days treatment, (depending on 
study schedule) plus overage, will be distributed. Prior to the final DCO, individual bottles 
will be dispensed in accordance with the medication identification numbers provided by the 
IVRS/IWRS. Dispensing of study treatment post final OS DCO will be completed outside of 
the IVRS/IWRS system.
Subjects should swallow one AZD9291 80 mg tablets once daily, commencing on Cycle 1 
Day 1.  Tablets should be taken whole with water, with or without food.
The initial dose of 80 mg AZD9291 can be reduced to 40 mg AZD9291 once daily under 
circumstances described in Section 6.7
On clinic days on which PK samples are scheduled, the dosing should be delayed until arrival 
at the clinic.  Subjects should not take their dose until instructed to do so by site personnel.
Doses should be taken approximately 24 hours apart at the same time point each day.  Doses 
should not be missed.  If a subject 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 dose time, the 
missed dose should not be taken, and subjects should be instructed to take the next dose at the 
next scheduled time.  If a subject vomits after taking their AZD9291, they should not make up 
for this dose, but should take the next scheduled dose.
Prior to the final OS DCO, any change from dosing schedule, dose interruptions, dose 
reductions should be recorded in the eCRF. Post final OS DCO, drug accountability 
information will be stored in the patient notes at the site.


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Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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Tablets will be packed in high-density polyethylene (HDPE) bottles with child-resistant 
closures. Bottles will be dispensed to subjects in the AstraZeneca packing provided. The 
packaging includes bottles, caps and a label. Bottle tampers should not be broken prior to 
dispensing investigational product to a subject.
Additional information about the Investigational product may be found in the Investigators’ 
Brochure.
7.2
Identity and Dose of Comparator Product – Platinum-based 
Doublet-Chemotherapy
Comparator product
Dosing 
pemetrexed + 
carboplatin 
500mg/m2
AUC5 on Day 1 of every 21d cycle
pemetrexed + 
cisplatin 
500mg/m2
75mg/m2 on Day 1 of every 21d cycle
Platinum-based Doublet-chemotherapy is available in a range of strengths and will be sourced 
locally or centrally and should be administered according to local prescribing information, 
including any treatment restrictions.
To reduce the incidence and severity of skin reactions, a corticosteroid should be given the 
day prior to, on the day of, and the day after pemetrexed administration. The corticosteroid 
should be equivalent to 4mg of dexamethasone administered orally twice a day. 
To reduce toxicity, subjects treated with pemetrexed must also receive vitamin 
supplementation. Subjects must take oral folic acid or a multivitamin containing folic acid 
(350 to 1000 micrograms) on a daily basis. At least five doses of folic acid must be taken 
during the approximately 7 days preceding the first dose of pemetrexed, and dosing must 
continue during the full course of therapy and for 21 days after the last dose of pemetrexed. 
Subjects must also receive vitamin B12 (e.g. i.m.1000 micrograms or equivalent) in the week 
preceding the first dose of pemetrexed and once every three cycles thereafter. Subsequent 
vitamin B12 doses may be given on the same day as pemetrexed. Subjects may also receive 
other pre-treatment / concomitant treatment as recommended by approved label for 
pemetrexed, carboplatin or cisplatin as clinically indicated by the investigator.
Anticipated treatment duration is approximately six months.
7.3
Labelling
Labels for IP (if required also for chemotherapy) will be prepared in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines.  Label text will be translated 
into local language.


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Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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The label will include the Name of the Sponsor, Study Code, For Clinical trial use only and/or 
any other market specific requirements.
7.4
Storage
All investigational products should be kept in a secure place under appropriate storage 
conditions.  The investigational product label on the IP specifies the appropriate storage.
7.5
Compliance
Prior to the final OS DCO the administration of all study treatments (including investigational 
products) should be recorded in the appropriate sections of the Case Report Form. Post final 
OS DCO, drug accountability information will be stored in the patient notes at the site.
Subjects should return all unused investigational product and empty containers to the 
investigator.
7.6
Accountability
The investigational product provided for this study will be used only as directed in the study 
protocol.
The study personnel will account for all investigational products dispensed to and returned 
from the subject.
The study personnel at the investigational site will account for all treatments dispensed and for 
appropriate destruction.  Certificates of delivery and destruction should be signed.
7.7
Concomitant and other treatments 
Information on any treatment in the 4 weeks prior to starting study treatment and all 
concomitant treatments given during the study, with reasons for the treatment, will be 
recorded in the CRF.  After permanent discontinuation of study treatment and 28 day follow 
up, only subsequent regimens of anti-cancer therapy will be recored in CRF. If medically 
feasible, subjects taking regular medication, with the exception of potent inducers of CYP3A4 
(see Appendix D), should be maintained on it throughout the study period.  Subjects taking 
concomitant medications whose disposition is dependent upon BCRP 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. 
Guidance on medications that require close monitoring is given in Appendix E.  
Patients taking rosuvastatin (due to BCRP mediated increase in exposure) should have CPK 
levels monitored. If the subject experiences any potentially relevant adverse events suggestive 
of muscle toxicity including unexplained muscle pain, tenderness, or weakness, particularly if 
accompanied by malaise or fever, rosurvastatin should be stopped, and any appropriate further 
management should be taken.


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Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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Subjects taking warfarin should be monitored regularly for changes in prothrombin time or 
INR.
Other anticancer agents, investigational agents and radiotherapy should not be given while the 
subject is on study treatment. 
Pre-medication will be allowed for subjects randomized to the doublet chemotherapy arm.  It 
is also allowed for subjects randomized to AZD9291, but not before the first dose of 
AZD9291.  This includes management of diarrhoea, nausea and vomiting.
Leukocycte-depleted blood transfusions are allowed at any time during the study.
Granulocyte colony stimulating factors should not be used prophylactically during Cycle 1.  
Use of prophylactic colony stimulating factors may be considered after Cycle 1 following 
discussion with the AstraZeneca Study Team Physician.
Subjects may receive treatment with corticosteroids and/or bisphosphonates for the treatment 
of bone metastases.  Subjects may also receive radiotherapy or medication (e.g. denosumab) 
for painful bony metastases. For questions related to specific mediations, please contact the 
Study Physician. 
Supportive care and other medications that are considered necessary for the subject’s well-
being, may be given at the discretion of the investigator.
Study Treatment (Subjects randomized to AZD9291)
Tablets should be taken whole with approximately 240 mL water, with or without regard to 
food.
Study Treatment (Subjects randomized to platinum-based doublet chemotherapy)
Platinum-based doublet chemotherapy should be administered according to local prescribing 
information, including any treatment restrictions. 
Prohibited Medication/Class of drug:
Usage:
Other anticancer agents, investigational agents 
and radiotherapy
Should not be given while the subject is on study 
treatment.
Rescue/Supportive Medication/Class of 
drug:
Usage:


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Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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Pre-medication will be allowed for subjects 
randomized to the doublet chemotherapy arm.  
It is also allowed for subjects randomized to 
AZD9291, but not before the first dose of 
AZD9291.  
To be administered as directed by the investigator.  
This includes management of diarrhoea, nausea and 
vomiting.
Blood transfusions
Allowed at any time during the study.
Granulocyte colony stimulating factors
Should not be used prophylactically during Cycle 1.  
Use of prophylactic colony stimulating factors may 
be considered after Cycle 1 following discussion with 
the AstraZeneca Study Team Physician.
Corticosteroids and/or bisphosphonates
Subjects may receive treatment with corticosteroids 
and/or bisphosphonates for the treatment of bone 
metastases.  
Palliative radiation
Subjects may receive radiotherapy for painful bony 
metastases.
Supportive care and other medications that are 
considered necessary for the subject’s well-
being
To be administered as directed by the investigator  
(e.g. denosumab for painful bony metastases).
7.7.1
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
subject’s safety and well-being, may be given at the discretion of the Investigator and 
recorded in the appropriate sections of the Case Report Form. Some medications may be 
limited due to their QT potential, please refer to Appendix E.
7.8
Post Study Access to Study Treatment
Subjects receiving AZD9291 at the time of study completion (ie, after final OS DCO date) 
may continue to receive AZD9291, if in the opinion of their treating physician they are 
continuing to derive clinical benefit from continued treatment. Study treatment will continue 
until a study discontinuation criterion (eg, withdrawal of consent, adverse event, clinical 
progression, or no longer deriving benefit) has been met as assessed by the investigator. 
Investigators will report all SAEs, overdose and pregnancy to the sponsor until 28 days after 
receipt of their last dose of study treatment. Post final OS analysis DCO, recording and follow 
up of SAEs will be done via paper.  Drug accountability data will also be collected.
Assessments will revert to standard of care at their particular site.
A CSR addendum will be prepared to summarise any additional safety data collected.
7.9
Cross-over to AZD9291
Subjects who are eligible and choose to enter cross-over AZD9291 treatment will be 
dispensed bottles of AZD9291 80mg, once daily, tablets.  For details on AZD9291, please 
refer to Section 7.1.


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Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
A comprehensive Statistical Analysis Plan (SAP) will be prepared and finalised prior to first 
subject in (FSI). The aim of the study is to compare the efficacy and safety of AZD9291 
versus platinum-based doublet chemotherapy. All analyses will be performed by AstraZeneca 
or its representatives. 
The primary analysis will be performed when at least 221 PFS events have occurred, so that 
the PFS data are approximately 54% mature. Three analyses of OS are planned; two interim 
analyses and final analysis. The data cut-off for the first analysis of overall survival will be 
conducted approximately 4 months after data cut-off for the primary analysis of PFS and the 
second analysis will be conducted when the OS data are approximately 50% mature 
(approximately 205 death events). A final analysis of overall survival will be performed when 
the OS data are approximately 70% mature (approximately 287 death events).
Multiple Testing Strategy
In order to describe the benefits of AZD9291 treatment, the primary and secondary endpoints 
will be tested at a 2-sided significance level of 5%.
However, in order to provide strong control of the type I error rate (2-sided 5%), the primary 
endpoint of PFS and key efficacy secondary endpoints, ORR and OS will be tested in this 
sequential order. If any previous analysis in the sequence is not statistically significant, the 
alpha spending cannot be transferred to subsequent analyses. A 2-sided 5% alpha will be used 
in all testing, with the exception of overall survival endpoint. Since three analyses of OS are 
planned, the Lan DeMets approach that approximates the O’Brien and Fleming spending 
function will be used to maintain an overall 2-sided 5% type I error across the three planned 
analyses of OS. Note, any non-statistically significant analyses at the interims will not 
preclude further testing of OS. 
For PRO symptoms and health related quality of life endpoints, the overall type I error (5% 2 
sided) will be controlled across the five primary PRO measures of cough, dyspnoea and pain 
as assessed by the EORTC QLQ-LC13 and fatigue and appetite loss as assessed by the 
EORTC QLQ-C30 using the Bonferroni-Holm procedure.
The physical functioning and global health status/QoL domains of the EORTC QLQ-C30 are 
pre-specified endpoints of interest.
8.2
Sample size estimate
PFS is the primary endpoint for this study. Approximately 410 subjects will be randomized in 
a 2:1 ratio (AZD9291: chemotherapy) to this study.    
The primary analysis of PFS will occur when at least 221 progression events have been 
observed out of the 410 globally randomized subjects. With 221 progression events, the study 


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Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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will have at least 80% power to show a statistically significant PFS at the 5% 2-sided 
significance level if the assumed treatment effect were HR 0.67; this translates to a 3 month 
improvement on an estimated median PFS of 6 months on the control arm, assuming PFS is 
exponentially distributed.  The smallest treatment difference that would be statistically 
significant is a PFS HR of 0.76 (this translates into an approximate 2 month improvement on 
an estimated median PFS of 6 months on the control arm, assuming PFS is exponentially 
distributed).Assuming 15 months non-linear recruitment, 221 PFS events are expected to 
occur approximately 20 months after the first subject is randomized in the study.
In order to randomize 410 subjects assuming a 10% screen failure rate, 455 T790M+ subjects 
will need to be enrolled. In order to enrol 455 T790M+ subjects, 1034 subjects will need to be 
screened [assuming 827 (55%) of subjects are T790+ and allowing for a 20% attrition rate]. 
8.3
Definitions of analysis sets
8.3.1
Full analysis set
The full analysis set will include all randomized subjects prior to the end of global 
recruitment.  Any subjects randomized in China, after global recruitment has ended, will not 
be included in the FAS (see Section 8.6). The full analysis set will be used for all efficacy 
analyses and treatment groups will be compared on the basis of randomized treatment, 
regardless of the treatment actually received.
8.3.2
Safety analysis set
The safety analysis set will consist of all subjects randomized prior to the end of global 
recruitment who received at least one dose of randomized treatment and for whom post dose 
data are available. Any subjects randomized in China only, after global recruitment has ended, 
will not be included in the safety analysis set (see Section 8.6). Safety data will not be 
formally analysed but summarised using the safety analysis set, according to the treatment 
received, i.e. erroneously treated subjects (e.g., those randomized to treatment A but actually 
given treatment B) will be summarised according to the treatment they actually received.
8.3.3
PK analysis set
Subjects in the Full Analysis Set who have at least one measurable PK concentration, 
supported by the relevant date and time of this sample and for each time a PK sample was 
taken the dosing data for that day and for samples taken after multiple dosing the dosing data 
for the 2 days prior to the sample day as well as the sample day. For any individual sample to 
be included in the PK analysis set the full sample data and dosing data needs to be present for 
that sample.
8.4
Outcome measures for analyses
8.4.1
Calculation or derivation of efficacy variables
Investigator RECIST based assessments


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Drug Substance AZD9291
Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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From the investigators review of the imagining scans, the RECIST tumour response data will 
be used to determine each subject’s visit response according to RECIST version 1.1. It will 
also be used to determine the endpoints ORR, DoR, DCR and PFS from the overall visit 
response and scan dates.
At each visit, subjects will be programmatically assigned a RECIST 1.1 visit response of CR,
PR, SD or PD depending on the status of their disease compared with baseline and previous 
assessments. If a subject has had a tumour assessment, which cannot be evaluated, then the 
subject will be assigned a visit response of not evaluable (NE) (unless there is evidence of 
progression in which case the response will be assigned as PD).
Please refer to Appendix G for the definitions of Complete Response, Partial Response, Stable 
Disease and Progressive Disease.
Blinded Independent Central Review of RECIST based assessments
The Blinded Independent Central Review of radiological imagining data will be carried out 
using RECIST version 1.1. All radiological scans for all subjects (including those at 
unscheduled visits, or outside visit windows) will be provided to the BICR. The imaging scans 
will be reviewed by two independent radiologists using RECIST 1.1 criteria and will be 
adjudicated if required. The independent reviewers will be blinded to treatment. For each 
subject, the BICR will define the overall visit response data (CR, PR, SD, PD or NE) and the 
relevant scan dates for each time point (ie, for visits where response or progression is/is not 
identified). If a subject has had a tumour assessment, which cannot be evaluated, then the 
subject will be assigned a visit response of not evaluable (NE) (unless there is evidence of 
progression in which case the response will be assigned as PD 
Further details of the Blinded Independent Central Review will be documented in the Blinded
Independent Review Charter. 
Progression Free Survival (PFS)
PFS is defined as the time from randomization until the date of objective disease progression 
or death (by any cause in the absence of progression) regardless of whether the subject 
withdraws from randomized 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 from their last evaluable RECIST assessment.  
However, if the subject progresses or dies after two or more missed visits, the subject will be 
censored at the time of the latest evaluable RECIST assessment.  If the subject has no 
evaluable visits or does not have baseline data they will be censored at 0 days unless they die 
within two visits of baseline.
The PFS time will always be derived based on scan/assessment dates not visit dates.
RECIST assessments/scans contributing towards a particular visit may be performed on 
different dates.  The following rules will be applied:

Date of progression will be determined based on the earliest of the dates of the component that 
triggered the progression


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Edition Number 5
Date January 10, 2017
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
When censoring a subject for PFS the subject will be censored at the latest of the dates 
contributing to a particular overall visit assessment
Objective Response Rate (ORR)
ORR rate is defined as the number (%) of subjects with measurable disease with at least one 
visit response of CR or PR that is confirmed at least 4 weeks later.  Data obtained up until 
progression, or last evaluable assessment in the absence of progression, will be included in the 
assessment of ORR.  However, any complete response or partial response, which occurred 
after a further anticancer therapy was received, will not be included in the numerator for the 
ORR calculation.  
In the case where a subject has two non-consecutive visit responses of PR, then, as long as the 
time between the 2 visits of PR is greater than 4 weeks and there is no PD between the PR 
visits, the subject will be defined as a responder.  Similarly, if a subject has visit responses of 
CR, NE, CR, then, as long as the time between the 2 visits of CR is greater than 4 weeks, then 
a best response of CR will be assigned.
Duration of Response (DoR)
Duration of response will be defined as the time from the date of first documented response,
(that is subsequently confirmed) until date of documented progression or death in the absence 
of disease progression, the end of response should coincide with the date of progression or 
death from any cause used for the PFS endpoint. The time of the initial response will be 
defined as the latest of the dates contributing towards the first visit response of PR or CR. If 
the response is not confirmed, it will not be included.
If a subject does not progress following a response, then their duration of response will use the 
PFS censoring time.
Disease control rate (DCR)
Disease control rate is defined as the percentage of subjects who have a best overall response 
of CR or PR or SD.
Tumour shrinkage
Tumour shrinkage will be assessed using RECIST tumour response. The absolute change and 
percentage change from baseline in sum of tumour size at each assessment will be calculated. 
The best change in tumour size will include all assessments prior to progression or start of 
subsequent anticancer therapy.      
Overall Survival (OS)
Overall survival is defined as the time from the date of randomization 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. 
Note: Survival calls will be made in the 2 weeks following the date of the data cut-off for each 
OS analysis, and if subjects are confirmed to be alive, or if the death date is post the final data 


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Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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cut-off date, these subjects will be censored at the date of the final data cut off. Death dates 
may be found by checking publicly available death registries.
HRQoL & Symptoms
Patient reported outcomes will be assessed using the EORTC QLQ-C30 and QLQ-LC13 
questionnaires.  The QLQ-C30 consists of 30 questions, which can be combined to produce 5 
functional scales (Physical, Role, Cognitive, Emotional, Social), 3 symptom scales (Fatigue, 
Pain, Nausea/vomiting), 5 individual items (dyspnoea, insomnia, appetite loss, constipation, 
diarrhoea) and a global measure of health status.  The QLQ-LC13 is a lung cancer specific 
module comprising 13 questions to assess lung cancer symptoms (cough, haemoptysis, 
dyspnoea and site-specific pain), treatment related side-effects (sore mouth, dysphagia, 
peripheral neuropathy and alopecia) and pain medication.  With the exception of a multi-item 
scale for dyspnoea, all are single items.   
An outcome variable consisting of a score from 0 to 100 will be derived for each of the 
symptom scales/symptom items, the functional scales and the global health status scale in the 
QLQ-C30 and for each of the symptom scales/items in the QLQ-LC13 according to the 
EORTC QLQ-C30 Scoring Manual and EORTC QLQ-LC13 instructions. 
Higher scores on the global health status and functioning scales indicate better health 
status/function.  Higher scores on the symptoms scales indicate greater symptom burden.
The primary PRO outcome measures will be patient-reported lung cancer symptoms assessed 
using the EORTC QLQ-LC13, namely 

dyspnoea (multi-item scale based on three questions: “Were you short of breath when you 
rested; walked; climbed stairs”), 

cough: one item (“How much did you cough?”), 

pain: one item (“Have you had pain in your chest”).

fatigue (a composite score of three items: “Did you need rest; Have you felt weak; Were 
you tired”)

appetite loss: one individual item (“Have you lacked appetite”)
Definition of clinically meaningful changes
Changes in score compared to baseline will be evaluated.  A minimum clinically meaningful 
change is defined as a change in the score from baseline of ≥10 for scales/items from the 
QLQ-LC13 and the QLQ-C30 (Osoba et al 1998).
For example, a clinically meaningful deterioration or worsening in chest pain (as assessed by 
QLQ-LC13) is defined as an increase in the score from baseline of ≥10.  A clinically 
meaningful improvement in fatigue (as assessed by QLQ-C30) is defined as a decrease in the 
score from baseline of ≥10.  
At each post-baseline assessment, change in symptoms/functioning from baseline will be 
categorised as improved, stable or worsening as shown in Table 12.


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Edition Number 5
Date January 10, 2017
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Table 12
Visit Response for HRQoL and disease-related symptoms
Score
Change from baseline
Visit Response
LC13 symptom scales/items
≥+10
Worsened
≤-10
Improved
Otherwise
Stable
C30 symptom scales/items
≥+10
Worsened
≤-10
Improved
Otherwise
Stable
C30 functional scales and
≥+10
Improved
Global health status
≤-10
Worsened
Otherwise
Stable
Time to symptom deterioration 
For each of the symptoms scales/items in QLQ-LC13, time to symptom deterioration will be 
defined as the time from randomization until the date of first clinically meaningful symptom 
deterioration (an increase in the score from baseline of ≥10) or death (by any cause) in the 
absence of a clinically meaningful symptom deterioration, regardless of whether the subject 
withdraws from randomized therapy or receives another anticancer therapy prior to symptom 
deterioration.  Death will be included as an event only if the death occurs within two visits of 
the last PRO assessment where the symptom change could be evaluated.  
Subjects whose symptoms (as measured by QLQ-LC13) have not shown a clinically 
meaningful deterioration and who are alive at the time of the analysis will be censored at the 
time of their last PRO assessment where the symptom could be evaluated. Also, if symptoms 
progress after two or more missed PRO assessment visits or the subject dies after two or more 
missed PRO assessment visits, the subject will be censored at the time of the last PRO 
assessment where the symptom could be evaluated. If a subject has no evaluable visits or does 
not have baseline data they will be censored at day 1. The population for analysis of time to 
symptom deterioration will include a subset of the ITT population who have baseline scores   
≤ 90.
Symptom Improvement Rate
The symptom improvement rate will be defined as the number (%) of subjects with two 
consecutive assessments at least 18 days apart (ie, 21 days allowing a visit window of 3 days), 
which showed a clinically meaningful improvement (a decrease from baseline score ≥10 for 


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Edition Number 5
Date January 10, 2017
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LC13 scales/items or C30 scales/items) in that symptom from baseline.   The denominator will 
consist of a subset of the ITT population who have a baseline symptom score ≥10.
Mixed Models Repeated Measures (MMRM) Analysis
Change from baseline in cough, dyspnoea and pain scores as assessed by the EORTC QLQ-
LC13 and fatigue and appetite loss as assessed by the EORTC QLQ-C30 will be the primary 
analysis and assessment of PRO outcome measures. The analysis will be performed using a 
linear mixed model for repeated measures (MMRM) analysis of change from baseline in the 
scores for each visit.
Symptom improvement rate and Time to symptom deterioration analyses will be considered 
as supportive analyses.  
Time from randomization to second progression (PFS2) (exploratory)
Time from randomization to second progression (PFS2) is defined as the time from the date of 
randomization to the earliest of the progression event subsequent to that used for the primary 
variable PFS or death. Subjects alive and for whom a second disease progression has not been 
observed should be censored at the last time known to be alive and without a second disease 
progression, ie, censored at the last progression assessment date if the subject has not had a 
second progression or death.
Time to first subsequent therapy or death (TFST)
Time to first subsequent therapy or death is defined as the time from the date of randomization
to the earlier of the date of anticancer therapy start date following study treatment 
discontinuation, or death. Any subject not known to have had a subsequent therapy or not 
known to have died at the time of the analysis will be censored at the last known time to have 
not received subsequent therapy, ie, the last follow-up visit where this was confirmed.
Time to second subsequent therapy or death (TSST) 
Time to second subsequent therapy or death is defined as the time from the date of 
randomization to the earlier of the date of second subsequent anticancer therapy start date 
following study treatment discontinuation, or death. Any subject not known to have died at the 
time of the analysis and not known to have had a second further intervention of this type will 
be censored at the last known time to have not received second subsequent therapy, ie, the last 
follow-up visit where this was confirmed.
Patient reporting of CTCAE symptoms
The PRO-CTCAE questionnaire will be used to derive subject reporting of CTCAE 
symptoms. 
Health State Utility


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The EQ-5D-5L index comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression). For each dimension, respondents select which 
statement best describes their health on that day from a possible 5 options of increasing levels 
of severity (no problems, slight problems, moderate problems, severe problems and unable 
to/extreme problems). A unique EQ-5D health state is referred to by a 5-digit code allowing 
for a total of 3125 health states. For example, state 11111 indicates no problems on any of the 
5 dimensions. These data will be converted into a weighted health state index by applying 
scores from EQ5D value sets elicited from general population samples (the base case will be 
the United Kingdom valuation set, with other country value sets applied in scenario analyses). 
Where values sets are not available, the EQ-5D-5L to EQ-5D-3L crosswalk will be applied. In 
addition to the descriptive system, respondents also assess their health on the day of 
assessment on a visual analogue scale, ranging from 0 (worst imaginable health) to 100 (best 
imaginable health). This score is reported separately.
Health Resource Utilisation
Health resource utilisation will be assessed in terms of hospitalization, outpatient visits and 
emergency department visits
8.4.2
Calculation or derivation of safety variable(s)
Safety and tolerability will be assessed in terms of AEs, deaths, laboratory data, vital signs 
(pulse and BP) and ECG. These will be collected for all subjects.
Adverse events
AEs (both in terms of MedDRA preferred terms and CTCAE grade) will be listed individually 
by subject.  
Any AE occurring before treatment with AZD9291 will be included in the data listings but 
will not be included in the summary tables of AEs.
Any AE occurring within 28 days of discontinuation of investigational product (ie, the last 
dose of AZD9291/chemotherapy) will be included in the AE summaries.  Any events in this 
period that occur after a subject has received further therapy for cancer (following 
discontinuation of AZD9291) will be flagged in the data listings. Please refer to Section 6.3.1
Other significant adverse events (OAEs)
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and AEs leading to discontinuation.  Based on 
the expert’s judgement, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered OAEs and reported as 
such in the CSR.  A similar review of laboratory/vital signs (pulse and BP)/ECG data will be 
performed for identification of OAEs.


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Study Code D5160C00003
Edition Number 5
Date January 10, 2017
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Examples of these could be marked haematological and other laboratory abnormalities, and 
certain events that lead to intervention (other than those already classified as serious), dose 
reduction or significant additional treatment.
8.4.3
Calculation or derivation of pharmacokinetic variables
Pharmacokinetic analysis of the plasma concentration data for AZD9291 and AZ5104 and 
AZ7550 will be performed by Quantitative Clinical Pharmacology, AZ or delegate on behalf 
of Quantitative Clinical Pharmacology.  Plasma concentration will be summarized by normal 
time window.  The ratio of metabolite to AZD9291 will be calculated.
The plasma concentration data for AZD9291 and metabolites will also be analysed using a 
population pharmacokinetic approach, which may include exploring the influence of 
covariates on PK, if the data allows. A pharmacokinetic-pharmacodynamic approach will be 
used to investigate the relationship between PK and selected primary, secondary and/or 
exploratory endpoints, where deemed appropriate. Results may be reported separately from 
the Clinical Study Report for the main study.
The data collected in this study may also be combined with similar data from other studies and 
explored using population pharmacokinetic and/or pharmacokinetic-pharmacodynamic 
method. The results of any such analyses will be reported separately from the Clinical Study 
Report.
8.5
Methods for statistical analyses
All efficacy analyses will be performed on the FAS population. Results of all statistical 
analyses will be presented using a 95% confidence interval and 2-sided p-value. 
8.5.1
Analysis of the primary variable (s)
PFS will be analyzed using a log rank test stratified by ethnicity (Asian, Non-Asian) for 
generation of the p-value and using the Breslow approach for handling ties. The hazard ratio 
(HR) and confidence interval will be obtained directly from the U and V statistics as follows 
(Berry G et al 1991, Selke & Siegmund 1982): 
HR = exp(U/V)
95% CI for HR = (exp{U/V – 1.96/V}, exp{U/V + 1.96V})
Where U = i(d1i – e1i) is the log-rank test statistic (with d1i and e1i the observed and expected 
events in group 1) and V the standard deviation of the log-rank test statistic obtained from 
the LIFETEST procedure with a STRATA term for the stratification variable.
A Kaplan-Meier (KM) plot of PFS will be presented by treatment group.
Subgroup analysis


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Subgroup analyses will be conducted by comparing PFS between treatments in the following 
groups: 

Ethnicity (Asian versus Non-Asian)

Gender (Male versus Female)

Age at randomisation (<65 versus ≥65)

Mutation status prior to start of study (ex19 versus L858R)

Duration of prior EGFR TKI (<6 months, 6 months)

Brain metastases at entry

Smoking history
The HR (AZD9291: chemotherapy) and associated CI will be calculated from a Cox 
proportional hazards model (ties=Efron) that contains the treatment term, factor and 
treatment-by-factor interaction term. The treatment effect HRs for each treatment comparison 
along with their confidence intervals will be obtained for each level of the subgroup from this 
single model. The HRs and 95% CIs will be presented on a forest plot including the HR and 
95% CI from the overall population (using the primary analysis).
The assumption of proportionality will be assessed. In the event on non-proportionality, the 
HR will be interpreted as an average HR over the observed extent of follow-up. 
Proportionality will be tested firstly by examining the plots of complementary log-log (event 
times) versus log (time) and, if necessary, a time dependent covariate will be fitted to assess 
the extent to which this represents random variation.    
No adjustment to the significance level for testing will be made since the subgroup analysis 
will be considered exploratory and may only be supportive of the primary analysis of PFS.
The presence of quantitative interactions will be assessed by means of an overall global 
interaction test. This will be performed in the overall population by comparing the fit of a Cox 
proportional hazards model including treatment, all covariates, and all covariate-by-treatment 
interaction terms, with one that excludes the interaction terms and will be assessed at the 2-
sided 10% significance level. If the fit of the model is not significantly improved then it will 
be concluded that overall the treatment effect is consistent across the subgroups.
If the global interaction test is found to be statistically significant, an attempt to determine the 
cause and type of interaction will be made. Stepwise backwards selection will be performed 
on the saturated model, whereby (using a 10% level throughout) the least significant 
interaction terms are removed one-by-one and any newly significant interactions re-included 
until a final model is reached where all included interactions are significant and all excluded 
interactions are non-significant. Throughout this process all main effects will be included in 
the model regardless of whether the corresponding interaction term is still present. This 
approach will identify the factors that independently alter the treatment effect and prevent 
identification of multiple correlated interactions.
Any quantitative interactions identified using this procedure will then be tested to rule out any 
qualitative interaction using the approach of Gail and Simon 1985. 


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Sensitivity analyses 
(a) Ascertainment bias
The possibility of bias in assessment and measurement of PFS by investigators will be 
assessed by comparing the hazard ratios derived from investigator review with the hazard ratio 
derived using the blinded independent central review assessment of disease progression by 
RECIST.  
(b) Evaluation-time bias
In order to assess possible evaluation-time bias, that could occur if scans are not performed at 
the protocol-scheduled time points, the midpoint between the time of progression and the 
previous evaluable RECIST assessment will be analyzed using a stratified log rank test, as 
described for the primary analysis of PFS. For patients who die in the absence of progression, 
the date of death will be used to derive the PFS time used in the analysis.
(c) Attrition bias
Possible attrition bias will be assessed by repeating the primary PFS analysis, except that the 
actual PFS event times, rather than the censored times, of subjects who progressed or died in 
the absence of progression immediately following two, or more, non-evaluable tumour 
assessments will be included. In addition, subjects who take subsequent therapy prior to 
progression or death will be censored at their last evaluable assessment prior to taking the 
subsequent therapy. A Kaplan-Meier plot of the time to censoring, where the censoring 
indicator of the primary PFS analysis is reversed, will be presented.
(d) Exploratory Analysis
Recently, it has been suggested that, in order to assess the potential for bias amongst 
investigators, a BICR amongst only a sample of subjects could be performed; if evidence of 
bias is detected, according to a pre-defined threshold, the BICR is then assessed in all 
subjects, otherwise it is concluded the sample was sufficient to rule-out meaningful levels of 
bias. A proposed sample BICR method has been submitted to a peer reviewed statistical 
journal for publication as of August 2014 and in order to demonstrate that this is a valid 
methodology for use in future trials, an exploratory analysis will be carried out using this 
methodology. Further details will be provided in the SAP.
8.5.2
Analysis of the secondary variable(s)
8.5.2.1
Analysis of ORR
ORR will be analyzed using a logistic regression with a covariate for ethnicity (Asian, Non-
Asian). The results of the analysis will be presented in terms of an odds ratio together with its 
associated 95% profile likelihood confidence interval and 2-sided p-value. The p-value will be 
based on twice the change in log-likelihood resulting from the addition of a treatment factor to 
a model that contains the covariates defined above. 


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8.5.2.2
Analysis of DoR
In order to analyze the secondary outcome variable of Duration of Response between arms the 
Expected Duration of Response (EDoR) will be derived for each treatment arm (Ellis S et al 
2008). The EDoR is the product of the proportion of subjects responding to treatment and the 
mean DoR in responding subjects, and provides an estimate based on all randomized subjects. 
Treatments will be compared by calculating the ratio of EDoRs using an appropriate 
probability distribution for duration of response in responding subjects. The choice of 
probability distribution will be detailed in the SAP.  The analysis of DoR will be stratified by 
the same covariates as the primary analysis, weighting each stratum inversely proportional to 
the within stratum variance of the log of the ratio of EDoRs. Additionally, descriptive data 
will be provided for the duration of response in responding subjects, including associated 
Kaplan-Meier curves (without any formal comparison of or p-value attached). 
8.5.2.3
Analysis of DCR
DCR will be analyzed using a logistic regression with a covariate for ethnicity (Asian, Non-
Asian). The results of the analysis will be presented in terms of an odds ratio together with its 
associated 95% profile likelihood confidence interval and 2-sided p-value. The p-value will be 
based on twice the change in log-likelihood resulting from the addition of a treatment factor to 
a model that contains the covariates defined above.
8.5.2.4
Analysis of Tumour Shrinkage
The best absolute change in target lesion tumour size from baseline and percentage change in 
target lesion tumour size from baseline will be summarized using descriptive statistics and 
presented at each timepoint and by randomized treatment group. The effect of AZD9291 on 
percentage change in tumour size will be estimated from an analysis of covariance 
(ANCOVA) model with a covariate for ethnicity (Asian, Non-Asian). The number of subjects, 
unadjusted mean and lsmeans for each treatment group will be presented, together with the 
difference in lsmeans, 95% confidence interval and corresponding p-value.
8.5.2.5
Analysis of OS
OS data will be analyzed using the same methodology and model as for the analysis of PFS 
(provided there are sufficient events available for a meaningful analysis [>20 deaths], if not 
descriptive summaries will be provided). Two interim analyses of OS will be performed and a 
final, optional analysis of OS may be performed. The first interim analysis of OS will be 
performed at the time of the primary analysis of PFS. The second interim analysis of OS will 
be performed when the OS data are approximately 50% mature.
8.5.2.6
Analysis of Time to PRO Symptom Deterioration
Time to PRO symptom deterioration will be analyzed using a log rank test stratified by 
ethnicity (Asian, Non-Asian) for generation of the p-value and using the Breslow approach for 
handling ties. The hazard ratio (HR) and confidence interval will be estimated using the same 
methods as for the primary endpoint of PFS, as described in Section 8.5.1.


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8.5.2.7
Analysis of PRO Symptom Improvement Rate
Symptom Improvement Rate will be analyzed using a logistic regression with a covariate for 
ethnicity (Asian, Non-Asian). The results of the analysis will be presented in terms of an odds 
ratio together with its associated 95% profile likelihood confidence interval and 2-sided p-
value. The p-value will be based on twice the change in log-likelihood resulting from the 
addition of a treatment factor to a model that contains the covariates defined above.
8.5.2.8
Pharmacokinetics
Pharmacokinetic concentration data will be summarised using appropriate summary statistics 
and further details will be provided in the SAP.
8.5.2.9
Patients with EGFR T790M mutation status detected in baseline plasma 
sample (ctDNA)
The efficacy of AZD9291 versus chemotherapy will be evaluated for the subgroups of patients 
with T790M detected in their baseline plasma sample and patients that are T790M negative by 
the plasma test. For PFS, the HR and associated 95% CI will be calculated and KM plots 
presented for each group. For ORR, the odds ratio and associated 95% CI will be presented 
for each group.
8.5.3
Exploratory analysis
PRO-CTCAE
PRO-CTCAE data will be presented using summaries and descriptive statistics based on the 
Full Analysis Set and further details will be provided in the SAP.
Healthcare Resource Use
Healthcare Resource Use data will be presented using summaries and descriptive statistics, 
based on the Full Analysis Set and further details will be provided in the SAP.
Exploratory analysis of post progression outcomes
PFS2 will be analysed using the same method as the analysis of PFS. Time to first subsequent 
therapy, time to second subsequent therapy and time to change in symptoms (measured by 
PRO HRQoL questionnaires) will be summarised as appropriate and further details will be 
provided in the SAP. 
Exploratory analysis of characterising survival
All further analysis of overall survival will be exploratory. The effect of baseline 
characteristics on overall survival in each randomized treatment arm will be summarised. As 
appropriate, time-varying outcomes measured during the study treatment and post progression 
phases will also be summarised. All subsequent treatments in each treatment arm will be 
summarised, including duration of treatments. For summaries, anti-cancer treatments will be 
grouped by mode of action (e.g. 1st/2nd generation EGFR TKIs, 3rd generation EGFR TKIs 


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with T790M activity (e.g. AZD9291, others), platinum-based doublet chemotherapy, single 
agent chemotherapy). 
Additional analysis of overall survival adjusting for the impact of subjects randomized to 
chemotherapy, who subsequently receive a 3rd generation EGFR TKI with T790M activity 
(ie, those who “switch” treatment) may be completed if this treatment sequence occurs in a 
significant proportion of subjects. Methods such as Rank Preserving Structural Failure Time 
(RPSFT) (Robins et al 1991), Inverse Probability of Censoring Weighting (IPCW) (Robins et 
al 1993) and other methods in development may be explored.  The decision to adjust and final 
choice of methods will be based on a blinded review of the data and the plausibility of the 
underlying assumptions.
Further detail will be provided in the SAP and Payer Analysis Plan.
Summaries and analyses for other exploratory objectives will be documented in a separate 
analysis plan and will be reported outside the CSR in a separate report.
8.6
China Cohort
In order to adequately compare the efficacy and safety of AZD9291 versus chemotherapy in 
Chinese patients to fulfil China FDA requirements, subjects recruited in China after global 
recruitment has ended will be combined with any subjects recruited from China prior to the 
end of the global recruitment. This China-only cohort will be analysed and reported separately 
from the Clinical Study Report. 
8.6.1
Definition of China analysis sets
8.6.1.1
China-only Full Analysis Set
The China-only Full analysis set will include all subjects randomized in China. This includes 
all subjects randomized in China prior to the end of global recruitment and all additional 
subjects recruited in mainland China after global recruitment is completed. 
The China-only Full analysis set will be used for all China-only efficacy analyses and 
treatment groups will be compared on the basis of randomized study treatment, regardless of 
the treatment actually received.
8.6.1.2
China-only Safety Analysis Set
The China-only safety analysis set will consist of all subjects randomized in China who 
received at least one dose of study treatment and for whom post-dose data are available.
8.6.1.3
China-only Pharmacokinetic Analysis Set
The China-only Pharmacokinetic Analysis Set is defined as subjects in the China-only FAS 
who have at least one evaluable PK concentration.


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8.6.2
China-only analyses
All efficacy, safety, PRO and PK variables will be derived in the same way as detailed in 
Section 8.4.
All analyses detailed in Section 8.5 will be repeated for the China-only cohort using the 
analysis sets described in Section 8.6.1.
All statistical analyses will be considered exploratory and only performed if sufficient 
numbers of events or subjects are available (e.g. > 20 PFS or OS events), otherwise 
descriptive statistics only will be presented. No adjustment for multiplicity will be made and 
so the procedure for hierarchical testing detailed in Section 8.5.2.1 will not be followed.
Statistical analyses will not be stratified by ethnicity (Asian versus Non-Asian).
The analyses be performed at the time of the primary PFS analysis if at least 20 PFS events 
have been observed out of approximately 50 Chinese subjects, otherwise summaries of 
efficacy will be provided only. Additional follow-up of Chinese subjects if deemed 
appropriate may be performed when the PFS data are more mature (for example, 70% 
maturity, as consistent with the primary global PFS analysis).
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first subject is entered into the study, an AstraZeneca representative will review 
and discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC and 
ePRO system(s) utilised.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:

Provide information and support to the Investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the CRFs, that biological samples are handled in 


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accordance with the Laboratory Manual and that investigational product accountability 
checks are being performed

This study plans to follow the principles of targeted monitoring and perform 100% Source 
Data Verification (SDV) on critical variables (including eligibility criteria) only. The 
expected overall SDV will be at least 50%

Perform source data verification (a comparison of the data in the CRFs with the subject’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating subjects. This will require 
direct access to all original records for each subject (e.g., clinic charts)

Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject.
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
9.2.1
Source data
Refer to the Clinical Study Agreement for location of source data.
9.2.2
Study agreements
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of subjects and in all other respects, not relating to study conduct or treatment of 
subjects, the terms of the Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or subjects are screened.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA).
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last subject undergoing the study’.
The study is expected to start in Q3 2014 and to end by approximately Q4 2018.
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with AZD9291.


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9.4
Data management by AstraZeneca
Data management will be performed by Cognizant Data Management Centre staff, according 
to the Data Management Plan.  Adverse events and medical/surgical history will be classified 
according to the terminology of the latest version the Medical Dictionary for Regulatory 
Activities (MedDRA).  Medications will be classified according to the AstraZeneca Drug 
Dictionary.  Classification coding will be performed by the Medical Coding Team at the 
Cognizant Data Management Centre.
The data collected through third party sources will be obtained and reconciled against study 
data.
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.
When all data have been coded, validated, signed and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
Data Management of Genotype Data
Any genotype data generated in this study will be stored in the AstraZeneca genotyping 
Laboratory Information Management System (LIMS) database, or other appropriate secure
System within AstraZeneca and/or third party contracted to work with AstraZeneca to analyse 
samples. 
Data Associated with Human Biological Samples
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca.
Management of External Data
Data associated with ePRO will be transferred from vendor to Cognizant Data Management 
Centre.


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10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
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 ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
10.2
Subject data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law.
Precautions are taken to preserve confidentiality and prevent genetic data being linked to the 
identity of the subject. In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a subject’s 
identity and also have access to his or her genetic data. Also Regulatory authorities may 
require access to the relevant files, though the subject’s medical information and the genetic 
files would remain physically separate.
10.3
Ethics and regulatory review
An Ethics Committee should approve the final study protocol, including the final version of 
the Informed Consent Form and any other written information and/or materials to be provided 
to the subjects.  The Investigator will ensure the distribution of these documents to the 
applicable Ethics Committee, and to the study site staff.
The opinion of the Ethics Committee should be given in writing. The Investigator should 
submit the written approval to AstraZeneca before enrolment of any subject into the study. 
The Ethics Committee should approve all advertising used to recruit subjects for the study.
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually.


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Before enrolment of any subject into the study, the final study protocol, including the final 
version of the Informed Consent Form are to be approved by the national regulatory authority 
or a notification to the national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements.
Each Principal Investigator is responsible for providing the Ethics Committees/IRB with 
reports of any serious and unexpected adverse drug reactions from any other study conducted 
with the investigational product.  AstraZeneca will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements.
10.4
Informed consent
The Principal Investigator(s) at each centre will:

Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study

Ensure each subject is notified that they are free to discontinue from the study at any time

Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided

Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study

Ensure the original, signed Informed Consent Form(s) is/are stored in the Investigator’s 
Study File

Ensure a copy of the signed Informed Consent Form is given to the subject

Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in the 
informed consent form that is approved by an Ethics Committee.
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the International 
coordinating Investigators and AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols.


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AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to Ethics Committee see Section 10.3. 
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s Ethics Committee are to approve the revised Informed Consent Form before 
the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee.
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), and any 
applicable regulatory requirements.  The Investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the centre.
11.
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Clinical Study Protocol Appendix A
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Version 5
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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
International Airline Transportation Association (IATA) 6.2 
Guidance Document
Labelling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus:

are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations

Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging 

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable

Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.


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Appendix C
Pharmacogenetics Research
BACKGROUND AND RATIONALE
AstraZeneca intends to perform genetic research in the AZD9291 clinical development 
programme to explore how genetic variations may affect the clinical parameters associated 
with AZD9291.  Collection of deoxyribonucleic acid (DNA) samples from populations with 
well described clinical characteristics may lead to improvements in the design and 
interpretation of clinical trials and, possibly, to genetically guided treatment strategies.
Future research may suggest other genes or gene categories as candidates for influencing not 
only response to AZD9291 but also susceptibility to the ‘response’/disease for which 
AZD9291 may be evaluated.  Thus, this genetic research may involve study of additional un-
named genes or gene categories, but only as related to disease susceptibility and drug action.
GENETIC RESEARCH OBJECTIVES
The objective of this research is to collect and store DNA for future exploratory research into 
genes/genetic variation that may influence response (i.e. distribution, safety, tolerability and 
efficacy) to AZD9291.
GENETIC RESEARCH PLAN AND PROCEDURES
Selection of genetic research population
Study selection record
All subjects will be asked to participate in this genetic research.  Participation is voluntary and 
if a subject declines to participate there will be no penalty or loss of benefit.  The subject will 
not be excluded from any aspect of the main study.
Inclusion criteria
For inclusion in this genetic research, subjects must fulfil all of the inclusion criteria described 
in the main body of the Clinical Study Protocol, Section 3.1.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main body of the Clinical Study Protocol, Section 3.2.
Discontinuation of subjects from this genetic research
Specific reasons for discontinuing a subject from this genetic research are:


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Withdrawal of consent for genetic research:  Subjects may withdraw from this genetic 
research at any time, independent of any decision concerning participation in other aspects of 
the main study.  Voluntary discontinuation will not prejudice further treatment.  Procedures 
for discontinuation are outlined in Section 3.7 and 3.8 of the main Clinical Study Protocol.
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the subjects at Visit 1 or after 
randomisation.  Although genotype is a stable parameter, early sample collection is preferred 
to avoid introducing bias through excluding subjects who may withdraw due to an adverse 
event (AE), such subjects would be important to include in any genetic analysis.  If for any 
reason the sample is not drawn at Visit 1, it may be taken at any visit until the last study visit.  
Only one sample should be collected per subject for genetics during the study.  Samples will 
be collected, labelled, stored and shipped as detailed in the Laboratory Manual.
For blood volume, see Section 5.2.2 of the Clinical Study Protocol.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality.  Samples will be stored for a maximum of 15
years, from the date of last subject last visit, after which they will be destroyed.  DNA is a 
finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached.
For all samples irrespective of the type of coding used the DNA will be extracted from the 
blood sample.  The DNA sample will be assigned a unique number replacing the information 
on the sample tube.  Thereafter, the DNA sample will be identifiable by the unique DNA 
number only.  The DNA number is used to identify the sample and corresponding data at the 
AstraZeneca genetics laboratories, or at the designated contract laboratory.  No personal 
details identifying the individual will be available to any person (AstraZeneca employee or 
contract laboratory staff working with the DNA.)
The samples and data for genetic analysis in this study will be single coded.  The link between 
the subject enrolment/randomisation code and the DNA number will be maintained and stored 
in a secure environment, with restricted access within the Clinical Genotyping Group 
Laboratory Information Management System (LIMS) at AstraZeneca.  The link will be used 
to identify the relevant DNA samples for analysis, facilitate correlation of genotypic results 
with clinical data, allow regulatory audit and to trace samples for destruction in the case of 
withdrawal of consent.
ETHICAL AND REGULATORY REQUIREMENTS
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 10 of the main Clinical Study Protocol.


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Informed consent
The genetic component of this study is optional and the subject may participate in other 
components of the main study without participating in the genetic component.  To participate 
in the genetic component of the study the subject must sign and date both the consent form for 
the main study and the genetic component of the study.  Copies of both signed and dated 
consent forms must be given to the subject and the original filed at the study centre.  The 
principal investigator(s) is responsible for ensuring that consent is given freely and that the 
subject understands that they may freely discontinue from the genetic aspect of the study at 
any time.
Subject data protection
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject.  For example, in the case of 
a medical emergency, an AstraZeneca Physician or an investigator might know a subject’s 
identity and also have access to his or her genetic data.  Also Regulatory authorities may 
require access to the relevant files, though the subject’s medical information and the genetic 
files would remain physically separate.
DATA MANAGEMENT
Any genotype data generated in this study will be stored in the AstraZeneca genotyping LIMS 
database, or other appropriate secure system within AstraZeneca and/or third party contracted 
to work with AstraZeneca to analyze the samples.
The results from this genetic research may be reported in the CSR for the main study, or in a 
separate report as appropriate.
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
The number of subjects that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A statistical 
analysis plan will be prepared where appropriate.


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LIST OF REFERENCES
None


Clinical Study Protocol Appendix D
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Appendix D
Actions Required in Cases of Combined Increase of 
Aminotransferase and Total Bilirubin - Hy’s Law
1.
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.
2.
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, e.g. 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 
(i.e. on the same day) the elevation in TBL, but there is no specified timeframe within which 
the elevations in transaminases and TBL must occur.
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:


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
ALT ≥ 3xULN

AST ≥ 3xULN

TBL ≥ 2xULN
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 Section 2 of this Appendix for 
definition) by reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory CRF.
4.
FOLLOW-UP
4.1
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
4.2
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
treatment in the presence of liver metastases (See Section 6).

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 subjects’ 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.

Complete the three Liver CRF Modules as information becomes available.

If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures.


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5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW 
CASES
The instructions in this Section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
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.
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.


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6.
ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW
CRITERIA ARE MET BEFORE AND AFTER STARTING 
STUDY TREATMENT 
This section is applicable to subjects who meet PHL criteria on study treatment (including the 
28 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 subjects’ condition compared 
with the last visit where PHL criteria were met

If there is no significant change no action is required

If there is a significant change notify the AstraZeneca representative, who will inform 
the central Study Team, then follow the subsequent process described in Section 4.2 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.
7.
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 
28-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 
Section 6?
If No: Follow the process described in Section 4.2 of this Appendix


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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 Section 4.2 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.
8.
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


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Appendix E
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 
concomitant medications must be recorded in the eCRF.
1. 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 1     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.
2. 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).


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Table 2     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.
Doxorubicin
Daunorubicin
Topotecan
Sulfasalazine
3. 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.
3.1.     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 3     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


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3.2.     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 4     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
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


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Appendix F
Patient Reported Outcomes (EOR-QLQ-C30, EOR-QLQ-
LC13, PRO-CTCAE and EQ-5D-5L)


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©QLQ-C30-LC13 Copyright 1994 EORTC Quality of life Group. All rights reserve


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Appendix G
Guidelines for Evaluation of Objective Tumour Response 
Using RECIST 1.1 (Response Evaluation Criteria in Solid Tumours)
1. INTRODUCTION
This appendix details the implementation of RECIST (Response Evaluation Criteria in Solid 
Tumours) 1.1 guidelines (Eisenhauer et al 2009) for the study with regards to investigator 
assessment of tumour burden including protocol-specific requirements for this study.
2. DEFINITION OF MEASURABLE, NON-MEASURABLE, TARGET 
AND NON-TARGET LESIONS
Subjects with at least one lesion measurable that can be accurately assessed at baseline by 
computerised tomography (CT), magnetic resonance imaging (MRI) or plain X-ray should be 
included in this study.
Measurable lesions
At least one lesion, not previously irradiated, that can be accurately measured and not chosen 
for biopsy during the study screening period, at baseline as ≥ 10mm in the longest diameter 
(except lymph nodes which must have short access ≥ 15mm) with computered tomograpghy 
(CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated 
measurements. If only one measurable lesion exists, it is acceptable to be used as long as it has 
not been previously irradiated and baseline tumour assessment scans are done at least 14 days 
after the screening biopsy is performed.
Non-measurable lesions

All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 mm to < 15 mm short axis at baseline.  Nodes with < 10 mm 
short axis are considered non-pathological and should not be recorded as non-target 
lesions (NTLs)

Truly non-measurable lesions include the following: 

Bone lesions, leptomeningeal disease, ascites, pleural / pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical examination that are not 
measurable by CT or MRI

Previously irradiated lesions as localised post-radiation changes, which affect lesion 
sizes, may occur.  Therefore, lesions that have been previously irradiated will not be 
considered measurable and should be selected as NTLs at baseline and followed up as 
part of the NTL assessment


Clinical Study Protocol Appendix G
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
158 (164)

Lesions chosen for biopsy during the study screening period if still present should be 
selected as NTL at baseline and follow up as part of the NTL assessment unless they 
fulfil the critieria for measurability when there is only one measurable lesion

Skin lesions assessed by clinical examination

Brain metastasis
Special cases

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability.  Blastic lesions are considered non-measurable.

Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present in 
the same patient; these non-cystic lesions should be selected as the target lesions 
(TLs).
Target lesions
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as TLs 
at baseline.
Non-target lesions
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline.
3.
METHODS OF MEASUREMENT
The same method of assessment and the same technique should be used to characterise 
each identified and reported lesion at baseline and during follow-up.
The methods to be used for RECIST assessment are summarised in Table 13 and those 
excluded for tumour assessments in this study are discussed below, with the rationale 
provided.
Table 13
Summary of Methods of Assessment
Target Lesions
Non target lesions
New Lesions
CT (preferred)
MRI
CT (preferred)
MRI
Clinical examination
X-ray, chest X-ray
CT (preferred)
MRI
Clinical examination
X-ray, chest X-ray
Ultrasound
Bone scan
FDG-PET


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3.1 CT and MRI 
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TLs selected for response assessment and to assess NTLs and 
identification of new lesions.
In this study it is recommended that CT examinations of the chest and abdomen will be used 
to assess tumour burden at baseline and follow-up visits.  CT examination with intravenous 
contrast media administration is the preferred method.  MRI should be used where CT is not 
feasible or it is medically contra-indicated.  For assessment of brain lesions MRI is the 
preferred method.  
3.2 Clinical examination 
Clinical examination will not be used for assessment of TLs.  Clinically detected lesions can 
be selected as TLs if they are then assessed by CT or MRI scans.  Clinical examination can be 
used to assess NTLs in subjects that also have other lesions assessable by CT, MRI or plain X-
ray and to identify the presence of new lesions.
3.3 X-rays
3.3.1
Plain X-ray
Plain X-rays may be used as a method of assessment for bone NTLs and to identify the 
presence of new bone lesions. 
3.3.2 Chest X-ray
Chest X-rays will not be used for assessment of TLs as they will be assessed by CT or MRI 
examination.  Chest X-rays can, however, be used to assess NTLs and to identify the presence 
of new lesions.
3.4 Ultrasound 
Ultrasound examination will not be used for assessment of TLs and NTLs as it is not a 
reproducible method, does not provide an accurate assessment of tumour size and it is 
subjective and operator dependent. Ultrasound examination can, however, be used to identify 
the presence of new lesions.  If new clinical symptoms occur and an ultrasound is performed
then new lesions should be confirmed by CT or MRI examination.
3.5 Endoscopy and laparoscopy
Endoscopy and laparoscopy will not be used for tumour assessments as they are not validated 
in the context of tumour measurements.
3.6 Tumour markers 
Tumour markers will not be used for tumour response assessments per RECIST 1.1.


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Study Code D5160C00003
Version 5
Date January 10, 2017
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3.7 Cytology and histology 
Histology will not be used as part of the tumour response assessment per RECIST 1.1.
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumour has met criteria for response or 
stable disease.  In such circumstances, the cytology is necessary to differentiate between 
response / stable disease (an effusion may be a side effect of the treatment) and progressive 
disease (if the neoplastic origin of the fluid is confirmed).  Where cytology findings are not 
available, any effusion that significantly worsens (from trace to large) or the appearance of a 
clinically significant effusion (requiring change in drug therapy) during the study treatment 
will be considered to be progression of NTLs or disease progression due to new lesions.
3.8 Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI or X-
ray at baseline should be recorded as NTLs and followed by the same method as per baseline 
assessment.
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits.  New lesions will be recorded where a positive hot-spot that 
was not present on the baseline bone scan assessment is identified on a bone scan performed 
at any time during the study.  The Investigator should consider the positive hot-spot to be a 
significant new site of malignant disease and represent true disease progression in order to 
record the new lesion.  Confirmation by CT, MRI and x-ray is recommended where bone scan 
findings are equivocal.
3.9 FDG-PET scan 
FDG-PET (fluorodeoxyglucose positron emission tomography) scans may be used as a 
method for identifying new lesions, according with the following algorithm: New lesions will 
be recorded where there is positive FDG uptake (defined as when an uptake greater than twice 
that of the surrounding tissue is observed) not present on baseline FDG-PET scan or in a 
location corresponding to a new lesion on CT/MRI at the same follow-up visit.  If there is no 
baseline FDG-PET scan available, and no evidence of new lesions on CT/MRI scans then 
follow-up CT/MRI assessments should be continued, scheduled as per protocol or clinical 
indicated, in order to confirm new lesions.
4.
TUMOUR RESPONSE EVALUATION 
4.1 Schedule of evaluation
CT examinations of the chest and abdomen (including liver adrenal glands) will be used to 
assess tumour burden at baseline and follow-up visits.  CT examination with intravenous 
contract media administration is the preferred method.  MRI should be used where CT is no 
feasible or it is medically contra-indicated.


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Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
161 (164)
Baseline tumour assessments should encompass all areas of known predilection for metastases 
in the disease under evaluation and should additionally investigate areas that may be involved 
based on signs and symptoms of individual subjects and should be performed no more than 28 
days before the start of study treatment.  CT/MRI scan of the brain should be performed in 
subjects with known or suspected brain metastases.  Follow-up assessments should be 
performed every 6 weeks (± 7 days) after randomization until discontinuation of study 
treatment or withdrawal of consent.  Any other sites at which new disease is suspected should 
also be adequately imaged at follow-up.
If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments as their scheduled visits.  This 
schedule is to be followed in order to minimise any unintentional bias caused by some 
subjects being assessed at different frequency than other subjects.
4.2 Target lesions
4.2.1 Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), representative of all lesions involved, should be identified as TLs at baseline.  
Target lesions should be selected on the basis of their size (longest diameter for non-nodal 
lesions or short axis for nodal lesions) but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest
lesion, which can be measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes).  All measurements should be recorded in 
millimetres.  At baseline, the sum of the diameters for all TLs will be calculated and reported 
as the baseline sum of diameters.  At follow-up visits the sum of diameters for all TLs will be 
calculated and reported as the follow-up sum of diameters.  
Special cases:

For TLs measurable in 2 or 3 dimensions, always report the longest diameter.  For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis. 

If the CT/MRI slice thickness used is > 5mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the longest diameter should be recorded as 0 mm.

If a TL splits into two or more parts, then record the sum of the diameters of those parts

If two or more TLs merge then the sum of the diameters of the combined lesion should be 
recorded for one of the lesions and 0 mm recorded for the other lesion(s)

If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned.  If an accurate measure can be given, this should be 
recorded, even if it is below 5mm.


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Study Code D5160C00003
Version 5
Date January 10, 2017
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
If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion

When a TL has had any intervention e.g. radiotherapy, embolization, surgery etc., during 
the study, the size of the TL should still be provided where possible
4.2.2 Evaluation of target lesions
Table 14 provides the definitions of the criteria used to determine objective tumour visit 
response for TLs.
Table 14
Overall Visit Response for Target Lesions
Complete Response (CR)
Disappearance of all TLs since baseline.  Any pathological lymph 
nodes selected as TLs must have a reduction in short axis to < 10 
mm.
Partial Response (PR)
At least a 30% decrease in the sum of diameters of TLs, taking as 
reference the baseline sum of diameters.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD.
Progressive Disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study).  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at 
least 5mm.
Not Evaluable (NE)
Only relevant if any of the TLs were not assessed or not evaluable 
or had a lesion intervention at this visit.
Note: If the sum of diameters meets the progressive disease 
criteria, progressive disease overrides not evaluable as a TL 
response
4.3 Non-Target lesions
4.3.1 Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline.  Measurements are not required for these lesions but their status should be followed 
at subsequent visits.  At each visit, an overall assessment of the NTL response should be 
recorded by the investigator.  Table 15 provides the definitions of the criteria used to 
determine and record overall response for NTLs at the investigational site at each visit.
Table 15
Overall Visit Response for Non-Target Lesions
Complete Response (CR)
Disappearance of all NTLs since baseline.  All lymph nodes must 
be non-pathological in size (< 10 mm short axis).
Non-CR/Non-PD
Persistence of one or more NTLs.


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Version 5
Date January 10, 2017
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Progressive Disease (PD)
Unequivocal progression of existing NTLs.  Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions.  In all cases the progression MUST 
clinically significant for the physician to consider changing or 
stopping therapy.
Not Evaluable (NE)
Only relevant when one or some of the NTLs were not assessed 
and in the investigator’s opinion they are not able to provide an 
evaluable overall NTL assessment at this visit.
Note: For subjects without TLs at baseline, this is relevant if any of 
the NTLs were not assessed at this visit and the progression criteria 
have not been met.
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, 
the overall tumour burden has increased sufficiently to merit discontinuation of therapy.  A 
modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify for 
unequivocal progression status.
4.4 New Lesions
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
one or more new lesions is assessed as progression.
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: i.e. not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour.
If a new lesion is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the new lesion has been confirmed.  If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan.
4.5 Symptomatic deterioration
Symptomatic deterioration is not a descriptor of an objective response: it could be a reason for 
stopping study therapy.
Subjects with ‘symptomatic deterioration’ requiring discontinuation of study treatment 
without objective evidence of disease progression at that time should continue to undergo 
RECIST 1.1 assessments according to the clinical study protocol until objective disease 
progression is observed.


Clinical Study Protocol Appendix G
Drug Substance AZD9291
Study Code D5160C00003
Version 5
Date January 10, 2017
164 (164)
4.6 Evaluation of Overall Visit Response
The overall visit response will be derived using the algorithm shown in Table 16.
Table 16
Overall Visit Response
Target lesions
Non-Target lesions
New Lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
CR
Non-CR/Non PD
No
PR
CR
NE
No
PR
PR
Non PD or NE
No
PR
SD
Non PD or NE
No
SD
NA
Non CR/Non PD
No
SD (Non CR/non PD)
NE
Non-PD or NE
No
NE
NA
NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease
IR = incomplete response, NE = not evaluable, NA = not applicable (relevant when no NTLs at baseline)
5.
CONFIRMATION OF RESPONSE 
In this study, imaging for confirmation of response (CR or PR) should be performed at the 
next scheduled RECIST assessment
6.
CENTRAL REVIEW
The Contract Research Organisation appointed by AstraZeneca to perform the independent 
central review for this study will provide specification for radiological imaging protocols in 
standard acquisition guidelines documentation. 
7.
REFERENCES
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck 
S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij 
J.  New response evaluation criteria in solid tumours: Revised RECIST guideline (version 
1.1).  European Journal of Cancer.  45 (2009) 228-247.

SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D5160C00003
Edition Number
4
Date
07 July 2016
A Phase III, Open Label, Randomized Study of AZD9291 versus Platinum-
Based Doublet Chemotherapy for Patients with Locally Advanced or 
Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with 
Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor 
Therapy and whose Tumours harbour a T790M mutation within the 
Epidermal Growth Factor Receptor Gene (AURA3)


4.9
PDF Edit
Statistical Ana$sis Plan
Stu@ Code D5160C00003
EditioaNumber4
Date 07 July 2016
A Phase III, Open Label, Randomized Study of AZ,D929I versus Platinum-
Based lloublet Chemotherapy for Patients with Locally Advanced or
Metastatic Non-SmaII Cell Lung Cancerwhose Disease has Progressed with
Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor
Therapy and whose Tumours harbour a T790M mutation within the
Epidermal Growth Factor Receptor Gene (A{}RA:})
Study Stetisficten
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4:22:21PM
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Statistical Analysis Plan 
Study Code D5160C00003
Edition Number 4
Date 07 July 2016
3
A Phase III, Open Label, Randomized Study of AZD9291 versus Platinum-
Based Doublet Chemotherapy for Patients with Locally Advanced or 
Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with 
Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor 
Therapy and whose Tumours harbour a T790M mutation within the 
Epidermal Growth Factor Receptor Gene (AURA3)
Global Product Statistician
Date
PDF Edit
4.9
0903882082850281
4:22:21 PM
07/07/2016
PPD


Statistical Analysis Plan 
Study Code D5160C00003
Edition Number 4
Date 07 July 2016
4
TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
SIGNATURE OF STUDY STATISTICIAN ..........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN....................................3
TABLE OF CONTENTS.........................................................................................4
LIST OF TABLES...................................................................................................7
LIST OF FIGURES .................................................................................................7
LIST OF ABBREVIATIONS..................................................................................8
AMENDMENT HISTORY ...................................................................................11
1.
STUDY DETAILS.................................................................................................12
1.1
Study objectives .....................................................................................................12
1.2
Study design...........................................................................................................15
1.3
Number of subjects ................................................................................................18
2.
ANALYSIS SETS..................................................................................................18
2.1
Definition of analysis sets......................................................................................18
2.1.1
Full analysis set......................................................................................................18
2.1.2
Safety analysis set ..................................................................................................19
2.1.3
PK analysis set .......................................................................................................19
2.1.4
China extension......................................................................................................19
2.1.4.1
China-only Full Analysis Set.................................................................................20
2.1.4.2
China-only Safety Analysis Set .............................................................................20
2.1.4.3
China-only Pharmacokinetic Analysis Set.............................................................20
2.2
Violations and deviations.......................................................................................20
3.
PRIMARY AND SECONDARY VARIABLES...................................................21
3.1
Efficacy assessments..............................................................................................21
Investigator’s RECIST-based assessments............................................................21
Rounding of TL data..............................................................................................22
Missing TL data .....................................................................................................22
Lymph nodes..........................................................................................................22
TL visit responses subsequent to CR.....................................................................22
TL too big to measure............................................................................................23
TL too small to measure.........................................................................................23
Irradiated lesions/lesion intervention.....................................................................23


Statistical Analysis Plan 
Study Code D5160C00003
Edition Number 4
Date 07 July 2016
5
Lesions that split in two .........................................................................................25
Lesions that merge .................................................................................................25
Change in method of assessment of TLs ...............................................................25
BICR of RECIST based assessments.....................................................................25
3.1.1
PFS.........................................................................................................................26
3.1.2
ORR .......................................................................................................................26
3.1.3
DoR........................................................................................................................27
3.1.4
DCR .......................................................................................................................27
3.1.5
Tumor shrinkage ....................................................................................................27
3.1.6
OS...........................................................................................................................27
3.1.7
HRQoL and symptoms...........................................................................................28
Definition of clinically meaningful changes..........................................................29
Compliance ............................................................................................................29
3.1.7.1
Time to symptom deterioration..............................................................................30
3.1.7.2
Symptom improvement rate...................................................................................30
3.1.7.3
PFS2.......................................................................................................................30
3.1.7.4
TFST ......................................................................................................................31
3.1.7.5
TSST ......................................................................................................................31
3.1.8
PRO-CTCAE symptoms........................................................................................31
3.1.9
Health state utility..................................................................................................31
3.1.10
Health resource utilization .....................................................................................32
3.2
Safety variables......................................................................................................32
3.2.1
AEs.........................................................................................................................32
3.2.2
Other significant adverse events (OAEs)...............................................................32
3.2.3
dECG......................................................................................................................33
3.2.4
Duration of exposure..............................................................................................33
Exposure to AZD9291 ...........................................................................................33
Exposure to chemotherapy.....................................................................................33
3.2.5
Dose intensity.........................................................................................................34
3.3
PK variables ...........................................................................................................34
4.
ANALYSIS METHODS........................................................................................35
4.1
General principles ..................................................................................................35
4.1.1
Baseline measurements and change from baseline variables.................................35
4.1.2
Multiple testing strategy.........................................................................................35
4.1.3
Study day definitions .............................................................................................36
4.1.4
Visit windows ........................................................................................................37
4.1.5
Handling missing data............................................................................................38
Imputation of partial dates .....................................................................................38
Initial diagnosis date: .............................................................................................38
Concomitant medication start date.........................................................................38
Concomitant medication end date..........................................................................38
4.1.6
Imputation rules for lab values outside of quantification range.............................38
4.1.7
Rounding rules for reported percentages ...............................................................38


Statistical Analysis Plan 
Study Code D5160C00003
Edition Number 4
Date 07 July 2016
6
4.2
Analysis methods ...................................................................................................39
4.2.1
Subject disposition and data sets analyzed ............................................................39
4.2.2
Protocol deviations.................................................................................................39
4.2.3
Demographic and other baseline characteristics....................................................39
4.2.4
Medical history ......................................................................................................40
4.2.5
Anti-cancer medications and radiotherapy (prior, during, post-treatment 
with IP)...................................................................................................................40
4.2.5.1
Anti-cancer therapy................................................................................................41
4.2.5.2
Radiotherapy..........................................................................................................41
4.2.6
Exposure.................................................................................................................41
4.2.7
Brain metastases.....................................................................................................42
4.2.8
Efficacy..................................................................................................................42
4.2.8.1
Primary outcome: PFS ...........................................................................................42
Subgroup analysis ..................................................................................................42
Sensitivity analysis.................................................................................................44
4.2.8.2
Secondary outcomes ..............................................................................................45
ORR .......................................................................................................................45
DoR........................................................................................................................45
DCR .......................................................................................................................46
Tumor shrinkage ....................................................................................................46
OS...........................................................................................................................46
Mixed models repeated measures of change from baseline in primary PRO 
symptoms ...............................................................................................................46
Time to PRO symptom deterioration.....................................................................48
PRO symptom improvement rate...........................................................................48
Subjects with EGFR T790M mutation status detected in baseline plasma 
sample (ctDNA).....................................................................................................48
4.2.8.3
Exploratory outcomes ............................................................................................48
PRO-CTCAE .........................................................................................................48
Healthcare resource use .........................................................................................48
Post-progression outcomes ....................................................................................49
Further analysis of OS............................................................................................49
4.2.9
PK and CSF concentration data .............................................................................49
4.2.10
Safety and tolerability............................................................................................50
4.2.10.1
AEs.........................................................................................................................50
4.2.10.2
AEs of Special Interest...........................................................................................52
4.2.10.3
Deaths.....................................................................................................................52
4.2.10.4
Laboratory evaluations...........................................................................................52
4.2.10.5
Vital signs (pulse and BP) and weight...................................................................53
4.2.10.6
Physical examination .............................................................................................53
4.2.10.7
ECG........................................................................................................................54
dECG......................................................................................................................54
LVEF......................................................................................................................54
4.2.10.8
WHO performance status.......................................................................................54
4.2.11
Crossover ...............................................................................................................54


Statistical Analysis Plan 
Study Code D5160C00003
Edition Number 4
Date 07 July 2016
7
5.
INTERIM ANALYSES .........................................................................................55
6.
ADDITIONAL BRAIN METASTASES ANALYSIS..........................................55
7.
CHANGES OF ANALYSIS FROM PROTOCOL ...............................................55
8.
REFERENCES.......................................................................................................56
9.
APPENDIX............................................................................................................57
LIST OF TABLES
Table 1
Summary of outcome variables and analysis sets ....................................19
Table 2
Visit response for HRQoL and disease-related symptoms.......................29
Table 3
Laboratory safety variables ......................................................................53
LIST OF FIGURES
Figure 1
Study flow chart........................................................................................17


Statistical Analysis Plan 
Study Code D5160C00003
Edition Number 4
Date 07 July 2016
8
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
ANCOVA
Analysis of covariance
ATC
Anatomical Therapeutic Chemical
AUC 5
Area under the plasma concentration-time curve 5 mg/ml per minute
AUC(0-24)
Area under the curve (plasma concentration / time curve from zero to 24 
hours)
AUCss
Area under the plasma concentration-time curve at steady state
BICR
Blinded Independent Central Review
BP
Blood pressure
CSF
Cerebrospinal fluid
CI
Confidence interval
Clss/F 
Plasma clearance at steady state
Cmax
Maximum plasma concentration
CMET
Proto-oncogene encoding Hepatocyte Growth Factor Receptor
CR
Complete response
CSP
Clinical study protocol
CSR
Clinical study report
Css
Concentration at study state
CT
Computerized tomography scan
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
Circulating tumor DNA
DCR
Disease control rate
dECG
Digital electrocardiogram
DNA
Deoxyribonucleic acid
DoR
Duration of response
ECG
Electrocardiogram
eCRF
Electronic case report form
EDoR
Expected duration of response
EGFR
Epidermal growth factor receptor
EGFRm+
EGFR mutation positive


Statistical Analysis Plan 
Study Code D5160C00003
Edition Number 4
Date 07 July 2016
9
Abbreviation or 
special term
Explanation
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire - Core 30 items
EORTC QLQ-LC13
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire - Lung Cancer 13 items
EQ-5D-5L
European Quality of Life - 5 Dimensions - 5 Levels
EuroQoL
European Quality of Life
FAS
Full analysis set
FDA
Food and Drug Administration
HER2
Human epidermal growth factor receptor 2
HP
Haybittle-Peto
HR
Hazard ratio
HRR
Hazard ratio ratio
HRQoL
Health Related Quality of Life
IP
Investigational product
IPCW
Time Inverse Probability of Censoring Weighting
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
KM
Kaplan-Meier
L858R
An amino acid substitution at position 858 in EGFR, from a Leucine (L) to 
an Arginine (R)
LD
Longest diameter
LDH
Lactate dehydrogenase 
LE
Local evaluation
LLoQ
Lower limit of quantification 
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MUGA
Multi-gated acquisition scan
NE
Not evaluable
NSCLC
Non-small cell lung cancer
NTL
Non-target lesion
OAE
Other significant adverse event
ORR
Objective response rate


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Edition Number 4
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Abbreviation or 
special term
Explanation
OS
Overall survival
p.o.
Per os, by mouth, orally
PD
Progression of disease
PFS
Progression Free Survival
PID
Percentage intended dose
PFS2
Time from randomization to second progression
PK
Pharmacokinetics 
PR
Partial response
PRO
Patient reported outcome
PT
Preferred term
QD
Once daily
RAC
Ratio of AUCss after multiple dosing to AUC(0-24) after single dose
RDI
Relative dose intensity
RECIST
Response Evaluation Criteria in Solid Tumors
RPSFT
Rank Preserving Structural Failure
SAE
Serious adverse event
SD
Stable disease
SLD
Sum of longest diameter
SOC
System organ class
T790M
An amino acid substitution at position 790 in EGFR, from a Threonine (T) 
to a Methionine (M)
T790M-
T790M mutation negative
T790M+
T790M mutation positive
TFST
Time to first subsequent therapy or death
TKI
Tyrosine kinase inhibitor
TL
Target lesion
tmax
Time to Cmax
tss max
Time to Css max
TSST
Time to second subsequent therapy or death
ULoQ
Upper limit of quantification 
WHO
World Health Organization


Statistical Analysis Plan 
Study Code D5160C00003
Edition Number 4
Date 07 July 2016
11
AMENDMENT HISTORY
Date
Brief description of change
02Jul2015
SAP updated based on protocol amendment 2
18Mar2016
SA updated based on protocol amendment 3


Statistical Analysis Plan 
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Edition Number 4
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1.
STUDY DETAILS
1.1
Study objectives
Primary objective
Objective:
Outcome Measure:
To assess the efficacy of AZD9291 compared 
with platinum-based doublet chemotherapy by 
assessment of Progression Free Survival (PFS).
PFS using investigator assessments according to 
Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1.
Sensitivity analysis of PFS using Blinded 
Independent Central Review (BICR).
Secondary objectives
Objective:
Outcome Measure:
To further assess the efficacy of AZD9291 
compared with platinum-based doublet 
chemotherapy in terms of:
- Objective Response Rate (ORR)
- Duration of Response (DoR)
- Disease Control Rate (DCR)
- Overall Survival (OS)
- Tumor shrinkage
ORR, DoR, DCR and tumor shrinkage using 
investigator assessments according to RECIST 1.1.
Analysis of OS.
To assess the effect of AZD9291 compared to 
platinum-based doublet chemotherapy on 
subjects’ disease-related symptoms and health 
related quality of life (HRQoL).
EORTC QLQ-C30: Questionnaire consisting of 30 
items measuring subjects general cancer symptoms 
and functioning.
EORTC QLQ-LC13: A complementary 
questionnaire measuring lung cancer symptoms
To characterize the pharmacokinetics (PK) of 
AZD9291, AZ5104 and AZ7550 in subjects 
receiving AZD9291.
Plasma concentrations of AZD9291, and metabolites 
AZ5104 and AZ7550.
PK parameters (such as Clss/F, Css min and Css max
AUCss) will be derived using population PK analysis 
and reported separately to the Clinical Study Report 
(CSR). Data from this study may form part of a 
pooled analysis with data from other studies.


Statistical Analysis Plan 
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Edition Number 4
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Safety objective
Objective:
Outcome Measure:
To assess the safety and tolerability profile of 
AZD9291 compared with platinum-based 
doublet chemotherapy.
- Adverse events, graded by Common Terminology 
Criteria for Adverse Event (CTCAE v4)
- Clinical chemistry, hematology and urinalysis
- Vital signs (pulse and blood pressure), physical 
examination, weight
- Centrally reviewed digital electrocardiogram 
(dECG) 
- Multi-gated acquisition scan (MUGA) for left 
ventricular ejection fraction (LVEF)
- World Health Organization (WHO) performance 
status
Exploratory objectives
Objective:
Outcome Measure:
To explore the relationship between PK and 
selected endpoints (which may include 
efficacy, safety and/or Patient Reported 
Outcome [PRO]), where deemed appropriate.
Correlation of PK with other primary/secondary/
exploratory endpoints in subjects treated with 
AZD9291.
Results from such analyses will be reported 
separately from the CSR. 
Data from this study may also form part of a pooled 
analysis with other AZD9291 studies.
To compare the effects of AZD9291 compared 
with chemotherapy on post-progression 
outcomes
Time from randomization to second progression 
(PFS2)
Time to subsequent therapy
Time to change in symptoms (including post-
progression assessments)
To further characterize the effects of 
AZD9291 on survival outcomes.
Assess the impact on OS of baseline potentially 
prognostic factors (e.g., tumor stage, performance 
status, sex, baseline lactate dehydrogenase [LDH]).
Assess the impact on OS of subsequent treatments 
and other potential covariates (e.g., changes in 
performance status).
To compare adverse events by subject self-
reporting of specific CTCAE symptoms 
(where applicable) between AZD9291 and 
chemotherapy.
Collection of approximately 28 PRO-CTCAE 
symptoms via an electronic device solution (in 
countries where language is available).


Statistical Analysis Plan 
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Edition Number 4
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Objective:
Outcome Measure:
To compare AZD9291 treatment with 
chemotherapy treatment on health state utility.
The European Quality of Life - 5 Dimensions - 5 
Levels (EQ-5D-5L) health state utility index will be 
used to derive health state utility based on subject 
reported data.
To compare health resource use associated 
with AZD9291 treatment with chemotherapy 
treatment.
Health resource utilization measures including 
hospitalization, outpatient visits, or emergency 
department visits.
To characterize the PK of AZD9291, AZ5104 
and AZ7550 in cerebrospinal fluid (CSF).
Concentration of AZD9291, AZ5104 and AZ7550. 
Ratio of metabolites to AZD9291.
Ratio of CSF to plasma concentration.
Summaries of PK concentration data.
To collect and store deoxyribonucleic acid 
(DNA) for future exploratory research into 
genes/genetic variation that may influence PK 
or response to AZD9291, platinum-based 
doublet chemotherapy (i.e., absorption, 
distribution, metabolism, excretion, safety and 
efficacy) and/or susceptibility to/development 
of cancers.
Correlation of polymorphisms with variation in PK, 
pharmacodynamics, safety or response observed in 
subjects treated with AZD9291 or comparator.
Data generated may be reported separately and may 
also form part of a pooled analysis with other 
AZD9291 studies.
To collect and store tumor samples and blood-
based samples for potential for exploratory 
research into factors that may influence 
susceptibility to/development of non-small cell 
lung cancer (NSCLC)/cancer and/or response 
to AZD9291 (where response is defined 
broadly to include efficacy, tolerability or 
safety).
Analysis of key genetic and proteomic markers to 
include, but not limited to, epidermal growth factor 
receptor (EGFR) mutations, human epidermal growth 
factor receptor 2 (HER2) and proto-oncogene 
encoding hepatocyte growth factor receptor (CMET)
expression and/or amplication. 
Collection of plasma samples to include, but not be 
limited to, extraction of circulating tumor DNA 
(ctDNA) for investigation of blood-borne 
biomarkers. The sample may be used to investigate 
the relationship between PK and blood-borne 
biomarkers.
Samples may be analyzed retrospectively. Any 
biomarker data generated may be reported separately 
and may also form part of a pooled analysis with 
other AZD9291 studies.
To collect and store plasma for isolation of 
ctDNA. Extracted ctDNA will be assessed for 
the presence of genetic aberrations including, 
but not limited to, EGFR mutations (T790M, 
L858R, etc). These samples may be shared 
with a diagnostic partner for development of a 
ctDNA test for T790M detection.
Retrospective/real-time analysis of EGFR (and other) 
mutations in ctDNA from all study subjects 
(mandatory).


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Objective:
Outcome Measure:
To collect and store residual CSF for potential 
exploratory research of factors that may 
influence development of NSCLC and/or 
response to AZD9291 (where response is 
defined broadly to include efficacy, 
tolerability or safety).
Collection of CSF for the investigation of PK and/or 
biomarkers. Samples may be analyzed
retrospectively.
Results from such analyses outlined above may be reported separately from the CSR.
1.2
Study design
This is a phase III, open-label, randomized study assessing the safety and efficacy of 
AZD9291 (80 mg, orally [p.o.], once daily [QD]) versus platinum-based doublet 
chemotherapy in second-line subjects with EGFR mutation and T790M mutation positive 
(EGFRm+/T790M+), locally advanced or metastatic NSCLC who have progressed following 
treatment with an approved EGFR Tyrosine Kinase Inhibitor (EGFR-TKI) agent.
A biopsy will be needed for central testing of T790M mutation status following confirmed 
disease progression on first-line treatment with an EGFR-TKI.
Approximately 410 subjects, stratified by ethnicity (Asian/non-Asian) will be centrally 
randomized to receive either AZD9291 (80mg QD p.o.) or platinum-based doublet 
chemotherapy (pemetrexed 500 mg/m2 + carboplatin area under the plasma concentration-
time curve AUC 5 or pemetrexed 500 mg/m2 + cisplatin 75 mg/m2) on Day 1 of every 21-day 
cycle in a 2:1 (AZD9291: platinum-based doublet chemotherapy) ratio using the Interactive 
Voice Response (IVRS) or Interactive Web Response System (IWRS). The investigational 
site must declare (in IVRS/IWRS), prior to randomization, their choice of chemotherapy for 
that subject. Once 410 subjects have been randomized globally, recruitment will continue only 
in mainland China until approximately 50 Chinese subjects have been randomized.
Subjects should continue on investigational product (IP) AZD9291 until a treatment 
discontinuation criterion is met. Subjects may continue to receive AZD9291 beyond RECIST 
1.1 defined progression as long as they show clinical benefit, as judged by the investigator.
Subjects can receive up to 6 cycles of pemetrexed + carboplatin/cisplatin as initial treatment.
Subjects whose disease has not progressed after four cycles of platinum-based first-line 
chemotherapy may receive pemetrexed maintenance therapy. Subjects who progress according 
to RECIST 1.1 criteria prior to completion of initial doublet chemotherapy treatment or during 
pemetrexed maintenance monotherapy, may continue with chemotherapy treatment as long as 
they are continuing to show clinical benefit, as judged by the investigator.
Subjects must be followed until evidence of RECIST 1.1 defined progression (regardless of 
reason for treatment discontinuation). It is important that subjects are assessed according to 
the intended scanning schedule to prevent the bias in analysis that can occur if one treatment 
group is assessed more or less often than the other.


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Once subjects on the platinum-based doublet chemotherapy arm are determined to have
objective radiological progression according to RECIST 1.1 by the investigator and confirmed
by independent central imaging review, they will be given the opportunity to begin treatment
with AZD9291 80mg, once daily. These subjects may continue treatment with AZD9291, as 
long as they are continuing to show clinical benefit, as judged by the investigator.
If a subject has been deemed to have objective disease progression according to Investigator 
tumour assessment according to RECIST 1.1, but is not confirmed by independent central 
imaging review, he/she is not eligible to cross-over to AZD9291 at that time. Should it be in 
the subjects’ best interests, and only if further randomized chemotherapy is warranted, he/she 
may continue to receive randomized doublet chemotherapy (if initial doublet chemotherapy 
treatment has not yet been completed) or Pemetrexed maintenance monotherapy, sites are to 
submit the next scheduled tumour assessment for central imaging review according to Table 2
of the CSP.
If subjects are not eligible to cross-over to AZD9291, they will enter into the follow-up phase 
of the study, and other treatment options should be discussed by the investigator.
Note: Throughout this document the term “platinum-based doublet chemotherapy”, refers to 
“platinum” as both carboplatin and cisplatin.
The overall study design is shown in Figure 1 of the clinical study protocol (CSP) and the 
study flow chart in Figure 1 below. The study schedule for AZD9291 subjects and for 
platinum-based doublet chemotherapy subjects is detailed in Tables 1 and 2 of the CSP,
respectively.


Figure 1
Study flow chart
(a)  Approximately 410 subjects will be randomized into the trial; from these approximately 273 subjects will be treated with AZD9291 and approximately 137 subjects will be treated with a 
platinum based doublet-chemotherapy.
(b)  Subjects will be considered in “Treatment phase” at the time AZD9291/Doublet-Chemotherapy (study treatment) is started. Subjects will continue to receive study treatment until objective 
disease progression (according to RECIST 1.1). Subjects randomized to AZD9291 may continue to receive AZD9291 as long as they are continuing to show clinical benefit, as judged by the 
investigator, and in the absence of discontinuation criteria. Subjects randomized to the platinum-based double chemotherapy arm with objective radiological progression according to RECIST 
1.1 by the investigator and confirmed by independent central imaging review will be given the opportunity to begin treatment with AZD9291, 80 mg once daily.
Screening Period
Subjects with 
confirmed EGFRm+, 
locally advanced or 
metastatic NSCLC 
who have progressed 
following prior therapy 
with approved EGFR-
TKI
Post Treatment Follow-Up
Treatment Phaseb
Central testing of tumor 
biopsy sample collected 
following confirmed 
progression on the most 
recent treatment with 
EGFR TKI
AZD9291
80 mg p.o. QD 
(n=273a)
T790M+
T790M-
All subjects 
to be 
followed for 
PFS and OS 
every 
6weeks
Confirm Eligibility
Not eligible for
randomization
Doublet-
Chemotherapy 
every 3 weeks 
(n=137a)
All subjects to 
have RECIST 
1.1 
assessments 
every 6 weeks 
until objective 
progression
All subjects to 
have RECIST 
1.1 
assessments 
every 6 weeks 
until objective 
progression
Optional:
Subjects on 
chemotherapy 
may begin post-
progression open 
label AZD9291 
treatment 
Crossover
All subjects 
to be 
followed 
for OS 
every 
6weeks


1.3
Number of subjects
PFS is the primary endpoint for this study. Approximately 410 subjects, stratified by ethnicity 
(Asian/non-Asian) will be randomized in a 2:1 ratio to the treatments as specified below:

AZD9291 80mg QD p.o.

Platinum-based doublet chemotherapy (pemetrexed 500mg/m2 + carboplatin AUC5 
or pemetrexed 500mg/m2 + cisplatin 75mg/m2)
The primary analysis of PFS will occur when at least 221 progression events have been 
observed out of the 410 globally randomized subjects. With 221 progression events, the study 
will have at least 80% power to show a statistically significant PFS at the 5% 2-sided 
significance level if the assumed treatment effect were hazard ratio (HR) 0.67; this translates 
to a 3 month improvement on an estimated median PFS of 6 months on the control arm, 
assuming PFS is exponentially distributed. The smallest treatment difference that would be 
statistically significant is a PFS HR of 0.76. Assuming 15 months non-linear recruitment, 221
PFS events are expected to occur approximately 20 months after the first subject is 
randomized to the study.
Three analyses of OS are planned; two interim analyses and a final analysis. The data cut-off 
for the first analysis of overall survival will be conducted approximately 4 months after data 
cut-off for the primary analysis of PFS and the second analysis will be conducted when the 
OS data are approximately 50% mature (approximately 205 death events). A final analysis of 
overall survival will be performed when the OS data are approximately 70% mature 
(approximately 287 death events).
In order to randomize 410 subjects (assuming a 10% screen failure rate), 455 T790M+ 
subjects will need to be enrolled. In order to enroll 455 T790M+ subjects, 1034 subjects will 
need to be screened (allowing for a 20% attrition rate and assuming 55% of subjects are 
T790M+).
2.
ANALYSIS SETS
2.1
Definition of analysis sets
2.1.1
Full analysis set
The full analysis set (FAS) will include all randomized subjects prior to the end of global 
recruitment. Any subjects randomized in China, after global recruitment has ended, will not be 
included in the FAS. 
The FAS, or subsets thereof as per 2.1.1-2, will be used for all efficacy and exploratory 
analyses and treatment groups will be compared on the basis of randomized treatment, 
regardless of the treatment actually received.


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2.1.2
Safety analysis set
The safety analysis set will consist of all subjects randomized prior to the end of global 
recruitment who received at least one dose of randomized treatment and for whom post-dose 
data are available. Any subjects randomized in China only, after global recruitment has ended, 
will not be included in the safety analysis set.
Safety data will not be formally analyzed but summarized using the safety analysis set, 
according to the treatment received (i.e., erroneously treated subjects [e.g., those randomized 
to treatment A but actually given treatment B] will be summarized according to the treatment 
they actually received).
2.1.3
PK analysis set
The PK analysis set includes subjects in the FAS who have at least one measurable PK 
concentration and who have the relevant date, time and dosing data for this sample. The
dosing data must include the dosing data for the calendar day prior to the sample day as well 
as the sample day. 
Table 1
Summary of outcome variables and analysis sets
Outcome variable
Analysis Set
Efficacy Data: PFS, ORR, DoR, DCR, Tumor shrinkage, OS, symptoms/HRQoL
FAS
Demography
FAS
PK data
PK (subset of 
FAS)
Safety Data
Safety
Exploratory Data
FAS
Data on the number of subjects and duration of treatment for subjects who begin treatment 
with AZD9291 following centrally confirmed objective progression will also be summarized 
separately, as described in Section 4.2.6.
2.1.4
China extension
In order to adequately compare the efficacy and safety of AZD9291 versus chemotherapy in 
Chinese patients to fulfill China Food and Drug Administration (FDA) requirements, subjects 
recruited in China after global recruitment has ended will be combined with any subjects 
recruited from China prior to the end of the global recruitment. This China-only cohort will be 
analysed and reported separately from the CSR.  These analyses will be performed when 
approximately 27 PFS events have been observed out of approximately 50 Chinese subjects 
(54% maturity, as consistent with the primary global PFS analysis).


Statistical Analysis Plan 
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All efficacy, safety, PRO and PK variables will be derived in the same way as detailed in 
Section 4. All analyses detailed in Section 4 will be repeated for the China-only cohort using 
the analysis sets described in this section.
All statistical analyses will be considered exploratory and only performed if sufficient 
numbers of events or subjects are available (e.g. > 20 PFS or OS events), otherwise 
descriptive statistics only will be presented. No adjustment for multiplicity will be made and 
so the procedure for hierarchical testing detailed in protocol Section 8.5.2.1 will not be 
followed. Statistical analyses will not be stratified by ethnicity (Asian versus Non-Asian).
2.1.4.1
China-only Full Analysis Set
The China-only FAS will include all subjects randomized in China. This includes all subjects 
randomized in China prior to the end of global recruitment and all additional subjects 
recruited in mainland China after global recruitment is completed.
The China-only FAS will be used for all China-only efficacy analyses and treatment groups 
will be compared on the basis of randomized study treatment, regardless of the treatment 
actually received.
2.1.4.2
China-only Safety Analysis Set
The China-only safety analysis set will consist of all subjects randomized in China who
received at least one dose of study treatment and for whom post-dose data are available.
2.1.4.3
China-only Pharmacokinetic Analysis Set
The China-only PK analysis set is defined as subjects in the China-only FAS who have at least 
one evaluable PK concentration without any violation or deviation that impacts the PK 
analysis.
2.2
Violations and deviations
All important deviations related to the study inclusion or exclusion criteria and study conduct 
will be listed and summarized by randomized treatment group. None of the deviations will 
lead to any subjects being excluded from any of the analysis sets described in Section 2.1
(with the exception of the PK analysis set, if the deviation is considered to impact upon PK). 
If the deviations are serious enough to have the potential to impact the primary analysis, 
sensitivity analyses may be performed.
The following general categories will be considered important deviations. This list is not 
exhaustive and additional important deviations may be added prior to database lock.

Informed consent procedure deviation (e.g., no informed consent signed prior to any 
screening procedure)

Eligibility criteria deviation (e.g., any inclusion criteria not met or exclusion criteria 
met)


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
Prohibited medication deviation (e.g., subject received other anticancer agents, 
investigational agents, or radiotherapy while on study treatment)
The categorization of these as important deviations is not automatic and will depend on 
duration and the perceived effect on efficacy.
In addition to the programmatic determination of the deviations above, monitoring notes or 
summaries will be reviewed to determine any important post-entry deviations that are not 
identifiable via programming, and to check that those identified via programming are correctly 
classified. The final classification will be made prior to database lock.
Misrandomizations in terms of errors in treatment dispensing, in addition to incorrect 
stratifications, will also be summarized and listed, separately to the important protocol 
deviations. A misrandomization is when a subject is not randomized or treated according to 
the randomization schedule. It includes subjects who receive no treatment whatsoever for a 
period of time due to errors in dispensing of medication. Note, this is not due to tolerability 
issues where subjects may stop taking drug.
The summary will include all subjects with a dispensing error and will also include 
information on how many of those subjects received at least one dose of the wrong treatment 
(AZD9291/platinum-based doublet chemotherapy) at any time. Subjects who receive the 
wrong treatment at any time will be included in the safety analysis set as described in Section 
2.1. During the study, decisions on how to handle misrandomizations will be made on an 
individual basis with written instruction from the study team leader and/or statistician.
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Efficacy assessments
Investigator’s RECIST-based assessments
From the investigator’s review of the imaging scans, the RECIST tumor response data will be 
used to determine each subject’s visit response according to RECIST 1.1. It will also be used 
to determine the endpoints ORR, DoR, DCR and PFS from the overall visit response and scan 
dates. The endpoint of tumor shrinkage will be assessed from tumor size measurements based 
on investigator assessment.
Baseline radiological tumor assessments are to be performed no more than 28 days before the 
start of randomized treatment. If a baseline radiological tumor assessment is performed more 
than 28 days before the start of randomized treatment, then the scan will still be included as 
baseline but will be recorded as an important protocol deviation. Tumor assessments are then 
performed every 6 weeks relative to randomization until disease progression. Baseline values 
recorded after treatment start should not be used as the baseline assessment; although such 
assessments can be used in the calculation of PD. At each visit, subjects will be 
programmatically assigned an overall visit response of complete (CR), partial (PR), stable 


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disease (SD) or progressive disease (PD) depending on the status of their disease compared 
with baseline and previous assessments. If a subject has had a tumor assessment which cannot 
be evaluated, then the subject will be assigned a visit response of not evaluable (NE) (unless 
there is evidence of progression in which case the response will be assigned as PD).
Please refer to CSP Appendix H for the definitions of CR, PR, SD and PD and the derivations 
of overall visit response using the information from target lesions (TL), non-target lesions 
(NTL) and new lesions.
Rounding of TL data
For calculation of PD and PR for TLs percentage changes from baseline and previous 
minimum should be rounded to 1 decimal place before assigning a TL response. For example,
19.95% should be rounded to 20.0% but 19.94% should be rounded to 19.9%.
Missing TL data
For a visit to be evaluable, all TL measurements should be recorded. However, a visit 
response of PD should be assigned if any of the following occurred:

A new lesion is recorded;

A NTL visit response of PD is recorded;

The sum of TLs is sufficiently increased to result in a 20% increase, and an absolute 
increase of ≥5 mm from nadir even assuming the non-recorded TLs have 
disappeared.
The nadir can only be taken from assessments where all the TLs had a longest diameter (LD)
recorded.
Lymph nodes
For lymph nodes, if the size reduces to <10 mm, these are considered non-pathological.
However a size will still be given and this size should still be used to determine the TL visit
response as normal. In the special case where all lymph nodes are <10 mm and all other TLs
are 0 mm, although the sum may be >0 mm, the calculation of TL response should be over-
written as a CR.
TL visit responses subsequent to CR
A CR response can only be followed by CR, PD or NE. If a CR has occurred, the following 
rules at the subsequent visits must be applied:

Step 1:  If all lesions meet the CR criteria (i.e., 0 mm or <10 mm for lymph nodes),
the response will be set to CR irrespective of whether the criteria for PD of TL is 
also met (i.e., if a lymph node LD increases by 20% but remains <10 mm). 


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
Step 2:  If some lesion measurements are missing but all other lesions meet the CR 
criteria (i.e., 0 mm or <10 mm for lymph nodes), the response will be set to NE 
irrespective of whether when referencing the sum of TL diameters the criteria for 
PD is also met. 

Step 3:  If not all lesions meet the CR criteria, and the sum of lesions meets the 
criteria for PD, the response will be set to PD.

Step 4:  If, after steps 1 through 3, a response cannot be determined, the response 
will be set to remain as CR.
TL too big to measure
If a TL becomes too big to measure, this should be indicated in the database and a size (‘x’) 
above which it cannot be accurately measured should be recorded. If using a value of x in the 
calculation of TL response would not give an overall visit response of PD, then this will be 
flagged and reviewed by the study team blinded to treatment assignment. It is expected that a 
visit response of PD will remain in the vast majority of cases.
TL too small to measure
If a TL becomes too small to measure a value of 5 mm will be entered into the database and 
used in TL calculations, unless the radiologist has indicated and entered a smaller value that 
can be measured reliably. If a TL response of PD results then this will be reviewed by the 
study team blinded to treatment assignment.
Irradiated lesions/lesion intervention
Previously irradiated lesions (i.e., lesion irradiated prior to entry into the study) should be 
recorded as NTLs and should not form part of the TL assessment.
Any TL (including lymph nodes), which has had intervention during the study (for example, 
irradiation/palliative surgery/embolization), should be handled in the following way:

Step 1: the diameters of the TLs (including the lesions that have had intervention) 
will be summed and the calculation will be performed in the usual manner. If the 
visit response is PD this will remain as a valid response category. 

Step 2: If there was no evidence of progression after step 1, the lesion diameter (for 
those lesions with intervention) will be treated as missing and scaled up as 
described below as long as there remain ≤1/3 of the TLs with missing 
measurements. If the scaling results in a visit response of PD then the subject will
be assigned a TL response of PD.

Step 3: If after both steps PD has not been assigned, then if ≤ 1/3 of the TLs have 
missing measurements), the scaled sum of diameters will be calculated, and PR or 
SD then assigned as the visit response. Subjects with intervention are evaluable for 


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CR as long as all non-intervened lesions are 0 (or <10 mm for lymph nodes) and the 
lesions that have been subject to intervention also have a value of 0 recorded.

If scaling up is not appropriate due to > 1/3 missing measurements then the visit 
response will be set as NE.
At subsequent visits the above steps will be repeated to determine the TL and overall visit 
response. When calculating the previous minimum, lesions with intervention should be treated 
as missing and scaled up (as per step 2 above).
Once a lesion has had intervention then it should be treated as having intervention for the 
remainder of the study noting that an intervention will most likely shrink the size of tumors.
Scaling (applicable only for irradiated lesions/lesion intervention)
If > 1/3 of TL measurements are missing (because of intervention) then the TL response will 
be NE, unless the sum of diameters of non-missing TL would result in PD (i.e. if using a value 
of 0 for missing lesions, the sum of diameters has still increased by 20% or more compared to 
nadir and the sum of TLs has increased by ≥5mm from nadir).  
If ≤ 1/3 of the TL measurements are missing (because of intervention) then the results will be 
scaled up (based on the sizes at the nadir visit to give an estimated sum of diameters and this 
will be used in calculations; this is equivalent to comparing the visit sum of diameters of the 
non-missing lesions to the nadir sum of diameters excluding the lesions with missing 
measurements.
Example of scaling
Lesion
Longest diameter at nadir 
visit
Longest diameter at follow-
up visir
1
7.2
7.1
2
6.7
6.4
3
4.3
4.0
4
8.6
8.5
5
2.5
Missing
Sum
29.3
26
Lesion 5 is missing at the follow-up visit. 
The sum of lesions 1-4 at the follow-up is 26 cm.  The sum of the corresponding lesions at the 
nadir visit is 26.8 cm.


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Scale up as follows to give an estimated TL sum of 28.4cm:
cm
4.
28
3.
29
8.
26
26


CR will not be allowed as a TL response for visits where there is missing data.  Only PR, SD 
or PD (or NE) could be assigned as the TL visit response in these cases.  However, for visits 
with ≤ 1/3 lesion assessments not recorded, the scaled up sum of TLs diameters will be 
included when defining the nadir value for the assessment of progression.
Lesions that split in two
If a TL splits in two, then the LDs of the split lesions should be summed and reported as the 
LD for the lesion that split.
Lesions that merge
If two TLs merge, then the LD of the merged lesion should be recorded for one of the TL 
sizes and the other TL size should be recorded as 0mm.
Change in method of assessment of TLs
Computerized tomography (CT) scan and magnetic resonance imaging (MRI) are the only 
methods of assessment that can be used within this trial. If a change in method of assessment 
occurs between CT scan and MRI this will be considered acceptable and no adjustment within 
the programming is needed.
BICR of RECIST based assessments
BICR of radiological imaging data will be carried out using RECIST 1.1. All radiological 
scans for all subjects (including those at unscheduled visits, or outside visit windows) will be 
provided to the BICR. The imaging scans will be reviewed by at least two independent 
radiologists using RECIST 1.1 criteria and will be adjudicated if required. 
Up to three qualified radiologists will independently review the imaging scans in the
following way. First a primary review will be performed by two independent radiologists for
each patient on a timepoint by timepoint basis to give an overall tumour assessment at each
timepoint using RECIST 1.1. Then a global radiology review will be performed whereby the
same independent radiologists will globally assess all timepoints for a patient in the review
period and adjust an overall assessment if necessary. Finally, if the overall assessment for at
least one timepoint for a patient does not agree between the two independent radiologists, a
third independent radiologist will adjudicate and identify which radiologist’s assessments they
agree with and should be used (for the whole patient). These visit responses (either from the
adjudicator selected reviewer, or the primary reviewer in the absence of adjudication) will be
used to report BICR visit responses, BICR best overall response, BICR time to response, 
BICR censoring of response, BICR progression date and BICR progression censoring.


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If adjudication is performed, the reviewer that the adjudicator agreed with will be selected as a 
single reviewer. In the absence of adjudication, the records for all visits for a single reviewer 
will be used. The reviewer selected in the absence of adjudication will be the reviewer who 
read the baseline scan first. The records from the single selected reviewer will be used to all 
BICR RECIST endpoints including dates of progression, response, visit response, censoring 
and changes in target lesion dimensions.
All independent reviewers will be blinded to treatment. For each subject, the BICR will define 
the overall visit response data (CR, PR, SD, PD or NE) and the relevant scan dates for each 
time point (i.e., for visits where response or progression is/is not identified). 
Further details of the BICR will be documented in the Blinded Independent Review Charter.
3.1.1
PFS
PFS is defined as the time from randomization until the date of objective disease progression 
or death (by any cause in the absence of progression) regardless of whether the subject 
withdraws from randomized therapy or receives another anti-cancer therapy prior to 
progression. Subjects who have not had PD or died at the time of analysis will be censored at 
the time of the latest date of assessment from their last evaluable RECIST assessment.
However, if the subject has PD or dies after two or more missed visits, the subject will be 
censored at the time of the latest evaluable RECIST assessment. If the subject has no 
evaluable visits or does not have baseline data they will be censored at 0 days unless they die 
within two visits of baseline.
The PFS time will always be derived based on scan/assessment dates not visit dates.
RECIST assessments/scans contributing towards a particular visit may be performed on 
different dates. The following rules will be applied:

Date of progression will be determined based on the earliest of the dates of the 
component that triggered the progression

When censoring a subject for PFS the subject will be censored at the latest of the 
dates contributing to a particular overall visit assessment
3.1.2
ORR
ORR rate is defined as the number and percentage of randomized subjects with at least one 
visit response of CR or PR. Data obtained up until progression, or last evaluable assessment in 
the absence of progression, will be included in the assessment of ORR. However, any
complete response or partial response, which occurred after a further anti-cancer therapy was 
received, will not be included in the numerator for the ORR calculation.


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3.1.3
DoR
DoR will be defined as the time from the date of first documented response until the date of 
documented PD or death in the absence of PD, the end of response should coincide with the 
date of PD or death from any cause used for the PFS endpoint. The time of the initial response 
will be defined as the latest of the dates contributing towards the first visit response of PR or 
CR. 
If a subject does not progress following a response, then the subject’s duration of response 
will use the PFS censoring time.
3.1.4
DCR
DCR is defined as the percentage of subjects who have a best overall response of CR or PR or 
SD at ≥6 weeks (± 7 day visit window), prior to any PD event.
3.1.5
Tumor shrinkage
Tumor shrinkage will be assessed using RECIST 1.1 tumor response. The absolute change and 
percentage change from baseline in sum of tumor size at each assessment will be calculated. 
Tumor size is the sum of the longest diameters (SLD) of the TLs. The percentage change in 
SLD at each week for which data are available will be obtained for each subject taking the 
difference between the SLD at each week and the SLD at baseline divided by the SLD at 
baseline multiplied by 100 [i.e., (week n - baseline) / baseline x 100]. The change from 
baseline will be obtained for each subject taking the difference between the SLD at each week 
and the SLD at baseline (i.e., week n - baseline). 
The best percentage change in SLD from baseline or the minimum increase from baseline in 
the absence of a reduction from baseline based on all post-baseline assessments prior to the 
visit when progression is detected or start of subsequent anti-cancer therapy.
If best percentage change cannot be calculated due to missing data, a value of +20% will be 
imputed as the best percentage change from baseline in the following situations (otherwise 
best percentage change will be left as missing):

If a subject has no post-baseline assessment and has died;

If a subject has new lesions or progression of NTLs;

If a subject has withdrawn due to PD and has no evaluable TL data before or at PD.
3.1.6
OS
OS is defined as the time from the date of randomisation 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.


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Note: Survival calls will be made in the 2 weeks following the date of the data cut-off for each 
OS analysis, and if subjects are confirmed to be alive, or if the death date is post the final data 
cut-off date, these subjects will be censored at the date of the final data cut off. Death dates 
may be found by checking publicly available death registries.
3.1.7
HRQoL and symptoms
PROs will be assessed using the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires. 
The EORTC QLQ-C30 consists of 30 questions, which can be combined to produce 5 
functional scales (Physical, Role, Cognitive, Emotional, Social), 3 symptom scales (Fatigue, 
Pain, Nausea/vomiting), 5 individual items (dyspnea, insomnia, appetite loss, constipation, 
diarrhea) and a global measure of health status. The EORTC QLQ-LC13 is a lung cancer 
specific module comprising 13 questions to assess lung cancer symptoms (cough, hemoptysis, 
dyspnea and site-specific pain), treatment related side-effects (sore mouth, dysphagia, 
peripheral neuropathy and alopecia) and pain medication. With the exception of a multi-item 
scale for dyspnea, all are single items.
An outcome variable consisting of a score from 0 to 100 will be derived for each of the 
symptom scales/symptom items, the functional scales and the global health status scale in the 
EORTC QLQ-C30 and for each of the symptom scales/items in the EORTC QLQ-LC13 
according to the EORTC QLQ-C30 Scoring Manual and EORTC QLQ-LC13 instructions, 
respectively. 
Higher scores on the global health status and functioning scales indicate better health 
status/function. Higher scores on the symptoms scales indicate greater symptom burden.
For each symptom/scale, if less than 50% of the subscale items are missing, the subscale score 
will be divided by the number of non-missing items and multiplied by the total number of 
items on the subscale. If at least 50% of the items are missing, that subscale also will be 
treated as missing. 
For analysis of time to symptom deterioration, the FAS will be subset to include subjects who 
have EORTC QLQ-LC13 baseline scores ≤90.
For analysis of symptom improvement rate, the FAS will be subset to include subjects who 
have a baseline score ≥10 for EORTC QLQ-C30 scales/items or EORTC QLQ-LC13 
scales/items.
The primary PRO measures will be subject-reported lung cancer symptoms assessed using the 
EORTC QLQ-LC13 and EORTC QLQ-C30, namely:

dyspnea (multi-item scale based on three questions: “Were you short of breath when 
you rested; walked; climbed stairs?”),

cough: one item (“How much did you cough?”),

pain: one item (“Have you had pain in your chest?”)


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
fatigue (multi-item scale based on three questions: “Did you need rest; Have you 
felt weak; Were you tired?”)

appetite loss: one item (“Have you lacked appetite?”).
Definition of clinically meaningful changes
Changes in score compared to baseline will be evaluated. A minimum clinically meaningful 
change is defined as a change in the score from baseline of ≥10 for scales/items (Obosa et al 
1998).
For example, a clinically meaningful deterioration or worsening in chest pain (as assessed by 
EORTC QLQ-LC13) is defined as an increase in the score from baseline of ≥10. A clinically 
meaningful improvement in fatigue (as assessed by EORTC QLQ-C30) is defined as a 
decrease in the score from baseline of ≥10.
At each post-baseline assessment, change in symptoms/functioning from baseline will be 
categorized as improved, stable or worsening as shown in Table 2.
Table 2
Visit response for HRQoL and disease-related symptoms
Score
Change from baseline
Visit response
EORTC QLQ-LC13 symptom 
scales/items
≥+10
Worsened
≤-10
Improved
Otherwise
Stable
EORTC QLQ-C30 symptoms 
scales/items
≥+10
Worsened
≤-10
Improved
Otherwise
Stable
EORTC QLQ-C30 functional scales and 
≥+10
Improved
Global health status
≤-10
Worsened
Otherwise
Stable
Compliance
Summary measures of compliance at each scheduled assessment will be derived for the 
EORTC QLQ-C13 and QLQ-C30 score. These will be based upon: 

Received questionnaire = a questionnaire that has been received and has a completion 
date and at least one individual item completed


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
Expected questionnaire =  a questionnaire that is expected to be completed at a 
scheduled assessment time, i.e. a questionnaire from a patient who has not withdrawn 
from the study at the scheduled assessment time but excluding patients in countries 
with no available translation. 

Evaluable questionnaire = a questionnaire with a completion date and at least one 
subscale that is non-missing. 
3.1.7.1
Time to symptom deterioration
For each of the symptoms scales/items in EORTC QLQ-LC13, time to symptom deterioration 
will be defined as the time from randomization until the date of first clinically meaningful 
symptom deterioration (an increase in the score from baseline of ≥10) or death (by any cause) 
in the absence of a clinically meaningful symptom deterioration, regardless of whether the 
subject withdraws from randomized therapy or receives another anti-cancer therapy prior to 
symptom deterioration. Death will be included as an event only if the death occurs within two 
visits of the last PRO assessment where the symptom change could be evaluated.
Subjects whose symptoms (as measured by EORTC QLQ-LC13) have not shown a clinically 
meaningful deterioration and who are alive at the time of the analysis will be censored at the 
time of their last PRO assessment where the symptom could be evaluated. Also, if symptoms 
progress after two or more missed PRO assessment visits or the subject dies after two or more 
missed PRO assessment visits, the subject will be censored at the time of the last PRO
assessment where the symptom could be evaluated. If a subject has no evaluable visits or does 
not have baseline data they will be censored at Day 1. The population for analysis of time to 
symptom deterioration will include a subset of the FAS who have EORTC QLQ-LC13 or 
EORTC QLQ-C30 baseline scores ≤90.
3.1.7.2
Symptom improvement rate
The symptom improvement rate will be defined as the number (%) of subjects with two 
consecutive assessments at least 18 days apart (i.e., 21 days allowing a visit window of 3 
days), which showed a clinically meaningful improvement (a decrease from baseline score 
≥10 for EORTC QLQ-LC13 scales/items and EORTC QLQ-C30 scales/items) in that 
symptom from baseline. The denominator will consist of a subset of the FAS who have a 
baseline symptom score ≥10.
3.1.7.3
PFS2
PFS2 is defined as the time from the date of randomization to the earliest of the progression 
event subsequent to that used for the primary variable PFS or death. Subjects who are alive 
and for whom a second PD has not been observed will be censored at their last assessment 
where the subject has not had a second progression or death. If a subject dies without a 
progression event, the subject’s PFS and PFS2 events would be equivalent.
For subjects with no PFS and no PFS2, the PFS2 censor date will be same as PFS censor date, 
with the following exceptions:


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
If there is no PFS event but a PFS2 event has been recorded, the PFS2 event should 
be used in the PFS2 analysis even though the subject will be censored in PFS 
analysis.

If there is no PFS event but the PFS2 form has been completed as no event with a 
date, then use this date as the censor date (rather than PFS censor date).
3.1.7.4
TFST
TFST is defined as the time from the date of randomization to the earlier of the date of anti-
cancer therapy start date following study treatment discontinuation, or death. Any subject not 
known to have had a subsequent therapy or not known to have died at the time of the analysis 
will be censored at the last known time to have not received subsequent therapy (i.e., the last 
follow-up visit where this was confirmed). If a subject terminates the study for a reason other 
than death before first subsequent anti-cancer therapy, the subject will be censored at the 
termination date.
3.1.7.5
TSST
TSST is defined as the time from the date of randomization to the earlier of the date of second 
subsequent anti-cancer therapy start date following study treatment discontinuation, or death. 
Any subject not known to have died at the time of the analysis and not known to have had a 
second further intervention of this type will be censored at the last known time to have not 
received second subsequent therapy (i.e., the last follow-up visit where this was confirmed). If 
a subject terminates the study for a reason other than death before the second subsequent anti-
cancer therapy, the subject will be censored at the termination date.
3.1.8
PRO-CTCAE symptoms
The PRO-CTCAE questionnaire will be used to derive subject reporting of CTCAE 
symptoms.
The PRO-CTCAE will only be administered in those countries where a linguistically validated 
version exists (languages available are English, German, Japanese and Spanish). PRO-
CTCAE is an item-bank of symptoms of the CTCAE experienced by subjects while 
undergoing treatment of their cancer that has been converted to subject terms (i.e., CTCAE 
term “myalgia” converted to “aching muscles”). Twenty-eight items from the PRO-CTCAE 
item-bank have been selected as being relevant for this study.
3.1.9
Health state utility
The EQ-5D-5L index comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression). For each dimension, subjects select which statement 
best describes their health on that day from a possible 5 options of increasing levels of 
severity (no problems, slight problems, moderate problems, severe problems and unable 
to/extreme problems). A unique EQ-5D health state is referred to by a 5-digit code allowing
for a total of 3125 health states. For example, state 11111 indicates no problems on any of the 
5 dimensions. These data will be converted into a weighted health state index by applying 


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scores from EQ-5D value sets elicited from general population samples (the base case will be 
the United Kingdom valuation set, with other country value sets applied in scenario analyses). 
Where values sets are not available, the EQ-5D-5L to EQ-5D-3L crosswalk will be applied. 
In addition to the descriptive system, subjects also assess their health on the day of assessment 
on a visual analogue scale, ranging from 0 (worst imaginable health) to 100 (best imaginable 
health). This score is reported separately.
3.1.10
Health resource utilization
Health resource utilization will be assessed in terms of hospitalization, outpatient visits and 
emergency department visits.
3.2
Safety variables
Safety and tolerability will be assessed in terms of AEs, deaths, laboratory data, vital signs 
(pulse, BP and weight), ECG, physical examinations, and WHO performance status. These 
will be collected for all subjects.
3.2.1
AEs
All AEs will be coded using the latest version of the Medical Dictionary for Regulatory
Activities (MedDRA) and graded according to the National Cancer Institute Common
Terminology Criteria for Adverse Event (CTCAE) (version 4.0.3 or later).
Preferred terms used to identify adverse events of special interest will be listed before
database lock and documented in the Study Master File. Groupings of certain MedDRA
preferred terms will be based on preferred terms provided by the medical team and a listing of
the preferred terms in each grouping will be produced. The grouped terms are as follows:
ocular surface effects, dry eye/conjunctivitis, interstitial lung disease and acute interstitial
pneumonitis, nail and nail bed conditions, skin disorders, upper GI tract inflammatory events,
cardiotoxicity, and diarrhoea.
Any AE occurring before treatment with AZD9291/chemotherapy will be included in the data 
listings but will not be included in the summary tables of AEs.
Any AE occurring within 28 days of discontinuation of IP (i.e., the last dose of 
AZD9291/chemotherapy) will be included in the AE summaries. Any events in this period 
that occur after a subject has received further therapy for cancer (following discontinuation of 
AZD9291) will be flagged in the data listings. Please refer to CSP Section 6.3.1
3.2.2
Other significant adverse events (OAEs)
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and AEs leading to treatment discontinuation. 
Based on the expert’s judgment, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered OAEs and reported as 


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such in the CSR. A similar review of laboratory, vital signs (pulse, BP and weight), and/or 
ECG data will be performed for identification of OAEs.
Examples of these could be marked hematological and other laboratory abnormalities, and 
certain events that lead to intervention (other than those already classified as serious), dose 
reduction or significant additional treatment.
3.2.3
dECG
Baseline is the pre-dose time point on the first dosing day (Day 1 Cycle 1). For each time 
point three dECG recordings should be taken within an approximate 5 minute period. The 
variables to be reported from the continuous dECG measurements are RR, PQ, QRS, and QT 
intervals. The QT interval will be corrected for RR (the duration of a heart beat) to obtain 
corrected (QTc) variables.
QTcF will be calculated using the formula:
QTcF=QT/RRb
Where b=1/3.
To obtain a single value of QTcF, RR, PR, QRS and QT at each specified time point, the
mean of the triplicate values at that time point will be used. If there are more than three values 
for a single time point, the mean of all the recorded values will be taken. For each patient, the 
change-from-baseline in a dECG variable at each time point will be calculated as the 
difference between the mean of the replicate value at each post-dose time point and the mean 
of pre-dose baseline replicate value. All ECG data will be obtained from the vendor, eRT, and 
there will be no site interpretation.
3.2.4
Duration of exposure
Exposure to AZD9291
Total exposure to AZD9291 will be time (days) from the first dose to the last dose: 
Total exposure = (last dose date where dose >0 mg - first dose 
date) + 1
Actual exposure to AZD9291 will be time (days) from first dose to the last dose, taking 
account of dose interruptions.
Actual exposure = ((last dose date where dose >0 mg - first dose 
date) + 1) - total duration of dose interruption (i.e., number of 
days with dose = 0mg).
Exposure to chemotherapy
Duration of treatment on chemotherapy will be in terms of the number of cycles. A cycle will 
be counted if chemotherapy is started, even if the full dose is not delivered. 


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If a new cycle is delayed, the day when chemotherapy dosing occurs will be deemed to be day 
1 of the next cycle. 
3.2.5
Dose intensity
Relative dose intensity (RDI) and percentage intended dose (PID) will be defined as follows:

RDI = 100% x d / D, where d is the actual cumulative dose delivered up to the 
earlier of progression (or a censoring event) or the actual last day of dosing, and D 
is the intended cumulative dose up to the earlier of progression (or a censoring 
event) or the actual last day of dosing plus the protocol-defined post-dose rest 
period. Protocol-defined post-dose rest period is 0 days for AZD9291.

PID = 100% x d1 / D1, where d1 is the actual cumulative dose delivered up to 
progression (or a censoring event), and D1 is the intended cumulative dose up to 
progression (or a censoring event). D1 is the total dose that would be delivered, if 
there were no modifications to dose or schedule.
3.3
PK variables
PK analysis of the plasma concentration data for AZD9291, AZ5104 and AZ7550 will be 
performed by Quantitative Clinical Pharmacology, AstraZeneca or delegate on behalf of 
Quantitative Clinical Pharmacology. Plasma concentration will be listed and summarized 
according to the time ranges.
The ratio of metabolite to AZD9291 will be calculated at the time-points. The plasma 
concentration data for AZD9291 and metabolites will also be analyzed using a population PK
approach, which may include exploring the influence of covariates on PK, if the data allows.
The data collected in this study may also be combined with similar data from other studies and 
explored using population PK and/or PK-pharmacodynamic methods. A separate analysis plan 
will be written to describe these analyses. The results of any such analyses will be reported 
separately from the CSR.
The concentration in CSF will be summarized and metabolite to AZD9291 ratio calculated. If 
the CSF was taken on a PK day then the CSF to pre-dose plasma concentration for AZD9291 
will be calculated. If there are no CSF samples collected in the study, CSF data will not be 
presented or summarized.


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4.
ANALYSIS METHODS
4.1
General principles
Continuous data will be summarized using descriptive statistics (number of observations, 
mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum). 
Frequencies and percentages will be used for summarizing categorical (discrete) data. 
Confidence intervals (CIs), when presented, will generally be constructed at the 95% level. 
For binomial variables, the normal approximation methods will be employed unless otherwise 
specified. 
A month is operationally defined to be 30.4375 days. Six months is operationally defined to 
be 183 days. 
Data will be presented in data listings by treatment group and subject number.
All summaries will be presented by treatment group unless otherwise specified.
Additional summaries of efficacy and other variables may be produced as a separate report(s) 
for specific regions (e.g. Japan), as required by local health authorities.
4.1.1
Baseline measurements and change from baseline variables
In general, for efficacy endpoints and PROs the last observed measurement prior to 
randomization will be considered the baseline measurement. However, if an evaluable 
assessment is only available after randomization but before the first dose of randomized 
treatment then this assessment will be used as baseline. For safety endpoints the last 
observation before the first dose of study treatment will be considered the baseline 
measurement unless otherwise specified. 
For assessments on the day of first dose where time is not captured, a nominal pre-dose 
indicator, if available, will serve as sufficient evidence that the assessment occurred prior to 
first dose.
Assessments on the day of the first dose where neither time nor a nominal pre-dose indicator 
are captured will be considered prior to the first dose if such procedures are required by the 
protocol to be conducted before the first dose.
In all summaries change from baseline variables will be calculated as the post-treatment value 
minus the value at baseline. The % change from baseline will be calculated as (post-baseline 
value - baseline value) / baseline value x 100.
4.1.2
Multiple testing strategy
In order to provide strong control of the type I error rate, the primary endpoint of PFS and key 
secondary endpoints, ORR and OS will be tested in this sequential order. If any previous 


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analysis in the sequence is not statistically significant, the alpha cannot be transferred to 
subsequent analyses. 
The analyses of primary and all secondary endpoints will all occur at the time of primary 
analysis of PFS with the exception of OS. Three analyses of OS are planned; two interim 
analyses and a final analysis. The data cut-off for the first analysis of overall survival will be 
conducted approximately 4 months after data cut-off for the primary analysis of PFS and the 
second analysis will be conducted when the OS data are approximately 50% mature 
(approximately 205 death events). A final analysis of overall survival will be performed when 
the OS data are approximately 70% mature (approximately 287 death events).
The analyses of PFS2, time to first subsequent therapy and time to second subsequent therapy 
will be performed at the time of the OS analyses since these endpoints are considered 
important to the interpretation of OS.
A 2-sided 5% alpha will be used in all testing, with the exception of overall survival endpoint. 
Since three analyses of OS are planned, the Lan DeMets approach that approximates the 
O’Brien and Fleming spending function will be used to maintain an overall 2-sided 5% type I 
error across the three planned analyses of OS. 
The significance level for the OS analyses will be calculated using the statistical software 
package EAST by specifying the information fraction for each analysis. The information 
fraction is calculated as the number of OS events at the analysis time-point divided by the 
total number of events at the final analysis time-point. For example, assuming a median OS on 
the chemotherapy arm of 16 months and a median OS of 22 months on the AZD9291 arm, 
that 119 OS events were observed at the first analysis, the information fraction would be 
entered as 0.41 (119/287 events) for the first analysis and 0.71 (205/287 events) for the second 
analysis, since 205 and 287 events are expected at the second and final analysis, respectively. 
This would result in a significance level for the first analysis of 0.001 (2-sided), a significance 
level for the second analysis of 0.016 (2-sided) and a significance level for the final analysis 
of 0.045 (2-sided).
Note, any non-statistically significant analyses at the interims will not preclude further testing 
of OS. 
For PRO symptoms, the overall type I error (5% 2 sided) will be controlled across the five 
primary PRO measures of cough, dyspnoea and pain as assessed by the EORTC QLQ-LC13 
and fatigue and appetite loss as assessed by the EORTC QLQ-C30 using the Bonferroni-Holm 
procedure.
4.1.3
Study day definitions
For the purpose of efficacy data summary, Study Day 1 is defined as the date of 
randomization to study treatment. For visits (or events) that occur on or after randomization, 
study day is defined as (date of visit [event] - date of randomization + 1). For visits (or events) 


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that occur prior to randomization, study day is defined as (date of visit [event] - date of 
randomization). There is no Study Day 0.
For the purpose of safety data summary, Dose Day 1 is defined as the date of first dose of 
study treatment (referred to in the protocol as Week 1 Day 1). For visits (or events) that occur 
on or after first dose, dose day is defined as (date of visit [event] - date of first dose of study 
treatment + 1). For visits (or events) that occur prior to first dose, dose day is defined as (date 
of visit [event] - date of first dose of study treatment). There is no Dose Day 0.
For listings (such as for AEs) that include the derivation of “days since last dose,” this is 
defined as (event date - date of last dose). Events that occur on the same day as the last dose of 
study drug will therefore be described as occurring zero days from the last dose of study drug.
4.1.4
Visit windows
For summaries of vital signs, laboratory data, ECG, HRQoL, and PROs etc., assessments will 
be assigned to calculated visit windows (using study day).
The time windows should be exhaustive so that data recorded at any time point have the 
potential to be summarized. Inclusion within the visit window should be based on the actual 
date and not the intended date of the visit. For summaries at a subject level, all values should 
be included, regardless of whether they appear in a corresponding visit-based summary, when 
deriving a subject level statistic such as a maximum.
The window for the visits following baseline (including unscheduled visits) will be 
constructed in such a way that the upper limit of the interval falls half way between the two 
visits.
For summaries showing the maximum or minimum values, the maximum/minimum value 
recorded on treatment will be used (regardless of where it falls in an interval). Listings should 
display all values contributing to a time point for a subject; they should also highlight the 
value for that subject that was used in the summary table, wherever feasible.
For visit based summaries:

If there is more than one value per subject within a visit window then the closest to 
the planned study day value should be summarized, or the earlier in the event the 
values are equidistant from the planned study day. The visit will be missing if no 
assessment was reported within the specified visit window around the planned study 
day.

To prevent very large tables or plots being produced that contain many cells with 
meaningless data, summary statistics will be presented where at least 10 subjects in 
either treatment group have data recorded at a particular visit.


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4.1.5
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.
4.1.6
Imputation rules for lab values outside of quantification range
Lab values below the lower limit of quantification (LLoQ) that are reported as “<LLoQ” or 
“≤LLoQ” in the database will be imputed by LLoQ x 0.99 for analysis purposes. The original 
value will be listed.
Lab values above the upper level of quantification (ULoQ) that are reported as “>ULoQ” or 
“≥ULoQ” in the database will be imputed by ULoQ x 1.01 for analysis purposes. The original
value will be listed.
4.1.7
Rounding rules for reported percentages
For percentages ≥10%:

Values ≥X.5 or above round to X+1.


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
Values >X but <X.5 round to X.
For percentages <10%:

Values ≥X.Y5 or above round to X.Y+0.1.

Values >X.Y but <X.Y5 round to X.Y.
4.2
Analysis methods
4.2.1
Subject disposition and data sets analyzed
Subject disposition will be listed and summarized for the FAS. Summaries will include the 
number and percentage of subjects:

Randomized

Treated

Subjects ongoing study treatment at the data cut-off

Included in each analysis set (FAS, Safety, and PK).
In addition, the number and percentage of subjects who discontinued treatment and who 
discontinued the study, including a breakdown of the main reason for discontinuation will be 
presented for all subjects.
4.2.2
Protocol deviations
All important protocol deviations will be listed and summarized for the FAS. All protocol 
deviations will be defined by the study team and identified before database lock.
4.2.3
Demographic and other baseline characteristics
Demographic and baseline subject characteristics will be listed and summarized for the FAS. 
Standard descriptive statistics will be presented for the continuous variables of:

Age (years).

Weight (kg).

Height (cm).

Body mass index (kg/m2) [calculated as (weight/height2) where weight is in kg and 
height is in m].

Nicotine consumption (cigarettes/cigars per day and pipe tobacco packs per week)


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The total counts and percentages of subjects will be presented for the categorical variables of:

Age group (years) (grouped as <50, ≥50-<65, ≥65)

Sex

Race

Ethnic group

EGFR mutation type (Exon 20 T790M, G719X, S768I, Exon 19 deletion, L858R, and 
other) (as reported prior to study screening) 

Overall disease classification (metastatic, locally advanced, both)

Site of disease

Baseline TL size (mean and categories: <40, 40-79, 80-119, ≥120mm)

Histology

Smoking status.

WHO performance status (0/1)
The number of subjects with all types of EGFR mutations identified by the cobas EGFR 
central test (by biopsy taken after confirmation of disease progression on the most recent 
treatment regime) will be summarized (i.e., T790M only, T790M and exon 19 deletion, 
T790M and L858R, and T790M with all other mutations with >5 subjects). Examples of other 
EGFR mutations which may be detected are G719X, S768I, and Exon 20 insertion). A listing 
of all subjects showing all the EGFR mutations reported prior to study screening and the 
EGFR mutations identified by the cobas central test after confirmation of disease progression 
will be presented.
4.2.4
Medical history
Disease related medical history and relevant surgical history will be coded using MedDRA. 
All disease related medical history will be listed and the number and percentage of subjects 
with any disease related medical history will be summarized for the FAS by system organ 
class (SOC) and preferred term (PT).
All relevant surgical history will be listed and summarized similarly.
4.2.5
Anti-cancer medications and radiotherapy (prior, during, post-treatment with 
IP) 
Medications received prior to, concomitantly, or post-treatment will be coded using the 
AstraZeneca Drug Dictionary Anatomical Therapeutic Chemical (ATC) Classification codes.


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Concomitant medications/radiotherapy will be listed and summarized for the FAS by ATC 
classification codes.
For the purpose of inclusion in prior and/or concomitant mediation or therapy summaries, 
incomplete medication or radiotherapy start and stop dates will be imputed as detailed in 
Section 4.1.5.
Prior medications, concomitant and post-treatment medications are defined based on imputed 
start and stop dates as follows:

Prior medications are those taken prior to screening with a stop date prior to the first 
dose of study treatment.

Concomitant medications are those with a stop date on or after the first dose date of 
study treatment (and could have started prior to or during treatment).

Post-treatment medications are those with a start date after the last dose date of study 
treatment.
EGFR-TKI therapies will be defined as approved EGFR-TKI therapies and will include 
gefitinib, erlotinib and afatinib only.
4.2.5.1
Anti-cancer therapy
All anti-cancer therapies will be summarized for the FAS. They will be summarized 
separately for prior, current, and post-withdrawal of IP anti-cancer therapies.
The number of anti-cancer therapy regimens and number of cycles will be summarized using 
descriptive statistics. The anti-cancer therapy agent, therapy class, best response, and 
treatment status will be summarized using frequencies and percentages. Any anti-cancer 
therapies will also be listed.
4.2.5.2
Radiotherapy 
All radiotherapies will be summarized for the FAS. They will be summarized separately for 
prior, current, and post-withdrawal of IP radiotherapies. 
The number of fraction doses and fraction dose (Gy) will be summarized using descriptive 
statistics. The radiotherapy site/region and treatment status will be summarized using 
frequencies and percentages.
Any radiotherapy will also be listed.
4.2.6
Exposure
Exposure will be listed and summarized for safety analysis set. The following summaries will 
be produced:


Statistical Analysis Plan 
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
Summary of duration of exposure of AZD9291

Summary of total number of cycles of chemotherapy received

RDI and PID of AZD9291

Summary of interruptions and reductions of AZD9291

Summary of delays and reductions of chemotherapy 
4.2.7
Brain metastases
The proportion of subjects who develop brain metastases during the trial will be summarized 
by treatment group.
The proportion of RECIST progression events by medical history of brain metastases will be 
summarized.
4.2.8
Efficacy 
All efficacy analyses will be performed on the FAS. Results of all statistical analyses will be 
presented using a 95% CI and 2-sided p-value.
The stratification factor for the efficacy analyses will be based on the values entered into the 
IVRS.
4.2.8.1
Primary outcome: PFS
PFS will be analyzed using a log rank test stratified by ethnicity (Asian, Non-Asian) for 
generation of the p-value and using the Breslow approach for handling ties. The HR and CI
will be obtained directly from the U and V statistics as follows (Berry G et al 1991, Selke & 
Siegmund 1982):
HR = exp(U/V)
95% CI for HR = (exp{U/V - 1.96/√V}, exp{U/V + 1.96√V})
Where U = Σi(d1i - e1i) is the log-rank test statistic (with d1i and e1i the observed and expected 
events in group 1) and √V the standard deviation of the log-rank test statistic obtained from 
the LIFETEST procedure with a STRATA term for the stratification variable.
A Kaplan-Meier (KM) plot of PFS will be presented by treatment group.
Subgroup analysis
Subgroup analyses will be conducted by comparing PFS between treatments in the following 
groups:

Ethnicity (Asian versus Non-Asian)


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
Gender (Male versus Female)

Age at screening (<65 versus ≥65)

Mutation status prior to start of study (ex19 versus L858R)

Duration of prior EGFR-TKI (<6 months, ≥6 months)

Brain metastases at entry

Smoking history
The HR (AZD9291: chemotherapy) and associated CI will be calculated from a Cox 
proportional hazards model (ties=Efron) that contains the treatment term, factor and 
treatment-by-factor interaction term. The treatment effect HRs for each treatment comparison 
along with their CIs will be obtained for each level of the subgroup from this single model. 
The HRs and 95% CIs will be presented on a forest plot including the HR and 95% CI from 
the overall population (using the primary analysis). 
If there are too few events available for a meaningful analysis of a particular subgroup (it is 
not considered appropriate to present analyses where there are less than 20 events per level in 
a subgroup), the relationship between that subgroup and PFS will not be formally analyzed. In 
this case, only descriptive summaries will be provided.
The assumption of proportionality will be assessed. Proportionality will be tested firstly by 
examining the plots of complementary log-log (event times) versus log (time) and, if 
necessary, a time dependent covariate will be fitted to assess the extent to which this 
represents random variation.
No adjustment to the significance level for testing will be made since the subgroup analysis 
will be considered exploratory and may only be supportive of the primary analysis of PFS.
The presence of quantitative interactions will be assessed by means of an overall global 
interaction test. This will be performed in the overall population by comparing the fit of a Cox 
proportional hazards model including treatment, all covariates, and all covariate-by-treatment 
interaction terms, with one that excludes the interaction terms and will be assessed at the 2-
sided 10% significance level. If the fit of the model is not significantly improved as assessed 
by twice the change in log-likelihood then it will be concluded that overall the treatment effect 
is consistent across the subgroups.
If the global interaction test is found to be statistically significant, an attempt to determine the 
cause and type of interaction will be made. Stepwise backwards selection will be performed 
on the saturated model, whereby (using a 10% level throughout) the least significant 
interaction terms are removed one-by-one and any newly significant interactions re-included 
until a final model is reached where all included interactions are significant and all excluded 
interactions are non-significant. Throughout this process all main effects will be included in 


Statistical Analysis Plan 
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the model regardless of whether the corresponding interaction term is still present. This 
approach will identify the factors that independently alter the treatment effect and prevent 
identification of multiple correlated interactions.
Any quantitative interactions identified using this procedure will then be tested to rule out any 
qualitative interaction using the approach of Gail and Simon 1985.
Sensitivity analysis
(a)
Ascertainment bias
The possibility of bias in assessment and measurement of PFS by investigators will 
be assessed by comparing the hazard ratio derived from investigator review with the 
hazard ratio derived using the BICR assessment of disease progression by RECIST
1.1. 
(b)
Evaluation-time bias
In order to assess possible evaluation-time bias, which could occur if scans are not 
performed at the protocol-scheduled time points, the midpoint between the time of 
progression and the previous evaluable RECIST 1.1 assessment will be analyzed 
using a stratified log rank test, as described for the primary analysis of PFS. For 
subjects who die in the absence of progression, the date of death will be used to 
derive the PFS time used in the analysis.
(c)
Attrition bias
Possible attrition bias will be assessed by:
(i)
Repeating the primary PFS analysis, except that the actual PFS event 
times, rather than the censored times, of subjects who progressed or died 
in the absence of progression immediately following two, or more, non-
evaluable tumor assessments will be included. 
(ii)
Subjects who take subsequent therapy prior to progression or death will 
be censored at their last evaluable assessment prior to taking the 
subsequent therapy. 
(iii)
A reversed KM plot of the time to censoring, where the censoring 
indicator of the primary PFS analysis is reversed, will be presented to 
assess the number of subjects being followed over time.
Post-hoc exploratory analysis of the use of a novel sample BICR methodology to assess bias 
in assessment of PFS by investigators
Recently, it has been suggested that, in order to assess the potential for bias amongst 
investigators, a BICR amongst only a sample of patients could be performed; if evidence of 


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bias is detected, according to a pre-defined threshold, the BICR is then assessed in all patients, 
otherwise it is concluded the sample was sufficient to rule-out meaningful levels of bias. A 
proposed sample BICR method has been submitted to a peer reviewed statistical journal for 
publication as of August 2014 and in order to demonstrate that this is a valid methodology for 
use in future trials, a post hoc exploratory analysis will be carried out using this methodology. 
The results of this exploratory analysis will be reported separately from the CSR. A random 
sample of subjects from the full study population will be selected and the results of the BICR 
review of these subjects will be used to rule out a concerning level of bias in the full study 
local evaluation (LE) estimate of the treatment effect (Hazard Ratio) for PFS. The hazard ratio 
ratio (HRR), the ratio of the hazard ratio (HR) for the treatment effect estimated from the 
sample BICR to the corresponding HR for the investigator assessments, will be used as the 
metric to assess bias. Lack of evidence of meaningful bias will be concluded if there is a low 
conditional probability that the HRR seen in the random sample would have been observed, if 
in fact, the point estimate in the full trial were unacceptably high (i.e., 1.25).
The subjects forming the sample BICR will be randomly selected from within each treatment 
group with separate sampling within subjects who have a LE progression event and from 
those censored for PFS by the LE. This is so that the BICR sample is representative of the 
study as a whole.
A sample BICR would be deemed to be acceptable if there was a low (conditional) probability 
(10%), given the sample, that the null hypothesis of concerning bias in the overall study (HRR 
≥1.25) was really true. This protects the sensitivity of the procedure at 90% (i.e., correctly 
failing to reject the hypothesis of concerning bias when this is really true).
4.2.8.2
Secondary outcomes
ORR
The ORR will be compared between treatment using logistic regression models adjusting for 
the covariate ethnicity (Asian/non-Asian). The results of the analysis will be presented in 
terms of an odds ratio together with its associated 95% profile likelihood CI. The p-value will 
be based on a test statistic that is calculated as twice the change in log-likelihood resulting 
from the addition of a treatment factor to a model that contains the covariate defined above.
The test statistics is chi-squared distributed with 1 degree of freedom.
A summary of best objective response will also be presented by treatment group.  
DoR
In order to analyze the secondary outcome variable of DoR between arms the Expected 
Duration of Response (EDoR) will be derived for each treatment group (Ellis S et al 2008). 
The EDoR is the product of the proportion of subjects responding to treatment and the mean 
DoR in responding subjects, and provides an estimate based on all randomized subjects. 
Treatments will be compared by calculating the ratio of EDoRs using the log Normal 
probability distribution for duration of response in responding subjects. The log Normal 


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distribution has been chosen based on a review of the fit of this distribution, the Exponential
distribution, the Weibull distribution and the log logistic distribution to duration of response 
data from pooled data from the two Phase II AZD9291 single-arm monotherapy studies: 
D5160C0001C (AURA extension) and D5160C00002 (AURA2), using the data cut-off date 
of 1st November 2015. The log Normal distribution had the lowest value Akaike information 
criterion and Bayesian Information Criterion and the fitted line for the model overlaid with the 
KM plot indicated visually that the distribution was a reasonable fit.
The analysis of DoR will be stratified by the same covariates as the primary analysis, 
weighting each stratum inversely proportional to the within stratum variance of the log of the 
ratio of EDoRs. The mean DoR will also be estimated, and the null hypothesis that the 
distribution of the ratio of EDoRs is 1 will be tested and a p-value and 95% CI provided. 
Additionally, descriptive data will be provided for the duration of response in responding 
subjects, including associated KM curves (without any formal comparison of or p-value 
attached).
DCR
DCR will be analyzed using a logistic regression with a covariate for ethnicity (Asian/non-
Asian). The results of the analysis will be presented in terms of an odds ratio together with its 
associated 95% profile likelihood CI and 2-sided p-value. The p-value will be based on twice 
the change in log-likelihood resulting from the addition of a treatment factor to a model that 
contains the covariates defined above.
Tumor shrinkage
The effect of AZD9291 on best percentage change in tumor size will be estimated from an 
analysis of covariance (ANCOVA) model with a covariate for ethnicity (Asian/non-Asian). 
The number of subjects, unadjusted mean and lsmeans for each treatment group will be 
presented, together with the difference in lsmeans, 95% CI and corresponding p-value.
OS
OS data will be analyzed using a log rank test stratified by ethnicity (Asian, Non-Asian) for 
generation of the p-value and using the Breslow approach for handling ties. The HR and CI 
will be obtained directly from the U and V statistics as described in Section 4.2.8.1 (provided 
there are sufficient events available for a meaningful analysis [>20 deaths], if not descriptive 
summaries will be provided). For the interim analysis, see Section 5.
Mixed models repeated measures of change from baseline in primary PRO symptoms
Change from baseline in the primary PRO symptom scores of dyspnea, cough, pain, fatigue 
and appetite loss (described in Section 3.1.7) will be analysed using a mixed model for 
repeated measures (MMRM) analysis. The analysis will be to compare the average treatment 
effect from the point of randomisation for the first 6 months unless there is excessive missing 
data (defined as >75% missing data). Following confirmed disease progression, patients on 
the chemotherapy arm are eligible to crossover to AZD9291 treatment, therefore only data up 
to 6 months is included in this analysis to limit any confounding caused by treatment 


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switching. However, if the time to first AZD9291 dose when approximately 50% of 
chemotherapy patients receive AZD9291 occurs prior to 6 months post-randomisation then 
only data until this earlier time-point will be used in the analysis. 
It is acknowledged that patients will discontinue treatment at different timepoints during the 
study and that this is an important time with regards to symptoms and HRQoL data collection. 
To account for this, and in order to include the discontinuation and follow up visits, a generic 
visit variable will be derived for each subject in order that the average treatment effect can be 
analyzed using the above method. Each visit will be assigned a sequential number. The time 
from randomization to each of these will be derived in order to select only those visits 
occurring within the first 6 months of randomization. 
As an example, say a patient X attends the first 4 scheduled visits of a 6-weekly schedule and 
then discontinues treatment, whilst patient Y discontinues treatment after the first scheduled 
visit, the first 5 generic visits would be as follows:
Generic visit
Days since randomization
Patient X
Patient Y
Baseline
Baseline
Baseline
1
42
42
2
84
50 (discontinuation) 
3
126
84
4
168
126
5
189 (discontinuation)
168
Thus, the first 5 generic visits could be used in the analysis of deriving the average treatment 
effect.
The MMRM model will include patient, treatment, and visit) and treatment by visit interaction 
as explanatory variables, and the baseline symptom score as a covariate along with the 
baseline symptom score by visit interaction. Treatment, visit and treatment by visit interaction 
will be fixed effects in the model; patient will be included as a random effect. Restricted 
maximum likelihood (REML) estimation will be used. An overall adjusted mean estimate will 
be derived that will estimate the average treatment effect over visits giving each visit equal 
weight.   For this overall treatment comparison, adjusted mean estimates per treatment group 
and corresponding 95% CIs will be presented along with an estimate of the treatment 


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difference, 95% CI and p-value. The treatment by visit interaction will remain in the model 
regardless of significance. 
An unstructured covariance matrix will be used to model the within-subject error and the 
Kenward-Roger approximation will be used to estimate the degrees of freedom. 
If the fit of the unstructured covariance structure fails to converge, the following covariance 
structures will be tried in order until convergence is reached: toeplitz with heterogeneity, 
autoregressive with heterogeneity, toeplitz, and autoregressive. If there are still issues with the 
fit of the model or estimation of the treatment effects, SUBJECT will be treated as a fixed 
effect.
Time to PRO symptom deterioration
Time to PRO symptom deterioration will be analyzed using a log rank test stratified by 
ethnicity (Asian/non-Asian) for generation of the p-value and using the Breslow approach for 
handling ties. The HR and CI will be estimated using the same methods as for the primary 
endpoint of PFS, as described in Section 4.1.
PRO symptom improvement rate
Symptom Improvement Rate at each visit will be analyzed using a logistic regression with a 
covariate for ethnicity (Asian/non-Asian). The results of the analysis will be presented in 
terms of an odds ratio together with its associated 95% profile likelihood CI and 2-sided p-
value. The p-value will be based on twice the change in log-likelihood resulting from the 
addition of a treatment factor to a model that contains the covariates defined above.
Subjects with EGFR T790M mutation status detected in baseline plasma sample (ctDNA)
The efficacy of AZD9291 versus chemotherapy will be evaluated in patients with baseline 
plasma T790M mutation status (positive, negative and unknown). For PFS, the HR and 
associated 95% CI will be calculated for each group. For ORR, the odds ratio and associated 
95% CI will be presented for each group. 
Note, plasma testing will not be performed on China patients due to sample export limitations, 
therefore the denominator for this analysis will exclude patients from China.
4.2.8.3
Exploratory outcomes
PRO-CTCAE
PRO-CTCAE data will be presented using summaries and descriptive statistics based on the 
FAS.
Healthcare resource use
Healthcare Resource Use data (i.e., the hospital admission details including type of attendance 
and primary symptom for admission) will be presented using frequencies and percentages the 
duration of admission/attendance and duration of ICU/HDU stay will be summarized using 
descriptive statistics, based on the FAS.


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Post-progression outcomes
PFS2, TFST and TSST will be analyzed using the same method as the analysis of PFS. 
Further analysis of OS
Additional analysis of OS adjusting for the impact of subjects randomized to chemotherapy, 
who subsequently receive AZD9291 may be completed if this treatment sequence occurs in a 
significant proportion of subjects. Methods such as Rank Preserving Structural Failure Time 
(RPSFT) (Robins et al 1991) Inverse Probability of Censoring Weighting (IPCW) (Robins 
1993) and other methods in development may be explored. The decision to adjust and final 
choice of methods will be based on a review of the data and the plausibility of the underlying 
assumptions. Further detail will be provided in a Payer Analysis Plan.
All further analyses of OS will be reported separately from the CSR.
4.2.9
PK and CSF concentration data
All plasma concentrations of AZD9291, AZ5104 and AZ7550 will be listed.
Secondary outcomes include summaries of plasma concentrations of AZD9292 and plasma 
metabolite (AZ5104 and AZ7550).
Exploratory outcomes include summaries of CSF concentrations, CSF metabolite: AZD9291 
ratio, and CFS: plasma ratio, if any CSF data is obtained. If no CSF data is obtained, then this 
exploratory outcome will not be listed or summarized.
The following summary statistics by nominal sample time will be presented for the PK 
analysis set:

The geometric mean (gmean, calculated as exp [μ], where μ is the mean of the data 
on a logarithmic scale).

Coefficient of variation (CV, calculated as 100 √ [exp(s2)-1], where s is the standard 
deviation of the data on a logarithmic scale).

Gmean ± standard deviation (calculated as exp[μ±s]).

Arithmetic mean calculated using untransformed data.

Standard Deviation (SD) calculated using untransformed data.

Minimum.

Median.

Maximum.


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
Number of observations (n).
Non-quantifiable (NQ) values of plasma concentrations will be handled as follows:

If, at a given time point, 50% or less of the plasma concentrations are NQ, the 
gmean, CV, gmean ± SD, arithmetic mean and standard deviation will be calculated 
by substituting the limit of quantification (LOQ) for values which are NQ.

If more than 50%, but not all, of the concentrations are NQ, the gmean, CV, gmean 
± SD, arithmetic mean and SD will be reported as not calculable (NC).

If all the concentrations are NQ, the gmean and arithmetic mean will be reported as 
NQ and the CV, gmean ± SD and SD as NC.

The number of values above LLOQ will be reported for each time point along with 
the total number of collected values.
If data are available for fewer than 3 subjects, no summary statistics other than minimum, 
maximum and n will be presented.
The PK data for Cycle 1 Day 1 and Cycle 3 Day 1 will also be displayed graphically for the 
PK analysis set. Displays will include plasma concentration subject profiles versus time and 
gmean concentrations (± SD) both on the linear and on the log-scale versus time by cohort.
4.2.10
Safety and tolerability
The safety analysis set will be used for all safety and tolerability tables, figures and listings 
except were expressly noted.
4.2.10.1
AEs
All AEs, both in terms of MedDRA PT and CTCAE grade, will be listed and summarized 
descriptively by count (n) and percentage (%) for each treatment group. MedDRA will be 
used for coding. Any AE occurring before AZD9291/chemotherapy treatment (i.e., before 
Study Day 1) will be included in the AE listings, but will not be included in the summary 
tables (unless otherwise stated). These will be referred to as ‘pre-treatment’. The summary 
tables will include all AEs that occurred after the start of treatment up until the end of the 28
day follow-up period. The 28 day follow-up period will be defined as 28 days following 
discontinuation of AZD9291/chemotherapy treatment.
All reported AEs will be listed along with the date of onset, date of resolution (if AE is 
resolved), investigator’s assessment of severity and relationship to study drug. Frequencies 
and percentages of subjects reporting each preferred term will be presented (i.e., multiple 
events per subject will not be accounted for apart from on the episode level summaries).
Summary information (the number and percent of subjects by treatment) will be tabulated for:


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
All AEs

All AEs causally related to study medication

AEs with CTCAE grade 3 or higher

AEs with CTCAE grade 3 or higher, causally related to study medication

AEs with outcome of death

AEs with outcome of death causally related to study medication

All SAEs

All SAEs causally related to study medication

AEs leading to discontinuation of AZD9291/chemotherapy

AEs leading to discontinuation of AZD9291/chemotherapy, causally related to 
AZD9291/chemotherapy

OAEs

OAEs causally related to AZD9291/chemotherapy
An overall summary of the number and percentage of subjects in each category will be 
presented, as will an overall summary of the number of episodes in each category. In addition, 
a truncated AE table of the most common AEs, showing all events that occur in at least 5% of 
subjects overall will be summarized by preferred term, by decreasing frequency. This cut-off 
may be modified after review of the data.
AEs will be assigned CTCAE grades and summaries of the number and percentage of subjects 
will be provided by maximum reported CTCAE grade, SOC, PT and actual treatment group.
Fluctuations observed in CTCAE grades during the study will be listed.
Summaries of the number and percentage of subjects with AEs leading to dose interruptions 
of AZD9291/chemotherapy will be presented by PT.
In addition, AEs with an outcome of death, SAEs, AEs leading to discontinuation of 
treatment, AEs causally related to AZD9291/chemotherapy and OAEs will be listed.
A separate summary will be produced that presents any events that occur prior to dosing or 
starting more than 28 days after discontinuing therapy.


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4.2.10.2
AEs of Special Interest
Summary tables of AEs of special interest will be produced including the number (%) of 
patients experiencing any of the specified terms presented by maximum CTCAE grade, time 
to onset of first AE for each grouped term and each preferred term within it, time to onset of 
first CTCAE grade 3 or higher, fluctuations in CTCAE grade, duration of AEs of special 
interest and number (%) of patients treated for AEs of special interest. 
Life table and prevalence plots for rash (rashes and acnes), diarrhoea and fatigue will be 
produced.
4.2.10.3
Deaths
A summary of deaths will be provided with the number and percentage of subjects, 
categorized as:

Related to disease under investigation,

AE outcome=death,

Both related to disease under investigation and with AE outcome=death,

AE with outcome=death >28 days after last treatment dose,

Deaths >28 days after last treatment dose, unrelated to AE or disease under
investigation, and

Subjects with unknown reason for death.
A corresponding listing will also be produced.
4.2.10.4
Laboratory evaluations
All laboratory data recorded in the electronic case report form (eCRF) will be listed. If any 
additional analytes to those in Table 3 are also recorded then these will be listed only.
All values will be classified as low (below range), normal (within range) and high (above 
range) based on reference ranges provided by the local or central laboratory. As applicable, 
values will be graded using CTCAE v4.0.
For clinical chemistry and hematology, shift tables of the number of CTCAE grade changes
from baseline will be provided. Corresponding shift tables (“Negative”, “Trace”, “Positive”, 
“0”, “+”, “++”, “+++”) will be produced for urinalysis. 
Plots of both the maximum post-baseline ALT and AST versus the maximum post-baseline 
total bilirubin, expressed as multiples of their upper limit of reference range will be produced.


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A pregnancy test performed at screening for women of child-bearing potential will be listed.
The following laboratory variables will be summarized:
Table 3
Laboratory safety variables
Clinical chemistry
(Serum/Plasma)
Hematology
(Blood)
Urinalysis
(Urine)
Albumin
Hemoglobin
Glucose
ALT
Leukocyte
Protein
AST
Hematocrit
Blood
Alkaline phosphatase
Red blood cell (RBC) count
Bilirubin, total
Absolute leukocyte differential count:
Calcium, total
          Neutrophils
Creatinine
          Lymphocytes
Calculated creatinine clearance
          Monocytes
Glucose (fasting, on PK days only)1
          Basophils
LDH2
          Eosinophils
HbA1C
Platelet count
Magnesium
Reticulocytes
Potassium
Sodium
Urea nitrogen/Blood urea nitrogen (BUN)
1 Subjects will be required to fast (water only) for at least 8 hours prior to the collection of a fasting glucose sample required on PK days. 
Random glucose sample will be collected on non-PK days.
2 LDH is an additional variable collected at Visit 1 only.
4.2.10.5
Vital signs (pulse and BP) and weight
All vital signs data will be listed. Absolute and percentage change from baseline for pulse, BP 
and weight will be summarized by treatment group and visit.
4.2.10.6
Physical examination
Abnormalities identified from physical examination will be listed. For each physical 
examination body system, the number and percentage of subjects with abnormalities at 
baseline and post-baseline will be summarized.


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4.2.10.7
ECG
dECG
All dECG data received will be presented in data listings. QTc summaries will be presented 
for subjects in the safety analysis set. 
The dECG parameters that will be summarized (absolute values and change from baseline) 
are: QTcF, RR, PR, QRS and QT.
The observed values and change from baseline in QTcF will be summarized by visit using 
summary statistics. Plots of mean observed QTc parameters and change from baseline in QTc 
parameters versus time will be presented. Shift plots of the maximum change from baseline 
versus the baseline value for QTcF, with reference lines for 450 ms, 480 ms, 500 ms, ±30 ms 
and ±60 ms change will be presented.
QTc outliers are defined as QTcF values following dosing that are greater than 450 ms or are 
increases from baseline greater than 30 ms. QTcF outliers will be highlighted in the data 
listings and summarized using the following categories: 

Values >450 ms, >480 ms, >500 ms 

Increase from baseline of >30 ms, Increase from baseline of >60 ms, Increase from 
baseline of >90 ms,

Values >450 ms and increases of >30 ms. Values >500 ms and increases of >60 ms.
The number and percentage of subjects who meet the ECG outlier criteria at any assessment 
post-date of first dose will be summarized.
LVEF
LVEF outliers are defined as LVEF values following dosing that are

≥10 percentage points decrease from baseline and <50% LVEF, or

≥15 percentage points decrease from baseline and ≥50% LVEF. 
LVEF outliers will be highlighted in the data listings and summarized.
4.2.10.8
WHO performance status
WHO performance status will be listed and summarized by treatment and visit.
4.2.11
Crossover
Summaries for subjects randomized to the chemotherapy arm that crossover to receive 
treatment with AZD9291 will be provided and will include patient disposition, duration of 


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exposure to AZD9291, treatment interruptions and dose reductions, and adverse events 
summaries.
5.
INTERIM ANALYSES
Three analyses of OS are planned:

First analysis of OS will be conducted approximately 4 months after data cut-off for 
the primary analysis of PFS. 

Second analysis will be conducted when the OS data are approximately 50% mature 
(approximately 205 death events).

A third analysis of OS will be performed when the OS data are approximately 70% 
mature (approximately 287 death events).
6.
ADDITIONAL BRAIN METASTASES ANALYSIS
An additional exploratory analysis will be conducted to explore efficacy in 2 subgroups of 
patients. 
a)
The first set of analysis will be conducted to explore the efficacy in patients who undertook a 
brain scan in the screening/baseline period, had their scan sent for independent radiology 
review and were identified by that review as having non-measurable and/or measurable brain 
disease at baseline at the time of randomization.
b) The second set of analysis will be conducted to explore the efficacy in patients with and 
without a prior history of brain metastases and/or current brain lesion at baseline.
The analysis sets, definition of required variables and description of analysis will be pre-
specified in a separate SAP. 
7.
CHANGES OF ANALYSIS FROM PROTOCOL
The China-cohort analyses will be performed when approximately 27 PFS events have 
occurred in approximately 50 Chinese patients so that the maturity of the PFS analysis is 
consistent with that of the global analysis. This update was not included in protocol 
amendment 3 in error. 
The definitions of ORR and DoR have been amended so that visit responses of CR or PR do
not need to be confirmed. This is in line with New response evaluation criteria in solid 


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tumours: Revised RECIST guideline (version 1.1) that, in randomised Phase III studies where 
progression is the primary endpoint, confirmation of response is not required.
The PK analysis set includes subjects in the FAS who have at least one measurable PK 
concentration and who have the relevant date, time and dosing data for this sample. The 
definition that the dosing data must include the dosing data for the 2 days prior to the sample 
day as well as the sample day has been changed to include the dosing data 1 calendar day 
prior to the sample day as there were very few samples for the 2 days prior to the sample day.
8.
REFERENCES
Berry G et al 1991
Berry G, Kitchin RM, Mock PA. A comparison of two simple hazard ratio estimators based 
on the logrank test. Stat Med. 1991 May;10(5):749-55.
Ellis S et al 2008
Ellis S, Carroll KJ, Pemberton K. Analysis of duration of response in oncology trials. 
Contemp Clin Trials. 2008 Jul;29(4):456-65.
Gail and Simon 1985
Gail M, Simon R. Testing for qualitative interactions between treatment effects and patient 
subsets. Biometrics. 1985 Jun;41(2):361-72.
Obosa et al 1998
Obosa D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol. 1998 Jan;16(1):139-44.
Selke & Siegmund 1982
Selke T, Siegmund D. Sequential analysis of the proportional hazards model. Biometrika.
1983;70(2): 315-26.
Robins et al 1991
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank-
preserving structural failure time models. Commun Stat Theory Methods. 1991;20(8):2609-
31.
Robins 1993
Robins JM. Information recovery and bias adjustment in proportional hazards regression 
analysis of randomized trials using surrogate markers. ASA Proceedings of Biopharmaceutical 
Section. 1993:24-33


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9.
APPENDIX
N/A