Clinical trial NCT02997501
Conditions: Lung Cancer
Sponsor: AstraZeneca
Start date: 2016-12-23; Completion date: 2018-10-24
Enrollment: 256 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The aim of this study is to evaluate concordance of T790M mutation plasma testing between the Cobas test and each of other platforms: Super-ARMS, digital PCR or NGS. And to assess the efficacy of AZD9291 monotherapy by assessment of PFS in adult patients with advanced or metastatic NSCLC, who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy and are T790M mutation positive detected by any one of the four plasma testing platforms: Cobas/Super-ARMS/ digital PCR/NGS.

Detailed description:
Objective: The primary objective of this study is to evaluate concordance of T790M mutation plasma testing between the Cobas test and each of other platforms: Super-ARMS, digital PCR or NGS. And to assess the efficacy of AZD9291 monotherapy by assessment of PFS in adult patients with advanced or metastatic NSCLC, who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy and are T790M mutation positive detected by any one of the four plasma testing platforms: Cobas/Super-ARMS/ digital PCR/NGS.

Study number of patients planned: Approximately 250 patients will be recruited in China.

Study Design: This is an open-label, multi-center testing and treatment study.

Target patient population: 250 locally advanced or metastatic EGFR mutation positive NSCLC patients with progression on a previous EGFR-TKI will be recruited.

Investigational product (IP), dosage, and mode of administration: AZD9291 is an oral, potent, selective, irreversible inhibitor of both EGFR-TKI sensitizing 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. All AEs/SAEs would be reported in ASTRIS main study and would not be reported repeatedly in current study.

Duration of IP administration: Patients may continue to receive AZD9291 as long as they continue to show clinical benefit, as judged by the investigator, and in the absence of discontinuation criteria. The study will be closed in a maximum period of 18 months after the last patient is enrolled. Contingencies will be made to ensure continued drug supply for patients who are still deriving benefit from AZD9291 at that time.

Study measures: Data collected will include patient demographics, smoking history, information needed to determine patient eligibility (including medical history, past and current disease characteristics, and tumor EGFR mutations status, T790M and sensitizing mutations status results and type of test performed), AZD9291 exposure, investigator-reported efficacy (including tumor response and disease progression), overall survival (OS).

Statistical methods: The concordance of T790M resistance mutation testing between the Cobas test and each of other platforms will be calculated. The sensitivity, specificity, PPV and NPV of each testing platform (Super-ARMS, digital PCR, and NGS) will be calculated with the Cobas test as the reference. The Kappa coefficient will be calculated to measure the agreement of T790M mutation testing between the Cobas test and each of other platforms. Descriptive statistics will be provided for all variables, as appropriate. Continuous variables will be summarized by the number of observations, mean, standard deviation, median, interquartile range (Q1, Q3), minimum, and maximum. Categorical variables will be summarized by frequency counts and percentages for each category. The 95% confidence interval (CI) will be calculated as appropriate. PFS and OS, respectively, will be summarized using Kaplan-Meier estimates of the median time to event (progression and death) and quartiles together with their 95% confidence intervals.The chi-square test will be used to compare the sensitivity, specificity, and concordance between any of the two platforms using Cobas as reference testing in an exploratory manner.

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

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol  
 
Drug Substance 
AZD9291 
 
Study Code 
D5160C00042 
 
Version 
3.0 
 
Date 
 25 Aug 2017 
 
Detect EGFR T790M mutation in ctDNA of Chinese Advanced/Metastatic 
NSCLC Patients by Cobas, Super-ARMS, digital PCR and NGS and 
evaluate clinical outcomes of T790M mutation positive patients who had 
AZD9291 monotherapy 
 
 
Sponsor:  AstraZeneca China 
 
 
 
 
 
 


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VERSION HISTORY 
Version 3.0, 25 Aug 2017 
May be applicable for all sites in this study. 
Changes to the protocol are summarized below. 
 
Add the following exploratory objectives: 
To evaluate concordance, sensitivity, specificity, PPV, NPV of EGFR mutation plasma testing 
by Bio-rad droplet digital PCR using other plasma tests or tissue test as reference, 
respectively. 
To evaluate the efficacy of patients who receive AZD9291 monotherapy and are T790M 
mutation positive detected by each of the five platforms, respectively. 
Add the “and/or blood” in the exploratory objective: “To explore the mechanisms of acquired 
resistance in patients who received AZD9291 treatment by NGS testing of tissue and/or blood 
samples from the collection at PD versus baseline.” 
In 1.2 Rationale for study design and doses, add “(Thermo Fisher QuantStudio3D digital 
PCR provided by Novogene Bioinformatics Technology Co. LTD)” after digital PCR in 
the sentence: “we will compare the Chinese current available methods including Roche 
Cobas, Super-ARMS (ARMS used in blood test, provided by Amoy Diagnostics Co., 
Ltd.), digital PCR and Illumina NGS (provided by Guangzhou Burning Rock Medical 
Examination Institute Co., Ltd.) to obtain descriptive information of each platform and 
clinically validate the usage of these platforms in companion diagnostic for AZD9291.” 
In Figure 1 Study flow chart, add note: “QuantStudio3D digital PCR will be used.” 
In Table 2 Testing Plan, add note: “Samples collected in other treatment visit will also be 
tested if necessary for exploratory objective.” 
In 4.1.2 Sample collection, add “QuantStudio3D” before digital PCR in the table and the 
following sentences: 
Remain DNA samples (if any) will be retested by Bio-rad droplet digital PCR platform 
retrospectively for T790M and sensitizing mutations (if enough amount of samples) and data 
will be compared with testing results of other four platforms. For retrospective test on all the 
remain samples, patient who are still on AZD9291 treatment will be informed (or EC approve 
informed consent waiver); for patient who can't get in touch will apply informed consent 
waiver. But the investigator should review the medical record to see if the patient expressed 
any objection to use his/her remain samples for scientific research purpose. If such objection 


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was recorded, then this patient’s remain samples should not be used.  
 
In 4.1.3 Mutation testing & Data management, add the following sentence: 
Remain DNA samples (if any) will be retested by Bio-rad droplet digital PCR retrospectively. 
Testing results and raw data will be transferred from central lab. 
In 8.5.3 Exploratory analysis, add the following sentence: 
The concordance, sensitivity, specificity, PPV, NPV of EGFR mutation plasma testing by 
Bio-rad droplet digital PCR using other plasma tests or tissue test as reference will be 
calculated according to the similar formulas as above. The efficacy of patients who receive 
AZD9291 monotherapy and are T790M positive patient by each of the five platforms, 
respectively, will be analyzed same as above.  
 
In 5. STUDY ASSESSMENTS and 8.4 Outcome measures for analyses, add “and 
sensitizing mutations” after T790M, for instance, “T790M and sensitizing mutations status 
results and type of test performed. ” 
In 8.5.4 Analysis timing, add the following: “The exploratory analysis of T790M testing 
concordance and other testing data at enrollment visit by Bio-rad droplet digital PCR will 
be conducted once the data is available. ” 
 
 
 
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.  


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PROTOCOL SYNOPSIS 
 
Detect EGFR T790M mutation in ctDNA of Chinese Advanced/Metastatic 
NSCLC Patients by Cobas, Super-ARMS, digital PCR and NGS and 
evaluate clinical outcomes of T790M mutation positive patients who had 
AZD9291 monotherapy  
 
 
National Principal Investigator  
Prof. Yilong Wu, Guangdong People Hospital, Guangzhou, P. R. China 
Prof. Zhiyong Liang, Peking Union Medical College Hospital, P. R. China 
Study site(s) and number of subjects planned 
250 patients from the ASTRIS (AccesS to TReatment with AZD9291- International Study) 
China study during screening will be recruited and 9 hospitals are planned to participate in this 
testing platforms comparison study. 
 
Total planned Study period 
 
Estimated CSP approved 
Q3 2016 
Estimated date of first patient in 
Q4 2016 
Estimated date of last patient in 
Q3 2017 
Estimated date of last patient last visit 
Q1 2019 
Estimated date of data base lock 
Q2 2019 
Estimated date of CSR 
Q3 2019 
Study design 
This is an open-label, multi-center testing and treatment study in 250 locally advanced or 
metastatic Non-Small Cell Lung Cancer (NSCLC) patients with documented epidermal 
growth factor receptor (EGFR) sensitive mutation and progression (PD) on previous EGFR-
TKI. T790M mutation in plasma ctDNA will be tested by four methods including Roche 
Cobas, Super-ARMS, digital PCR and NGS in order to compare the detection methodology 
and clinical outcomes of T790M mutation positive (by any one of the four platforms) patients 
who receive AZD9291 monotherapy in ASTRIS study will be evaluated and combined with 
the testing results. 
Objectives 


Clinical Study Protocol Synopsis 
Drug Substance AZD9291  
Study Code D5160C00042 
Version 3.0 
Date 25 Aug 2017 
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Primary Objectives: 
Outcome Measure: 
To evaluate concordance of T790M mutation plasma testing 
between the Cobas test and each of other platforms: Super-ARMS, 
digital PCR or NGS.  
Concordance 
To assess the efficacy of AZD9291 monotherapy by assessment of 
PFS in adult patients with advanced or metastatic NSCLC, who 
have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy 
and are T790M mutation positive detected by any one of the four 
plasma testing platforms: Cobas/Super-ARMS/ digital PCR/NGS. 
Progression-free survival  
(PFS) using investigator 
assessments according to 
Response Evaluation 
Criteria in Solid Tumors 
version 1.1 (RECIST v1.1)  
Secondary Objective: 
Outcome Measure : 
To evaluate the sensitivity, specificity, positive predictive value 
(PPV), negative predictive value (NPV) of Super-ARMS/digital 
PCR/NGS by using Cobas as the reference. 
Testing sensitivity, 
specificity, PPV, NPV 
To assess the efficacy of AZD9291 monotherapy by assessment of 
overall response rate (ORR) and overall survival (OS) in adult 
patients with advanced or metastatic NSCLC, who have received 
prior EGFR-TKI therapy and are EGFR T790M mutation positive 
detected by any one of the four plasma testing platforms: 
Cobas/Super-ARMS/ digitial PCR/NGS. 
Overall response rate 
(ORR), overall survival 
(OS) 
Exploratory objectives: 
Outcome Measure: 
To dynamically monitor EGFR mutations by NGS and digital PCR 
in ctDNA of patients receiving AZD9291 treatment. 
Proportion of patients with 
each EGFR mutation 
(C797S and T790M etc.) 
at different time point. 
To explore the mechanisms of acquired resistance in patients who 
received AZD9291 treatment by NGS testing of tissue and/or 
blood samples from the collection at PD versus baseline.  
Changes of distribution 
of resistance related 
genes at PD compared 
with baseline. 
To describe the genomic profile of long-term survivors, especially 
to find out potential genomic prognosis and/or predictive factors 
for AZD9291 long-term efficacy as compared to rapid PD 
patients. 
Key genetic and 
proteomic markers 
including, but not limited 
to, EGFR mutations 
To evaluate concordance, sensitivity, specificity, PPV, NPV of 
EGFR mutation plasma testing by Bio-rad droplet digital PCR 
using other plasma test or tissue test as reference, respectively. 
 
Testing concordance, 
sensitivity, specificity, 
PPV, NPV  
To evaluate the efficacy of patients who receive AZD9291 
monotherapy and are T790M mutation positive detected by each 
of the five platforms, respectively. 
ORR, PFS, OS 


Clinical Study Protocol Synopsis 
Drug Substance AZD9291  
Study Code D5160C00042 
Version 3.0 
Date 25 Aug 2017 
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Target subject population 
250 locally advanced or metastatic EGFR mutation positive NSCLC patients with progression 
on a previous EGFR-TKI will be recruited.  
Investigational product, dosage and mode of administration 
AZD9291 is an oral, potent, selective, irreversible inhibitor of both EGFR-TKI sensitizing and 
resistance mutations in NSCLC with a significant selectivity margin over wild-type EGFR. 
Patient who is positive in plasma T790M mutation test by any one of the four platforms and 
meet the eligibility criteria for treatment will receive AZD9291 monotherapy in ASTRIS 
study. 
AZD9291 will be administered orally as one 80 mg tablet once a day. 
Duration of treatment 
Patients may continue to receive AZD9291 as long as they continue to show clinical benefit, 
as judged by the investigator, and in the absence of discontinuation criteria (see section 3.11). 
The study will be closed in a maximum period of 18 months after the last patient is enrolled. 
Contingencies will be made to ensure continued drug supply for patients who are still deriving 
benefit from AZD9291 at that time. 
Statistical methods 
The concordance of T790M resistance mutation testing between the Cobas test and each of 
other platforms will be calculated. The sensitivity, specificity, PPV and NPV of each testing 
platform (Super-ARMS, digital PCR, and NGS) will be calculated with the Cobas test as the 
reference. The Kappa coefficient will be calculated to measure the agreement of T790M 
mutation testing between the Cobas test and each of other platforms. Descriptive statistics will 
be provided for all variables, as appropriate. Continuous variables will be summarized by the 
number of observations, mean, standard deviation, median, interquartile range (Q1, Q3), 
minimum, and maximum. Categorical variables will be summarized by frequency counts and 
percentages for each category.  The 95% confidence interval (CI) will be calculated as 
appropriate. PFS and OS, respectively, will be summarized using Kaplan-Meier estimates of 
the median time to event (progression and death) and quartiles together with their 95% 
confidence intervals.  
The chi-square test will be used to compare the sensitivity, specificity, and concordance 
between any of the two platforms using Cobas as reference testing in an exploratory manner. 


Clinical Study Protocol 
Drug Substance AZD9291  
Study Code D5160C00042 
Version 3.0 
Date 25 Aug 2017 
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TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ....................................................................................................... 1 
VERSION HISTORY .......................................................................................... 2 
PROTOCOL SYNOPSIS ..................................................................................... 4 
TABLE OF CONTENTS ..................................................................................... 7 
1.1 
Background and rationale for conducting this study ........................................... 14 
1.2 
Rationale for study design and doses .................................................................. 16 
Rationale for doses ............................................................................................................. 17 
1.3 
Benefit/risk and ethical assessment .................................................................... 17 
1.4 
Study Design...................................................................................................... 18 
2. 
STUDY OBJECTIVES ...................................................................................... 19 
2.1 
Primary objective ............................................................................................... 19 
2.2 
Secondary objectives .......................................................................................... 19 
2.3 
Safety objectives ................................................................................................ 19 
2.4 
Exploratory objectives ....................................................................................... 19 
3. 
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ..................... 20 
3.1 
Inclusion criteria for testing period ..................................................................... 20 
3.2 
Exclusion criteria for testing period .................................................................... 20 
3.3 
Inclusion criteria for treatment period................................................................. 21 
3.4 
Exclusion criteria for treatment period ............................................................... 21 
3.5 
Subject enrolment .............................................................................................. 22 
3.6 
Procedures for handling incorrectly enrolled subjects ......................................... 23 
3.7 
Methods for assigning treatment groups ............................................................. 23 
3.8 
Methods for ensuring blinding ........................................................................... 23 
3.9 
Methods for unblinding ...................................................................................... 23 
3.10 
Restrictions ........................................................................................................ 24 
3.11 
Discontinuation of investigational product ......................................................... 25 
3.11.1 
Procedures for discontinuation of a subject from investigational product ............ 25 
3.12 
Criteria for withdrawal ....................................................................................... 25 


Clinical Study Protocol 
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Study Code D5160C00042 
Version 3.0 
Date 25 Aug 2017 
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3.13 
Discontinuation of the study ............................................................................... 26 
4. 
STUDY PLAN AND TIMING OF PROCEDURES........................................... 27 
4.1 
Enrolment/screening period................................................................................ 31 
4.1.1 
Data collections.................................................................................................. 31 
4.1.2 
Sample collection ............................................................................................... 31 
4.1.3 
Mutation testing & Data management ................................................................ 32 
4.2 
Treatment period ................................................................................................ 33 
4.3 
Follow-up period................................................................................................ 33 
5. 
STUDY ASSESSMENTS .................................................................................. 34 
5.1 
Efficacy assessments .......................................................................................... 35 
5.2 
Safety assessments ............................................................................................. 36 
5.3 
Other assessments .............................................................................................. 36 
5.4 
Pharmacokinetics ............................................................................................... 36 
5.5 
Pharmacodynamics ............................................................................................ 36 
5.6 
Pharmacogenetics .............................................................................................. 36 
5.7 
Biomarker analysis ............................................................................................. 36 
5.7.1 
Storage, re-use and destruction of biological samples ......................................... 36 
5.7.2 
Labelling and shipment of biological samples .................................................... 36 
5.7.3 
Chain of custody of biological samples .............................................................. 36 
5.7.4 
Withdrawal of Informed Consent ....................................................................... 37 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT ............................. 37 
6.1 
Definition of adverse events ............................................................................... 37 
6.2 
Definitions of serious adverse event ................................................................... 38 
6.2.1 
Handling of deaths ............................................................................................. 38 
6.2.2 
Hy’s Law ........................................................................................................... 39 
6.3 
SAEs related to study procedures or conduct of a study ...................................... 39 
6.4 
Recording of adverse events ............................................................................... 39 
6.4.1 
Time period for collection of adverse events ...................................................... 39 
6.4.2 
Follow-up of unresolved adverse events ............................................................. 39 
6.4.3 
Adverse events after the 30 day follow-up period ............................................... 39 
6.4.4 
Causality collection ............................................................................................ 40 
6.5 
Reporting of serious adverse events ................................................................... 40 
6.6 
Management of toxicities related to AZD9291 ................................................... 40 
6.6.1 
Pulmonary Symptoms ........................................................................................ 41 
6.6.2 
QTc Prolongation (using Fredericia’s formula –QTcF–) ..................................... 41 
6.6.3 
Corneal Ulceration ............................................................................................. 42 
6.6.4 
Skin reactions .................................................................................................... 42 


Clinical Study Protocol 
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Study Code D5160C00042 
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6.6.5 
Diarrhoea ........................................................................................................... 42 
6.7 
Study governance and oversight ......................................................................... 42 
6.7.1 
Steering Committee............................................................................................ 42 
6.7.2 
Data Monitoring Committee ............................................................................... 42 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 42 
7.1 
Identity and dose of investigational product– AZD9291 ..................................... 42 
7.2 
Labelling ............................................................................................................ 43 
7.3 
Storage ............................................................................................................... 44 
7.4 
Compliance ........................................................................................................ 44 
7.5 
Accountability.................................................................................................... 44 
7.6 
Concomitant and other treatments ...................................................................... 44 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA .......................................... 44 
8.1 
Statistical considerations .................................................................................... 44 
8.2 
Sample size estimate .......................................................................................... 44 
8.3 
Definitions of analysis sets ................................................................................. 45 
8.4 
Outcome measures for analyses .......................................................................... 45 
8.5 
Methods for statistical analyses .......................................................................... 46 
8.5.1 
Analysis of the primary variable (s) .................................................................... 47 
8.5.2 
Analysis of the secondary variable(s) ................................................................. 47 
8.5.3 
Exploratory analysis ........................................................................................... 48 
8.5.4 
Analysis timing .................................................................................................. 48 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ......................... 49 
9.1 
Training of study site personnel ......................................................................... 49 
9.2 
Monitoring of the study ...................................................................................... 49 
9.2.1 
Source data ........................................................................................................ 50 
9.2.2 
Study agreements ............................................................................................... 50 
9.2.3 
Archiving of study documents ............................................................................ 50 
9.3 
Study timetable and end of study ........................................................................ 50 
9.4 
Data management by AstraZeneca or delegate ................................................... 50 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ....................................... 51 
10.1 
Ethical conduct of the study ............................................................................... 51 
10.2 
Subject data protection ....................................................................................... 51 
10.3 
Ethics and regulatory review .............................................................................. 51 
10.4 
Informed consent ............................................................................................... 52 
10.5 
Changes to the protocol and informed consent form ........................................... 52 


Clinical Study Protocol 
Drug Substance AZD9291  
Study Code D5160C00042 
Version 3.0 
Date 25 Aug 2017 
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10.6 
Audits and inspections ....................................................................................... 53 
11. 
LIST OF REFERENCES ................................................................................... 53 
 
LIST OF TABLES 
Table 1 
Study Plan ............................................................................................. 28 
Table 2 
Testing Plan .......................................................................................... 30 
Table 3 
Dose Interventions ................................................................................ 41 
 
LIST OF FIGURES 
Figure 1 
Study flow chart .................................................................................... 18 
Figure 2 
Study plan ............................................................................................. 27 
 
LIST OF APPENDICES 
Appendix A 
Additional Safety Information 
Appendix B 
RECIST Version 1.1 
Appendix C 
Guidance Regarding Potential Interactions with Concomitant Medications 
Appendix D 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law 
  


Clinical Study Protocol 
Drug Substance AZD9291  
Study Code D5160C00042 
Version 3.0 
Date 25 Aug 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 
ASTRIS 
AccesS to TReatment with AZD9291- International Study  
AE 
Adverse Event 
ADR 
Adverse Drug Reaction 
ALK  
Anaplastic lymphoma kinase 
ALT  
Alanine aminotransferase 
ARMS 
Amplification Refractory Mutation System 
AZ 
AstraZeneca 
aNSCLC 
advanced Non-small Cell Lung Cancer 
BCRP 
Breast Cancer Resistance Protein 
CI 
Confidence Interval 
CRF 
Case Report Form (electronic/paper) 
CRO 
Clinical Research Organisation 
CSA 
Clinical Study Agreement 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CT 
Computer tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
ctDNA 
Circulating Tumor DNA 
cfDNA 
Cell Free DNA 
CYP 
Cytochrome P450 
Digital PCR 
Droplet Digital Polymerase Chain Reaction 
DLT 
Dose limiting toxicity 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of Response 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
ECG  
Electrocardiogram 
eCRF 
Electronic case report form 


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Version 3.0 
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Abbreviation or 
special term 
Explanation 
EDC 
Electronic Data Capture 
EGFR 
Epidermal Growth Factor Receptor  
EGFRm+  
Epidermal Growth Factor Receptor mutation positive 
EGFR-TKI 
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor 
FFPE 
Formalin-Fixed, Paraffin-Embedded 
FAS 
Full Analysis Set 
FDA  
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP  
Good Manufacturing Practice 
IB  
Investigator’s Brochure 
ILD  
Interstitial lung disease 
ICH 
International Conference on Harmonisation 
IP 
Investigational Product 
IRB 
Independent Review Board 
IUS 
Intra uterine System 
IVRS  
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LSLV 
Last Subject Last Visit 
NGS 
Next Generation Sequence 
NPV 
Negative predictive value 
NSCLC 
Non-small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progression of disease 
PPV 
Positive predictive value 
PFS 
 Progression Free Survival 
PK  
Pharmacokinetics 
qPCR 
Quantitative Polymerase Chain Reaction 
QT 
Interval on the electrocardiogram representing the duration of 
depolarization and repolarization of the heart 
QTc 
The QT interval corrected for heart rate 
RECIST v1.1  
Response Evaluation Criteria in Solid Tumors version 1.1 


Clinical Study Protocol 
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Version 3.0 
Date 25 Aug 2017 
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Abbreviation or 
special term 
Explanation 
SAE  
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
T790M 
An amino acid substitution at position 790 in EGFR, from a Threonine (T)  
to a Methionine (M) 
TKI  
Tyrosine kinase inhibitor 
ULN  
Upper limit of normal 
Variable 
A characteristic of a property of a subject that may vary e.g., from time to 
time or between subjects 
WHO  
World Health Organization 


Clinical Study Protocol 
Drug Substance AZD9291  
Study Code D5160C00042 
Version 3.0 
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INTRODUCTION 
1.1 
Background and rationale for conducting this study 
Somatic mutations in EGFR are detected approximately 30 to 40% of NSCLCs from Asian 
patients (Lynch et al., 2004; Paez et al., 2004; Shigematsu et al., 2005). EGFR-TKI has 
opened a new paradigm for the treatment of advanced NSCLC (aNSCLC). Several studies 
have shown that EGFR-TKI significantly improves PFS (Progression-Free Survival) and ORR 
(Objective response rate) compared with platinum-doublets in the first line treatment for 
aNSCLC harbouring activating EGFR mutations (Maemondo et al., 2010; Rosell et al., 2012; 
Sequist et al., 2013). 
However, patients ultimately develop acquired resistance to these agents with progression of 
disease after approximately 9 to 13 months (Engelman and Janne, 2008; Mok et al., 2009; Pao 
et al., 2005; Rosell et al., 2012). In approximately 60% of these patients, the mechanism of 
acquired resistance is the development of an additional EGFR mutation, EGFR T790M(Yu et 
al., 2013). One strategy to overcome this mechanism of resistance is through the use of 
irreversible EGFR inhibitors for second-line treatment (Kobayashi et al., 2005). Osimertinib 
(TAGRISSO, AZD9291) is a highly selective, irreversible 3rd generation of EGFR-TKI that 
targets both EGFR-TKI-sensitizing mutations (e.g., exon 19 deletion and L858R) and the 
T790M resistance mutation (Cross et al., 2014). Oral presentations about AZD9291 from 
AURA studies in 2016 ELCC showed that AZD9291 80 mg QD as first-line treatment for 
EGFR active mutation (mPFS 19.3m) aNSCLC patients and for pre-treated EGFR-TKI 
aNSCLC patients harbouring T790M-positive mutation are safe and effective (mPFS 9.7-
11.0m). In patients with NSCLC, especially who initially respond to EGFR-TKI therapy 
develop resistance, it is now recommended to obtain a biopsy in order to characterize the 
mechanism of resistance. However, in clinical practice, tumour tissue testing, in general, faces 
two challenges: specimens with limited tumour cells and tissue heterogeneity. Obtaining 
sufﬁcient tissue for mutation analysis in patients with advanced disease is challenging, as 
invasive interventions may be ineffective and unsafe. Moreover, detection of disease-relevant 
mutations from the biopsy of a single tumor lesion may not be reﬂective of the patient’s 
complete disease burden, especially in heterogeneous cancers (Fisher et al., 2013; Weber et al., 
2014). Therefore, molecular assays that detect secondary mutations without repeat invasive 
tissue biopsies are needed. 
In recent years, circulating tumor DNA (ctDNA) has emerged as a speciﬁc and sensitive 
blood-based biomarker for detection of EGFR mutations. Several studies have demonstrated 


Clinical Study Protocol 
Drug Substance AZD9291  
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Date 25 Aug 2017 
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that mutations, including the EGFR T790M mutation, detected in plasma ctDNA are highly 
concordant with those detected in tumor tissue in patients (Douillard et al., 2014a; Douillard et 
al., 2014b; Gevensleben et al., 2013; Punnoose et al., 2012). A new study shows that plasma 
EGFR T790M ctDNA status is associated with clinical outcome in aNSCLC patients with 
acquired EGFR-TKI resistance(Zheng et al., 2016), indicating that ctDNA as a liquid biopsy 
is a feasible and minimally invasive alternative to tissue biopsy. In addition, because ctDNA 
analysis does not involve formaldehyde ﬁxation, there is reduced frequency of a false positive 
result due to deamination (Denis et al., 2015). In general, plasma ctDNA testing has the 
potential to rapidly identify NSCLC patients suitable for targeted therapy and availability of 
these simple blood tests may streamline diagnosis, including for patients where tumor samples 
are unavailable. Therefore, sensitive, specific, reliable and fast mutation analysis platforms for 
plasma are needed in diagnosis of EGFR T790M for AZD9291 clinical development program 
including testing the acquired C797S mutation upon treatment with AZD9291 (Song et al., 
2016).  
There are several methodologies available for mutation analysis using ctDNA. However, since 
ctDNA often represents a small fraction (<1.0%) of total cfDNA (cell-free DNA), its detection 
remains challenging (Diaz and Bardelli, 2014) and the sensitivity is still an issue in various 
platforms. Direct sequencing approaches like Sanger sequencing or pyrosequencing are not 
suitable for detecting EGFR mutations using ctDNA on this account. Several different types 
of PCR-based assays have been explored for ctDNA genotyping including non-digital 
platforms and digital platforms. Non-digital PCR mainly include Roche Cobas and 
amplification-refractory mutation system (ARMS). Roche Cobas ® EGFR Mutation Test is 
the approved companion diagnostic for AZD9291. ARMS, also known as allele-specific 
polymerase chain reaction (ASPCR), is a reliable method for detecting single base mutations 
or small deletions which is based on the use of sequence-specific PCR primers (Newton et al., 
1989). Because Taq DNA polymerase is effective at distinguishing between a match and a 
mismatch at the 3’ end of a primer, specific mutated sequences are selectively amplified. 
Specific ARMS primers have been designed and optimized for detecting various EGFR 
mutations and have been widely used for ctDNA based assays.  
Digital platform mainly refers to digital polymerase chain reaction (digital PCR), which is a 
refinement of conventional PCR that can be used to directly quantify and clonally amplify 
nucleic acids (Pohl and Shih, 2004; Vogelstein and Kinzler, 1999). Digital PCR is widely used 
for many clinical applications in China due to its unparalleled sensitivity and precision. It is to 
amplify a single DNA template from minimally diluted samples and generate amplicons that 
are exclusively derived from one template. These amplicons can be detected with different 


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Study Code D5160C00042 
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fluorophores or sequenced to distinguish different alleles. Thus, digital PCR transforms the 
exponential, analog nature of the conventional PCR into a linear, digital signal, suitable for 
statistical analysis. Digital PCR has been applied in quantification of EGFR mutants in 
clinical specimens, especially in dynamic monitoring of patients for the development of 
resistance mutations, providing a promising molecular diagnostic tool (Yung et al., 2009).  
The ability of Cobas, ARMS and digital PCR to detect EGFR mutations, including T790M, 
from ctDNA in aNSCLC was compared using a small number of samples in countries outside 
of China. For the T790M mutation, the digital platforms outperformed the non-digital 
platforms, and the Cobas® EGFR Mutation Test and BEAMing digital PCR demonstrated a 
high sensitivity for T790M (Thress et al., 2015). The feasibility of digital PCR was 
demonstrated in a recent study in monitoring EGFR mutation dynamics in serial plasma 
samples from NSCLC patients receiving TKI therapy and T790M can be detected in plasma 
ctDNA before and after PD as a poor prognostic factor (Zheng et al., 2016).  
In addition, next generation sequencing (NGS) has also been used in EGFR mutation testing 
in ctDNA, although there are also practical challenges to a successful implementation of NGS 
technologies for China clinical applications. In summary, a number of technologies have 
entered the market of T790M detection, with several types of equipment based on different 
molecular biological principles.  
To date, the Cobas® EGFR Mutation Test will be used to test the T790M resistance mutation 
in EGFR-TKI resistant patients in China for ASTRIS patient recruitment . Meanwhile 
alternative strategies are also being evaluated, namely EGFR mutation testing using plasma 
ctDNA. To this end, a comparison of multiple platforms for the detection of EGFR mutations 
in plasma ctDNA to identify technology that is more appropriate for use during AZD9291 
clinical development is needed.  
 
1.2 
Rationale for study design and doses  
Accurate identification of NSCLC patients carrying key molecular mutations is essential for 
delivering AZD9291 targeted therapies to those most likely to benefit. Detection of plasma 
ctDNA in a simple blood test offers a minimally invasive alternative to tumor tissue biopsy, 
and is already available for identifying patients suitable for treatment with Iressa. As reported 
in a recent study, the clinical response rate (ORR) and median PFS of AZD9291 monotherapy 
were similar in patients with T790M-positive plasma (ORR, 63%; PFS, 9.7 months) or 
T790M-positive tumor (ORR, 62%; PFS, 9.7 months) results (Oxnard et al., 2016). Because 


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different technology platforms data for T790M detection in blood is insufficient in China, we 
will compare the Chinese current available methods including Roche Cobas, Super-ARMS 
( ARMS used in blood test, provided by Amoy Diagnostics Co., Ltd.), digital PCR(Thermo 
Fisher QuantStudio3D digital PCR provided by Novogene Bioinformatics Technology Co. 
LTD) and Illumina NGS (provided by Guangzhou Burning Rock Medical Examination 
Institute Co., Ltd.) to obtain descriptive information of each platform and clinically validate 
the usage of these platforms in companion diagnostic for AZD9291. We hope to deliver the 
right treatment to the right patient based on scientific research, with updates from this 
pioneering plasma ctDNA trial. 
In addition, the potential to accurately quantify EGFR mutations in plasma from NSCLC 
patients would enable more rapid and more frequent analyses to assess disease status; however, 
the utility of such analyses for clinical purposes has only recently started to explore in China. 
In this study, we will try to use digital PCR and NGS to monitor EGFR mutations (C797S, 
reported acquired resistance to the 3rd generation of EGFR-TKIs, and T790M etc.) dynamics 
in serial plasma samples from NSCLC patients during AZD9291 treatment and get data about 
clinical response with relevant implications for patient management. We will also explore the 
acquired resistance to the 3rd generation of EGFR-TKIs by NGS testing of tissue samples 
from the collection at PD to compare with baseline and to investigate biomarker 
characteristics of long-term survival patients under AZD9291 treatment. 
Rationale for doses  
The selected AZD9291 starting dose of 80 mg is the recommended phase II dose , and the 
same dose of 80 mg AZD9291 is used in the phase III registration study. This is not the 
maximum tolerated dose (MTD) as AZD9291 was administered up to 240 mg daily with no 
dose-limiting toxicity (DLT) observed. 
1.3 
Benefit/risk and ethical assessment 
In this study, a minimally invasive alternative to tissue sample in diagnosis of T790M 
mutation will be used, namely plasma ctDNA will be tested by four methods (Roche Cobas, 
Super-ARMS, digital PCR and NGS), and patients with positive T790M mutation confirmed 
by any one of the platforms will receive AZD9291 treatment in ASTRIS studyif meet the 
eligibility criteria for treatment. Roche Cobas plasma test has already been approved as 
companion diagnostic for AZD9291, although the other three testing methods in plasma has 
not been approved yet. The key efficacy and safety findings from the clinical programme of 
AZD9291 are summarised below: 
x Patients with tumors harboring the T790M appeared to have improved responses 
(ORRs in these patients ranged from 66% to 71%) compared with responses in patients 
with tumors without the presence of T790M. The median duration of response 


Clinical Study Protocol 
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Date 25 Aug 2017 
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calculated as 9.6~12.5 months and the median PFS was 9.7~11.0 months for the 80 mg 
dose in patients with tumors harboring the T790M. (data cut-off date January 2016, 
2016ELCC).  
x The clinical response rate (ORR) and median PFS were similar in patients with 
T790M-positive plasma (ORR, 63%; PFS, 9.7 months) or T790M-positive tumor 
(ORR, 62%; PFS, 9.7 months) results(Oxnard et al., 2016). 
x The most commonly reported adverse events (AEs) were rash, diarrhoea, paronychia 
and dry skin.  The most common SAEs by System Organ Class (SOC) were 
respiratory, thoracic and mediastinal disorders, gastrointestinal disorders, metabolism 
and nutrition disorders, and blood and lymphatic system disorders.  
Given the clinical activity noted to date with AZD9291, the acceptable safety profile 
demonstrated thus far, and the inclusion/exclusion criteria of treatment period stipulated in 
this study protocol, it is reasonable and appropriate to make AZD9291 available to patients 
with T790M positive (by plasma testing) NSCLC that no longer responding to previous 
EGFR-TKI.  
1.4 
Study Design  
This is an open-label, multi-center testing and treatment study in 250 locally advanced or 
metastatic NSCLC patients with documented EGFR sensitive mutation and progression on 
previous EGFR-TKI. T790M mutation in plasma ctDNA will be tested by four methods 
including Roche Cobas, Super-ARMS, digital PCR and NGS in order to evaluate the 
concordance of T790M testing in plasma between the Cobas test and each of other platforms 
as one of the primary endpoint.  
Patients who are T790M mutation positive in plasma test by any one of the four platforms and 
meet the eligibility criteria of treatment period will receive AZD9291 treatment in ASTRIS 
study. The other primary endpoint for this study is PFS (defined by RECIST v1.1), as assessed 
by the Investigator. Patients may continue to receive AZD9291 as long as they continue to 
show clinical benefit, as judged by the investigator, and in the absence of discontinuation 
criteria (see section 3.11). The sponsor will be assessing OS and ORR as a secondary endpoint. 
 
 
Figure 1 
Study flow chart  
* 
QuantStudio3D digital PCR will be used. **Patients will be followed for progression and 
survival. 


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2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
Primary Objectives: 
Outcome Measure: 
To evaluate concordance of T790M plasma mutation testing 
between the Cobas test and each of other platforms: Super-
ARMS, digital PCR or NGS.  
Concordance 
To assess the efficacy of AZD9291 monotherapy by assessment 
of PFS in adult patients with advanced or metastatic NSCLC, 
who have received prior EGFR- TKI therapy and are T790M 
mutation positive detected by any one of the four plasma testing 
platforms: Cobas/Super-ARMS/ digital PCR/NGS. 
PFS using investigator 
assessments according to 
RECIST v1.1   
 
2.2 
Secondary objectives 
Secondary Objective: 
Outcome Measure : 
To evaluate the sensitivity, specificity, PPV and NPV of Super-
ARMS/digital PCR/NGS by using Cobas as the reference. 
Testing sensitivity, 
specificity, PPV, NPV  
To assess the efficacy of AZD9291 monotherapy by assessment 
of ORR and OS in adult patients with advanced or metastatic 
NSCLC, who have received prior EGFR-TKI therapy and are 
T790M mutation positive detected by any one of the four 
plasma testing platforms: Cobas/Super-ARMS/ digital 
PCR/NGS. 
ORR, OS  
 
2.3 
Safety objectives 
N/A 
2.4 
Exploratory objectives   
Exploratory objectives: 
Outcome Measure : 
To dynamically monitor EGFR mutations by NGS and digital 
PCR in ctDNA of patients receiving AZD9291 treatment.  
Proportion of patients with 
each EGFR mutation (C797S 
and T790M etc.) at different 
time point. 
To explore the mechanisms of acquired resistance in patients 
who received AZD9291 treatment by NGS testing of tissue 
and/or blood samples from the collection at PD versus baseline.  
Changes of distribution of 
resistance related genes at 
PD compared with baseline. 


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To describe the genomic profile of long-term survivors, 
especially to find out potential genomic prognosis and/or 
predictive factors for AZD9291 long-term efficacy as compared 
to rapid PD patients. 
Key genetic and proteomic 
markers including, but not 
limited to, EGFR mutations 
To evaluate concordance, sensitivity, specificity, PPV, NPV of 
EGFR mutation plasma testing by Bio-rad droplet digital PCR 
using other plasma test or tissue test as reference, respectively. 
Testing concordance, 
sensitivity, specificity, PPV, 
NPV  
To evaluate the efficacy of patients who receive AZD9291 
monotherapy and are T790M mutation positive detected by 
each of the five platforms, respectively. 
ORR, PFS, OS 
 
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 testing period 
For inclusion in the study subjects should fulfil the following criteria: 
1. 
Provision of informed consent prior to any study specific procedures.  
2. 
Adults (according to China regulations for age of majority) 
3. 
Histological or cytological confirmed locally advanced NSCLC (stage IIIB) or 
metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy. 
4. 
Patients who have progressed following prior therapy with an EGFR-TKI agent. 
 
3.2 
Exclusion criteria for testing period 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Patients who disagree to participate this study. 
2. 
Patients whose medical objection was recorded to use the existing data from 
medical practice for scientific research. 


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Study Code D5160C00042 
Version 3.0 
Date 25 Aug 2017 
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3.3 
Inclusion criteria for treatment period 
The study subjects must fulfil the following criteria for entry to treatment period: 
1. Documented EGFR mutation positive (at any time since the initial diagnosis of NSCLC) known to 
be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q).  
2. Confirmed T790M mutation positive in plasma by any one of the four platforms (Cobas, Super-
ARMS, digital PCR and NGS)  
3. World Health Organization (WHO) performance status 0-2. 
4. Adequate bone marrow reserve and organ function as demonstrated by complete blood 
count, biochemistry in blood and urine at baseline. 
5. ECG recording at baseline showing absence of any cardiac abnormality as per exclusion 
criterion #6. 
6. 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: 
a. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 
months following cessation of all exogenous hormonal treatments 
b. Women under 50 years would be consider post-menopausal if they have been amenorrheic 
for 12 months or more following cessation of exogenous hormonal treatments and with 
luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range 
for the institution 
c. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation 
7. Male patients must be willing to use barrier contraception. (see Restrictions, Section 3.10) 
8. 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 ≥10 mm in the longest 
diameter (except lymph nodes which must have a short axis of ≥15 mm) with 
computerized tomography (CT), and which is suitable for accurate repeated measurements. 
 
 
3.4 
Exclusion criteria for treatment period 
Patients will not entry to treatment period in this study if any of the following exclusion 
criteria are met: 
1. Previous (within 6 months) or current treatment with AZD9291. 


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2. Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first 
dose of AZD9291) any treatment known to be potent inhibitors or inducers of cytochrome 
P450 (CYP) 3A4 (Appendix C)  
3. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled 
hypertension, active bleeding diatheses, active infection including hepatitis B, hepatitis C 
and human immunodeficiency virus, or significantly impaired bone marrow reserve or 
organ function, including hepatic and renal impairment, which in the investigator’s opinion 
would significantly alter the risk/benefit balance. 
4. Patient with symptomatic central nervous system (CNS) metastases who is neurologically 
unstable or has required increasing doses of steroids to manage CNS symptoms within the 
2 weeks prior to start AZD9291 administration 
5. Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid 
treatment, or any evidence of clinically active ILD 
6. Any of the following cardiac criteria: 
a. Mean resting corrected QT interval (QTcF) > 470 ms  using Fredericia’s formula : 
 
b. Any clinically important abnormalities in rhythm, conduction or morphology of resting 
ECG (e.g., complete left bundle branch block, third degree heart block, second degree 
heart block) 
c. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
7. Any unresolved toxicity from prior therapy CTCAE > grade 3 at the time of starting 
treatment  
8. History of hypersensitivity to excipients of AZD9291 or to drugs with a similar chemical 
structure or class to AZD9291 
9. Women who are breast-feeding 
Procedures for withdrawal of incorrectly enrolled subjects see Section 3.6. 
3.5 
Subject enrolment  
Investigator(s) should keep a record, the subject screening log, of subjects who entered pre-
study screening. 


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The Investigator(s) will: 
1. 
Obtain signed informed consent from the potential subject or their guardian/legal 
representative before any study specific procedures are performed. 
2. 
Each patient will use a unique identifier assigned through the Interactive Voice 
Response System (IVRS)/ Interactive Web Response System (IWRS) of ASTRIS 
study in the following format SCCNN3XX: CC being the country code, NN being 
the centre number and 3XX being the subject enrolment code at the centre into the 
study.  
3. 
Determine subject eligibility. See Section 3.1&3.2. 
4. 
Collect blood samples from patients enrolled in this study. Tumor tissue is also 
recommended to be collected optionally (or cytological samples, pleural fluid etc., 
if tissue is not available) per the judgement of treating physician. 
3.6 
Procedures for handling incorrectly enrolled subjects 
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule.  Subjects who 
are enrolled, but subsequently found not to meet all the eligibility criteria for treatment period 
must not be initiated on treatment, and must be withdrawn from the study. 
Where a subject does not meet all the eligibility criteria but incorrectly started on treatment, 
the Investigator should inform the AstraZeneca study physician immediately, and a discussion 
should occur between the AstraZeneca study physician and the investigator regarding whether 
to continue or discontinue the patient from treatment.  The AstraZeneca study physician must 
ensure all decisions are appropriately documented. 
3.7 
Methods for assigning treatment groups 
Patient who is positive in plasma T790M mutation test by any one of the four platforms and 
meet the eligibility criteria (see section 3.3 & 3.4) for treatment period  will receive AZD9291 
treatment and be followed. If Subject negative for T790M mutation in plasma by all four 
platforms is T790M positive in tissue and then receives AZD9291 monotherapy, the subject 
will have RECISTv1.1 assessment every 6 weeks (provided with free CT scan) and be 
followed for OS and data will be collected. Patient negative for T790M mutation both in 
plasma by all four platforms and in tissue will not be followed in this study.  
3.8 
Methods for ensuring blinding 
Not applicable. 
3.9 
Methods for unblinding  
Not applicable. 


Clinical Study Protocol 
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Study Code D5160C00042 
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3.10 
Restrictions 
The following restrictions apply while the patient is receiving AZD9291 and for the specified 
times before and after: 
1. Female 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 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.  
2. Male patients should be asked to use barrier contraceptives (i.e., by use of condoms) during 
sex with all partners during the trial and for a washout period of 4 months. Patients should 
avoid procreation for 6 months after completion of trial treatment. Patients should refrain 
from donating sperm from the start of dosing until 6 months after discontinuing study 
treatment. If male patients wish to father children they should be advised to arrange for 
freezing of sperm samples prior to the start of study treatment. 
3. If medically feasible, patients taking regular medication, with the exception of potent 
inhibitors or inducers of CYP3A4 (see Appendix C to), should be maintained on it 
throughout the study period (30 days post-last dose).  Patients taking concomitant 
medications whose disposition is dependent upon CYP3A4 and breast cancer resistance 
protein and which have a narrow therapeutic index should be closely monitored for signs 
of changed tolerability as a result of increased exposure of the concomitant medication 
whilst receiving AZD9291.  Patients taking concomitant medications whose disposition is 
dependent upon CYP3A4, CYP1A2, CYP2C or p-glycoprotein and which have a narrow 
therapeutic index should be closely monitored for reduction in therapeutic activity as a 
result of the reduced exposure of the concomitant medication while receiving AZD9291.  
Guidance on medications to avoid, medications that require close monitoring and on 
washout periods is provided (see Appendix C). 
Up to 3-fold increase in exposure may occur in statin exposure when coadministered with 
AZD9291.  It is recommended that the starting and maintenance dose of statins should be 
as low as possible and should be guided by the statin prescribing information.  
Patients taking warfarin should be monitored regularly for changes in prothrombin time or 
international normalized ratio. 
4. Patients who wear contact lenses must discontinue wearing their lenses if they have any 
mild to moderate eye symptoms (CTCAE grade ≤2) while receiving treatment with 
AZD9291 until at least one week after symptoms have resolved.  If a patient has a 
recurrence of eye symptoms or experiences any severe (CTCAE grade ≥3) ocular events, 
they must discontinue wearing their contact lenses until at least one week after treatment 
with AZD9291 is permanently discontinued.  Patients must not use any eye drops or 
ointment for treatment of eye symptoms, unless agreed to by a study doctor, at any time 


Clinical Study Protocol 
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during the study until 1 week after AZD9291 has been permanently discontinued.  
Patients must consult their investigator promptly if they have any concerns.  
3.11 
Discontinuation of investigational product 
Subjects may be discontinued from AZD9291 treatment in the following situations: 
x The investigator thinks that it is in the patient’s best interest to stop therapy 
x Patient decision: the patient is at any time free to discontinue treatment, without 
prejudice to further treatment. 
x Confirmed diagnosis of ILD  
x Ulcerative ocular events  
x Other manifestation of unacceptable toxicity 
x Pregnancy 
x Patient incorrectly enrolled or treated on the study 
x Patient starts receiving additional anti-cancer therapy 
x Lost to follow up (unsuccessful contact with patient despite every effort made by 
investigator) 
x Termination of the study (see Sections 3.13 & 10.2.4) 
 
The patient or representative (e.g. caregiver, family member) must return all unused 
investigational product (IP). 
 
3.11.1 
Procedures for discontinuation of a subject from investigational product  
All reasons for discontinuation of treatment must be documented. Any subject who 
discontinues study treatment for reasons other than objective disease progression should have 
tumour assessments performed as scheduled in the protocol (serial plasma collection not 
required) until disease progression is documented or death occurs, unless consent is 
withdrawn.  
If a subject is withdrawn from study, see Section 3.12. 
3.12 
Criteria for withdrawal  
Patients are free to discontinue AZD9291 treatment or withdraw from the study without 
prejudice to further treatment.  
Reasons for withdrawal from the study: 
x Eligibility criteria not fulfilled 
x Death 
x Lost to follow up 
x Withdrawal of consent. 


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If a subject wishes to withdraw their consent to this study, it must be clear if the subject agrees 
to store their samples or destroy the remaining specimen (see section 5.7 for detail information 
on biological sample handling). 
 
If a subject wishes to withdraw their consent to both treatment and study assessments, they 
should be asked if they are willing to continue with survival follow-up (which can be 
conducted by telephone). If a subject wishes to withdraw their consent to further participation 
in the study entirely, including survival follow-up, this should be clearly documented in the 
subject notes and in the CRF.  
 
The status of ongoing, withdrawn (from the study) and “lost to follow-up” subjects at the time 
of an overall survival analysis should be obtained by the site personnel by checking the 
subjects notes, hospital records, contacting the subjects general practitioner and checking 
publicly available death registries. In the event that the subject has actively withdrawn consent 
to the processing of their personal data, the vital status of the subject can be obtained by site 
personnel from publicly available resources where it is possible to do so under applicable 
local laws. 
The withdrawal reasons must be documented and SAEs reported appropriately in the CRF.  If 
the patient agrees, the investigator must follow the patient for safety reasons until 30 days 
post-last dose, and then for survival status (and also for progression status if the subject had 
not progressed).  If patient declines, the investigator will separately follow up and manage any 
SAEs as a matter of clinical practice.  The patient or representative will return unused 
AZD9291 tablets.   
 
3.13 
Discontinuation 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: 
x 
meet individual stopping criteria  or are otherwise considered significant  
x 
are assessed as causally related to study drug,  
x 
are not considered to be consistent with continuation of the study 
Patients withdrawing from the treatment prior to study closure will be followed up as part of 
this 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 CRF.  
In terminating the study, AstraZeneca will ensure that adequate consideration is given to the 
protection of the subjects’ interests.


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4. 
STUDY PLAN AND TIMING OF PROCEDURES  
Figure 2 Study Plan 
 
 
 


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Table 1 
Study Plan 
 
Screening/ 
Enrolment 
visit 
Treatment visit  
Treatment 
Discontinuation 
30 day follow-
up(f) 
Progression  
Follow-up   
Survival visit  
 
-28 days 
 
Day 1 
(every 6 weeks) 
 
 
(every 6 
weeks) 
(every 6 
weeks) 
Windows (days) 
 
 
 
+/- 7 days 
+/- 7 days 
+/- 7 
days 
+/- 7 
days 
+/- 7 
days 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria (for 
testing period) check 
X 
 
 
 
 
 
 
 
Complete enrolment form 
X 
 
 
 
 
 
 
 
Patient demographics  
X 
 
 
 
 
 
 
 
Smoking history 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Disease characteristics 
X 
 
 
 
 
 
 
 
Cancer treatment history 
X 
 
 
 
 
 
 
 
Collect tumor tissue samples or 
or cytological samples like 
pleural fluid. (a) 
X 
 
 
If radiographic 
progression observed, 
collect tissue 
 
 
 
 
Collect blood sample 
X 
 
 
X(b) 
 
 
 
 
EGFR T790M status confirm 
X 
 
 
 
 
 
 
 
WHO Performance status 
X 
X 
 
X 
X 
 
 
 
Inclusion/Exclusion criteria (for 
treatment period) check 
 
X 
 
 
 
 
 
 
Plasma AZD9291 testing(c) 
 
X 
 
 
 
 
 
 
Concomitant medications 
 
X 
X 
X 
X 
 
 
 
Complete blood count 
 
X 
 
If clinically indicated or per 
institutional standard of 
care 
If clinically indicated 
or per institutional 
standard of care 
 
 
 
Biochemistry in blood and urine 
 
X 
 
If clinically indicated or per 
institutional standard of 
care 
If clinically indicated 
or per institutional 
standard of care 
 
 
 
Pregnancy test(d) 
 
X  
 
 
 
 
 
 


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Screening/ 
Enrolment 
visit 
Treatment visit  
Treatment 
Discontinuation 
30 day follow-
up(f) 
Progression  
Follow-up   
Survival visit  
Physical examination 
 
X 
 
 
X 
 
 
 
Weight 
 
X 
 
X 
X 
 
 
 
ECG recording 
 
X 
 
If clinically indicated or per 
institutional standard of 
care 
If clinically indicated 
or per institutional 
standard of care 
 
 
 
Visual test (slit-lamp) 
 
X 
 
If clinically indicated or per 
institutional standard of 
care 
If clinically indicated 
or per institutional 
standard of care 
 
 
 
Dispense  AZD9291 
(IVRS/IWRS) 
 
 
X 
AZD929
1 start-
dose 
X 
AZD9291 re-supply 
 
 
 
 
AZD9291 dosing (daily):  
- current dose; dose 
adjustment; 
interruption/discontinuation 
reason for change 
 
 
 
X 
 
 
 
 
Drug accountability 
 
 
 
X 
 
 
 
 
Tumor assessment (RECIST 
v1.1) 
 
X 
 
X 
X(e) 
 
X(e) 
 
AE/SAE report(f) 
 
X 
X 
X 
X 
X 
X 
 
Reason for withdrawal 
 
 
 
 
X 
 
 
 
Survival status 
 
 
 
 
 
 
 
X 
(a) Samples will be collected at enrolment visit and at disease progression, then tested by NGS retrospectively in patients who received AZD9291 
treatment to explore the resistance mechanisms. 
(b)  For dynamic monitoring, the peripheral blood will be collected every 6 weeks during the AZD9291 treatment, at radiographic progression and at 
1st visit post-PD (if patient continue to receive AZD9291 treatment as judged by the investigator). 
(c)    Before initiating treatment, the pre-dose plasma samples of T790M mutation positive patients will undergo bio-analysis testing for detecting 
AZD9291 for screening purpose according to validated testing procedures.  If AZD9291 are detected in the samples, patient will not receive 
treatment.   
(d)    Pregnancy test (pre-menopausal female patients only) to be performed in accordance with local standards. 
  


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 (e)    Patients who discontinue treatment prior to PD will continue to have efficacy assessment every 6 weeks (serial blood collection not required) until 
objective progression or death occurs, unless consent is withdrawn.  
(f)     All AEs/SAEs has reported in ASTRIS main study should not be reported repeatedly in current study. A 30 day post last dose follow up 
assessment will required if on treatment-assessment was abnormal at treatment discontinuation. 
 
Table 2 
Testing Plan 
 
 
Screening/ 
Enrolment 
period 
Treatment period 
(treatment visit every 6 weeks) 
 
Testing Windows (days) 
-28 days 
 
Day 
1 
First after 
treatment 
(6w) 
Best 
response 
6w before 
radiographic 
progression 
(optional) 
Radiographic 
progression 
 6w after 
radiographic 
progression 
(optional) 
Dynamic monitoring using 
serial plasma samples by NGS 
(168 genes) and digital PCR* 
X 
 
      X 
X 
X 
X 
X 
Tissue or cytological samples 
NGS test (295 genes) 
X 
(recommended 
option) 
 
 
 
 
X 
(recommended 
option) 
 
*Samples collected in other treatment visit will also be tested if necessary for exploratory objective. 
 


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4.1 
Enrolment/screening period 
Procedures will be performed according to the Study Plan.  
At screening, consenting subjects are assessed to ensure that they meet eligibility criteria for 
testing period. Subjects who do not meet these criteria must not be enrolled in the study.  
The investigator will inform the patients about the study, AZD9291, the potential benefits and 
risks, AE reporting, as well as other information collected within the scope of the study.  
Subsequently, the investigator will obtain signed informed consent from the potential patient 
or legally acceptable representative, as appropriate per local regulations.  
All subjects will be required to provide consent to supply tissue and blood samples for entry 
into this study. This consent is included in the main subject informed consent form.  
Each patient will use a unique identifier assigned through the Interactive Voice Response 
System (IVRS)/ Interactive Web Response System (IWRS) of ASTRIS study in the following 
format SCCNN3XX: CC being the country code, NN being the centre number and 3XX being 
the subject enrolment code at the centre into the study.  
4.1.1 
Data collections 
Collected clinical information will include patient demographics (gender, age), Smoking 
history (non-smoker, ex-smoker and current smoker according to the status before AZD9291 
treatment), disease characteristics like clinical TNM staging, medical history, cancer treatment 
history, WHO Performance status, etc. Collected molecular diagnosis information will include 
detection platform, date of sampling & submission & examining report and mutation type, 
etc..  
4.1.2 
Sample collection 
Available plasma and re-biopsy tumor tissue samples (or cytological samples, pleural fluid 
etc., if tissue is not available) will be collected from patients who meet the eligibility criteria 
for testing period. Blood samples should be obtained following progression on a previous 
EGFR-TKI, but prior to dosing with AZD9291.  
The sample requirements for each detection platform and for the plasma AZD9291 testing are 
as follows. Total 27ml blood will be collected at enrollment visit. (details please see the 
laboratory manual).  
 
blood (ml) 
Cobas 
5ml 
Super-ARMS 
8ml 


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QuantStudio3D digital PCR 
4ml 
NGS 
8ml 
Plasma AZD9291 testing 
2ml  
FFPE tumor tissue samples (or cytological samples, pleural fluid etc.) will be collected at 
enrolment visit and at disease progression in sufficient amount (recommended 15 FFPE slices 
(needle biopsy) or 4 FFPE slices (surgical specimen), thickness 5um, tumor cells≥20%; or 
cytological samples like pleural fluid. Detail requirements please see the laboratory manual), 
and be tested by NGS to explore the mechanisms of acquired resistance in patients who 
received AZD9291 treatment.  
Blood for dynamic monitoring of EGFR mutations (T790M, C797S etc.) will be collected at 
each treatment visit (every 6 weeks), at radiographic progression and 6w after radiographic 
progression (if patient continue treatment as judged by investigator). These samples will be 
tested by digital PCR and NGS retrospectively according to the testing plan (Table 2, details 
please see the laboratory manual).  
Remain DNA samples (if any) will be retested by Bio-rad droplet digital PCR platform 
retrospectively for T790M and sensitizing mutations(if enough amount of samples) and data 
will be compared with testing results of other four platforms. For retrospective test on all the 
remain samples, patient who are still on AZD9291 treatment will be informed (or EC approve 
informed consent waiver); for patient who can't get in touch will apply informed consent 
waiver. But the investigator should review the medical record to see if the patient expressed 
any objection to use his/her remain samples for scientific research purpose. If such objection 
was recorded, then this patient’s remain samples should not be used. 
All samples must be well labelled. A case report form (CRF) will be provided to fill in testing 
related data, and necessary information must be recorded in CRF and checked before 
transportation.  
For the details about sample collection, label, record, package and transportation see the 
laboratory manual. 
4.1.3 
Mutation testing & Data management 
Tumor DNA will be isolated from FFPE specimens and ctDNA will be recovered from 
plasma samples. DNA isolated from tissue will be qualified by measuring the A260/280 and 
A260/230. T790M and other mutations in plasma will be tested by different platforms: Cobas, 
Super-ARMS, digital PCR and NGS at enrolment visit. Remain DNA samples (if any) will be 
retested by Bio-rad droplet digital PCR platform retrospectively. Testing results and raw data 
will be transferred from central lab. 


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The following information should be recorded in the CRF and database: Subject’s identity, 
EGFR mutation testing results (including quantitative results, if available), Sample 
information (including source of anatomical location and the date of collection), and etc. 
4.2 
Treatment period 
Patient visits (e.g. physical exam, laboratory tests, etc.) must be performed according to the 
institutional standard of care and investigator’s best medical judgment. AZD9291 re-supply 
must always be preceded by a treatment visit per Table 1.  
Additionally, at each visit: 
Drug accountability must be documented in the case report form (CRF) and 
necessary paper logs. 
Patient needs to be screened for reportable safety events outlined in Section 6. 
Tumour assessments (RECIST v1.1) described in Section 5 needs to be 
documented in the CRF. 
Investigators are required to assess the patient’s performance status and confirm 
that the patient continues to be deriving benefit from AZD9291 at the time of study 
drug re-supply. 
If a patient withdraws from the treatment and/or completely from the study, the 
investigator will record the reason for withdrawal. 
**Please note that if the reason for withdrawal is an event meeting the definition 
of SAE, it must be recorded in both the safety and clinical forms** 
For patients lost to follow-up, every reasonable effort must be made to establish 
the survival status and document this in the CRF. 
As an investigational drug, AZD9291 must be stored appropriately and dispensed from a 
secure storage area (or site pharmacy).  Study sites are required to maintain accountability 
logs for drug receipt, dispensation, destruction and return (as applicable per local regulations).   
AZD9291 may only be used for the specific patient enrolled into the study. 
4.3 
Follow-up period 
Patients must be followed through the designated follow-up period (30 days post last dose of 
AZD9291) to collect SAEs occurring during this period and other required reporting per 
Section 6 and follow-up on any ongoing SAEs.  


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5. 
STUDY ASSESSMENTS 
The Electronic Data Capture (EDC) 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. 
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. 
The sources of information for all study variables collected for this study will be patient 
medical records or charts and patients surveys. All data collected will be entered by the 
investigator into a CRF. All patients receiving AZD9291 treatment will be followed from 
enrolment until completion of the study, discontinuation of AZD9291 administration 
(determined by investigator due to adverse events, toxicities or other relevant reasons), 
discontinuation due to disease progression, or death, whichever occurs earlier. 
Study measures will be collected at baseline and during the follow-up period.  For each 
patient, physicians will be required to provide date of enrolment, and thereafter during the 
follow-up visits, the date and outcome of the more recent disease assessment, and date of 
progression and death (if applicable).  The variables described in the following sections will 
be collected to address the study objectives.  
The study measures that will be assessed among patients participating in this study are listed 
below:  
x Baseline demographic characteristics: patient characteristics including age, 
gender, race (if available or allowed by local regulations) will be collected 
x 
Smoking history non-smoker, ex-smoker and current smoker according to the status 
before AZD9291 treatment 
x T790M and sensitizing mutations results and type of test performed 
x Relevant Medical history: comorbidities and relevant medical history (this 
includes any chronic conditions currently requiring medication) 
x Disease characteristics: tumor histology, stage at diagnosis, current stage, time of 
progression, WHO performance status at study enrollment and subsequent follow-
up visits (“if patient will be followed)  
x Cancer treatment history: first-line therapy type (targeted or non-targeted) and 
agents received, start and end-dates, subsequent-lines type and start and end-date, 
radiation therapy (yes/no), surgery (yes/no) received prior to study enrollment must 
be documented 
 


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For patients that are T790M mutation plasma test positive and receive AZD9291 treatment, 
the following will be measured during follow up:  
x Physical examination: at baseline and at treatment discontinuation 
x Weight: at each visit 
x Visual test: at screening, a slit-lamp examination should be obtained. 
Ophthalmologic exams to be performed as clinically indicated. A 30-day follow-up 
assessment will be required if an on treatment assessment was abnormal at the time 
of discontinuation of study therapy, to confirm reversibility of the abnormality 
x Relevant Concomitant medication: in case of SAE and AEs.  
x AZD9291 dosing: starting dose, dose adjustments, dose interruptions, dose 
discontinuation and reason for any dose change. 
x Tumor assessment (RECIST v1.1): see section 5.1. 
x Progression follow-up: after study medication discontinuation for reasons other 
than disease progression, the patient will continue tumor assessments and the 
physicians will report related data in the CRF at each follow-up visit. 
x 
Survival status: patient survival status (dead, alive, unknown) at each follow-up must 
be documented in the CRF. The time from the date of first dose in the study until death 
will be used to evaluate OS. Lost to follow-up patients will be censored at last 
documented contact with patient status “alive”.  
x Laboratory assessments: laboratory parameters will not be collected. If done, 
they will be assessed by the investigator as normal or abnormal and details about 
abnormality will be entered in the CRF 
     If Subject negative for T790M mutation in plasma by all four platforms is T790M positive in tissue 
and then receives AZD9291 monotherapy, the subject will have RECISTv1.1 assessment every 6 
weeks (provided with free CT scan) and be followed for OS and data will be collected.  
5.1 
 Efficacy assessments 
The imaging modalities used for RECIST v1.1 assessments will be CT scan of the chest and 
abdomen (including liver and adrenal glands, ect.). The methods used at baseline for 
assessment of tumor burden (CT scan) must be used at each subsequent follow-up 
assessments. Any other sites where disease is suspected or known at baseline must also be 
imaged and additional sites of disease, confirmed at baseline not covered by the protocol 
specified anatomy, should be followed at the same scheduled visits as the other RECIST 
assessments.  
For Investigator assessment, RECIST v1.1 criteria will be used to assess each patient's tumor 
response to treatment and allow calculation of PFS and ORR. The RECIST v1.1 guidelines for 
measurable, non-measurable, target and non-target lesions, and the objective tumor response 
criteria (complete response [CR], partial response [PR], stable disease [SD], or progression of 
disease [PD]) are presented in Appendix B. 


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5.2 
Safety assessments 
Not applicable. 
5.3 
Other assessments 
Not applicable. 
5.4 
Pharmacokinetics 
Not applicable. 
5.5 
Pharmacodynamics 
Not applicable. 
5.6 
Pharmacogenetics 
Not applicable. 
5.7 
Biomarker analysis  
The subject’s consent to the use of donated biological samples is mandatory.   
According to the study plan, biological samples (tumour samples and plasma samples) will be 
collected and may be analysed for EGFR mutations (T790M, C797S etc.) and other 
exploratory biomarkers to assess correlations with disease activity, effects of study drug, and 
clinical outcomes. 
5.7.1 
Storage, re-use and destruction of biological samples 
Samples will be stored until the end of the study, after which they will be returned to hospital 
sites as required or 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 study drug to generate hypotheses to be tested in future research that 
agreed by study steering committee. 
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. 
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. 


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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. 
5.7.4 
Withdrawal of Informed Consent  
If a subject withdraws consent, it must be clear if the subject agrees to store their samples or 
destroy the remaining specimen, and the action should be documented. If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research. 
As collection of the biological samples at enrolment visit is an integral part of the study, then 
the subject is withdrawn from further study participation. 
The Principal Investigator: 
x 
Ensures subjects’ withdrawal of informed consent is notified immediately 
to AstraZeneca 
x 
Ensures that biological samples from that subject, if stored at the study 
site, are immediately identified, disposed of /destroyed, and the action 
documented 
x 
Ensures the laboratories 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 
x 
Ensures that the subject and AstraZeneca are informed about the sample 
disposal. 
AstraZeneca ensures the central laboratories 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. 
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, 
whether or not considered causally related to the product.  An undesirable medical condition 


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can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).   
6.2 
Definitions of serious adverse event 
An SAE is an event occurring from the time the patient signs informed consent (as per local 
regulations) through the end of the post-treatment follow-up visit (30 days post-last dose) or 
until disease progression, whichever is the latest, which fulfils one or more of the following 
criteria: 
x Results in death 
x Is immediately life-threatening 
x Requires in-patient hospitalisation or prolongation of existing hospitalisation  
x Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
x Is a congenital abnormality or birth defect 
x Is an important medical event that may jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
For further guidance on the definition of an SAE, see Appendix A to the study protocol. 
6.2.1 
Handling of deaths 
All deaths that occur during the study or within the follow-up period after the administration 
of the last dose of AZD9291 (30 days post-last dose) or until disease progression, whichever 
is the latest, must be reported as follows: 
- 
Death, which is unequivocally due to disease progression, must be reported to the study 
representative and must be documented in the CRF, but must not be reported as an SAE during the 
study. 
- 
Where death is not clearly due to progression of the disease being treated as part of the study, the 
primary and most likely event causing the death must be reported to AstraZeneca’s representative 
as an SAE within 24 hours.  The report must contain a comment regarding the co-involvement of 
progression of disease, if appropriate, and must assign a single primary cause of death together 
with any contributory causes. 
- 
Deaths with an unknown cause must always be reported as an SAE but every effort should be 
made to establish a cause of death.  A post-mortem may be helpful in the assessment of the cause 
of death, and if performed a copy of the post-mortem results must be reported in an expedited 
fashion to an AstraZeneca representative within the usual timeframes. 
 


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6.2.2 
Hy’s Law 
Cases where a subject shows an AST or ALT ≥3xULN or total bilirubin ≥2xULN may need to 
be reported as SAEs.  The investigator is responsible for, without delay, determining whether 
a subject meets potential Hy’s law (PHL) criteria. Details of identification of PHL cases and 
actions to take are detailed in Appendix D. Those SAE will be collected until 30 days post last 
dose of study medication. 
6.3 
SAEs related to study procedures or conduct of a study 
An SAE related to a study procedure is considered as a SAE that has arisen as a direct 
consequence of the subject participating in the study, for any reason other than due to receipt 
of an Investigational Medicinal Products (IMP). 
6.4 
Recording of adverse events 
6.4.1 
Time period for collection of adverse events 
Adverse Events, including Serious Adverse Events, will be collected from time of signature of 
informed consent, throughout the treatment period and up to and including the 30-day follow 
up period*.  All ongoing and any new AEs/SAEs identified during the 30 calendar days 
follow up period after last dose of study medication must be followed to resolution. After any 
interim analysis, any ongoing AEs/SAEs need to be unlocked and followed for resolution.  
*Exception: all AEs/SAEs has reported in ASTRIS main study should not be reported in 
current study. 
6.4.2 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the time of the 30 day follow-up, must be followed up by the 
investigator through to resolution, and whilst the database is open should be recorded on the 
database.  
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
6.4.3 
Adverse events after the 30 day follow-up period 
At any time after a patient has completed the study, if an investigator learns of any SAE 
including death, and he/she considers there is a reasonable possibility that the event is causally 
related to the investigational product, the investigator should notify AstraZeneca, Patient 
Safety.  
If patients who are gaining clinical benefit are allowed to continue study treatment post data 
cut-off and/or post study completion then all SAEs must continue to be collected and reported 
to Patient Safety within the usual timeframe. 
Otherwise after study treatment completion (i.e. after any scheduled post treatment follow-up 
period has ended), there is no obligation to actively report information on new AEs or SAEs 


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occurring in former study patients.  This includes new AEs/SAEs in patients still being 
followed up for survival but who have completed the post treatment follow-up period (30 
days). 
6.4.4 
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’.  
6.5 
Reporting of serious adverse events 
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives immediately, but no later than 24 hours of when 
he or she becomes aware of it. 
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 i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it. 
Contact information of AZ PV China Team: 
Fax: +86 21 38683551;  
E-mail: China.AZDrugSafety@astrazeneca.com;  
Tel: +86 21 52929866Ə+86 21 58385073ƋEmergencyƌ  
 
6.6 
Management of toxicities related to AZD9291 
If a patient experiences a CTCAE grade 3 or higher and/or unacceptable toxicity (any grade), 
where the investigator considers the event of concern to be specifically associated with 
AZD9291 (and not attributable to the disease or disease-related processes for which patient is 
being treated), dosing will be interrupted and supportive therapy administered as required in 
accordance with local practice/guidelines.   
If the toxicity resolves or reverts to CTCAE grade ≤ 2 within 3 weeks of onset, treatment with 
AZD9291 may be restarted at the same dose (80 mg, daily) or a lower dose (40 mg, daily) 
using the rules below for dose modifications(Table 1) as per the investigator’s evaluation 
and/or in discussion and agreement with the study Medical Monitor as needed.  There will be 


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no individual modifications to dosing schedule in response to toxicity, only potential dose 
reduction or dose interruption.  Once a dose reduction is implemented, the dose of AZD9291 
cannot be reverted back to 80 mg. 
If the toxicity does not resolve to CTCAE grade ≤ 2 after 3 weeks, then the patient must be 
withdrawn from the study treatment and kept in observation until resolution of the toxicity. 
Table 3 
Dose Interventions 
Intervention 
AZD9291 Dose 
Starting Dose 
80 mg daily 
Reduced Dose 
40 mg daily 
 
If an event subsequently requires dose interruption, AZD9291 may restart at the same dose or 
the reduced dose, on resolution/improvement of the event at the discretion of the investigator. 
6.6.1 
Pulmonary Symptoms  
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormality 
suggestive of interstitial lung disease are observed, the administration of AZD9291 needs to 
be interrupted and the study Medical Monitor must be informed.  It is strongly recommended 
to perform a full diagnostic workup, to exclude alternative causes such as lymphangitic 
carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage.  The results 
of the full diagnostic workup (including high-resolution computed tomography, blood and 
sputum culture, haematological parameters) will be recorded in the CRF by the investigator.  
Where ILD is suspected, local practice must be followed in discussion with the study Medical 
Monitor.  In the absence of a confirmed diagnosis of ILD, AZD9291 may be restarted 
following consultation with the study Medical Monitor.  In case of a confirmed diagnosis of 
ILD, AZD9291 must be permanently discontinued. (refer to “Guidance for the Management 
of AE in studies using 80mg AZD9291”) 
6.6.2 
QTc Prolongation (using Fredericia’s formula –QTcF–)  
Patients with Grade 3 QTcF with QTcF prolongation (i.e., confirmed QTcF prolongation to > 
500 ms absolute or a > 60 ms increase from baseline) should have AZD9291 interrupted and 
regular ECGs performed until resolution to baseline.  If the QTcF interval resolves to Grade 1 
(<481 msec), AZD9291 may be restarted at the reduced dose of 40 mg.  If the QT 
prolongation does not resolve to ≤CTCAE grade 1 (<481 msec) after 3 weeks, then the patient 
will be permanently withdrawn from AZD9291 and observed until resolution of the toxicity.  
All QTcF prolongation of >470 ms at any point during the study must be reported to 
AstraZeneca, and ECGs sent to the Study Team for further analysis.  This does not alter the 
management guidance outlined above. 


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6.6.3 
Corneal Ulceration  
Following an ocular event, the results of eye investigation must be recorded in the CRF by the 
investigator.  Patients experiencing corneal ulceration will not be permitted to restart 
AZD9291 treatment.  
6.6.4 
Skin reactions  
Recommendations for appropriate management of skin reactions, including guidance on dose-
adjustments for clinically significant and/or intolerable skin reactions that are considered by 
the investigator to be causally related to AZD9291 will be provided to clinicians. 
6.6.5 
Diarrhoea 
Recommendations for appropriate management of diarrhoea, including uncomplicated 
CTCAE grade ≤2, and dose-adjustments for AEs of diarrhoea that are of CTCAE grade ≥3 or 
that are clinically significant and/or intolerable and considered by the investigator to be 
causally related to AZD9291, will be provided to participants in the study.  
For further guidance on skin reactions and diarrhoea, please refer to “Guidance for the 
Management of Adverse Events in Studies using 80 mg AZD9291” 
 
6.7 
Study governance and oversight 
6.7.1 
Steering Committee 
A Steering Committee comprising of the Principal Investigators for this study 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. 
 
6.7.2 
Data Monitoring Committee 
This is an open-label (non-randomised) testing and treatment study in 250 patients from the 
ASTRIS China study screening. Data Monitoring Committee will not be used in this study. 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity and dose of investigational product– AZD9291 
AZD9291 will be supplied as tablets for oral administration as a single daily dose of 80 mg. 
Each bottle will contain sufficient AZD9291 treatment for 21 days, plus overage. 40 mg 
tablets will be supplied as needed upon request to the AstraZeneca representative. 
Investigational product 
Dosage form and strength 
AZD9291 
40 mg Tablets 
 
80 mg Tablets 


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The tablets can be taken with or without food and should be swallowed whole with water. The 
tablet should not be crushed, split or chewed.  
If the patient is unable to swallow the tablet, it may first be dispersed in 50 mL of non-
carbonated water. The tablet should be dropped in the water, without crushing, stirred until 
dispersed and immediately swallowed. An additional half a glass of water should be added to 
ensure that no residue remains and then immediately swallowed. 
If administration via nasogastric tube is required, the same process as above should be 
followed but using volumes of 15 mL for the initial dispersion and 10 mL for the residue 
rinses. The total liquid should be administered as per the nasogastric tube instructions with 
appropriate water flushes. 
The initial dose of AZD9291 80 mg daily can be reduced to 40 mg once daily under 
circumstances described in Section6.7.   
Doses should be taken approximately 24 hours apart at the same time point each day.  Doses 
should not be missed.  If a patient misses taking a scheduled dose, within a window of 
12 hours, it is acceptable to take the dose.  If it is more than 12 hours after the scheduled dose 
time, the missed dose must not be taken, and patients must be instructed to take the next dose 
at the next scheduled time.  If a patient vomits after taking their AZD9291 treatment, they 
must not make up for this dose, but must take the next scheduled dose. 
Any change from dosing schedule, dose interruptions, or dose reductions must be recorded in 
the CRF.   
Tablets will be packed in high-density polyethylene bottles with child-resistant closures.  
Bottles will be dispensed to patients in the packaging provided.  The packaging includes 
bottles, caps and a label. Bottle tampers must not be broken prior to dispensing AZD9291 to a 
patient. 
Additional information about AZD9291 may be found in the IB. 
7.2 
Labelling 
Labels for AZD9291 will be prepared in accordance with Good Manufacturing Practice 
(GMP) and local regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for 
labelling.  Label text will be translated into local language. 
The label will include the following information the Name of the Sponsor, Protocol Code, For 
Clinical Trial use only, and/or any other market specific requirements. 
Patient’s leaflet will be inserted if required per local regulations 


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7.3 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
investigational product label on the bottles specifies the appropriate storage. 
7.4 
Compliance 
The administration of AZD9291 must be documented in the appropriate sections of the CRF.  
Patients must return all unused IP and empty containers to the investigator. 
7.5 
Accountability 
The study drug provided for this study will be used only as directed in the study protocol.The 
study personnel will account for all study drugs dispensed to and returned from the subject. 
The study personnel at the investigational site will account for all treatments dispensed and for 
appropriate return or destruction.  The site is required to maintain documentation of the 
delivery, return and destruction of IP.  AstraZeneca representatives will review and collect this 
documentation.   
7.6 
Concomitant and other treatments  
Concomitant treatments, other than anti-cancer treatments, should be taken according to local 
medical practice.  There are no restrictions on concomitant use in this study except per 
exclusion criteria.  However, it is advised that those medical products and other products 
known to have interactions with AZD9291 should be avoided (see Appendix C). 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA 
8.1 
Statistical considerations 
Analyses will be performed by AstraZeneca or its representatives.     
A comprehensive Statistical Analysis Plan (SAP) will be prepared and finalized before 
database lock.  
In general, descriptive statistics will be provided for the data collected. For continuous 
variables, mean, standard deviation, median, quartiles, minimum and maximum will be 
provided, and for categorical variables, frequency counts and percentages for each category 
will be provided. Data will be examined for skewness, outliers, and systematic missing data. 
Transformations will be undertaken as needed. 
8.2 
Sample size estimate 
Approximately 250 eligible patients from 9 hospitals will be enrolled to this study. Assuming 
the concordance of each platform of Super-ARMS, digital PCR, and NGS with Cobas ranges 


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from 70% to 90%, the precision of estimation (i.e., half-length of 95% confidence interval 
<CI>) will be around 3.7% to 5.7%. 
Platforms  
Possible concordance with Cobas  
Precision of estimation 
(i.e., half length of 95% 
CI)  
Super-ARMS 
70%  
5.7%  
Digital PCR 
80% 
5%  
NGS 
90%  
3.7%  
Assuming that around 40% to 60% (i.e., 100 ~ 150) patients will have T790M resistance 
mutation and receive AZD9291, the median PFS is around 9 to 11 months, and that disease 
progression or death will be observed for 60% of the patients after 12-month follow up of the 
last enrolled patients for the primary analysis of PFS data, the 95% CI of estimation of median 
PFS is illustrated in the table below: 
 
 
95% CI of median PFS* 
No. 
patients 
No. 
events 
Median PFS: 9 
months 
Median PFS: 
10 months 
Median PFS: 11 
months 
100 
60 
7.0 – 11.6 
7.8 – 12.9 
8.5 – 14.2 
125 
75 
7.2 – 11.3 
8.0 – 12.5 
8.8 – 13.8 
150 
90 
7.3 – 11.1 
8.1 – 12.3 
8.9 – 13.5 
*Based on the formula in Collett 1994 (D. Collett et al., 1994). 
8.3 
Definitions of analysis sets 
The full analysis set (FAS) will contain all patients who are eligible for the study and have any 
valid data of T790M mutation status. The FAS will be used for the analysis of biomarker data 
and others collected at screening visit.  
The As-treated analysis set will contain all patients who take at least one dose of AZD9291. It 
will be used for the analysis of data collected during treatment and follow up period.  
8.4 
Outcome measures for analyses 
Analysis will be conducted to evaluate the following as available in the CRF and database: 
x Baseline characteristics: demographics, relevant medical history, disease 
characteristics, cancer treatment history, smoking history.   


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x T790M and sensitizing mutations plasma testing results by Cobas, Super-ARMS, 
digital PCR, and NGS  
x T790M and sensitizing mutations tissue (or cytological samples, pleural fluid etc.) 
testing results (if available) 
x Exposure to AZD9291 
x Overall Survival (OS):  
Overall survival is defined as the time from the date of first dose of AZD9291 in this 
study until death due to any cause. Any subject not known to have died at the time of 
analysis will be censored at the last recorded date on which the subject was known to 
be alive. 
x Progression Free Survival (PFS): 
PFS is defined as the time from first dose of AZD9291 in this study until the date of 
disease progression as recorded in CRF or death (by any cause in the absence of 
progression) regardless of whether the subject withdraws from therapy or receives 
another anti-cancer therapy prior to progression. Subjects who have not progressed or 
died at the time of analysis will be censored at the time of the latest date of assessment. 
(or, if no tumor assessments are performed after the baseline visit, at the date of 
baseline visit). 
x Objective Response Rate漡Objective Response Rate is defined as the number (%) of 
patients with measurable disease with at least 1 visit response of CR or PR. Data 
obtained until progression or last evaluable assessment in the absence of progression 
will be included in the assessment of ORR. However, any CR or PR which occurred 
after a further anti-cancer therapy will not be included in the numerator for the ORR 
calculation (where the As-treated analysis set will be the denominator). 
x Percentages of EGFR mutations (C797S and T790M etc., respectively) at different 
time point by NGS and digital PCR, respectively, during dynamic monitoring. 
x Distribution of NGS testing results (contain 295 genes) at baseline and at PD. 
 
8.5 
Methods for statistical analyses 
All data will be presented for the full analysis set. The concordance of T790M resistance 
mutation testing between the Cobas test and each of other platforms will be calculated. The 
Kappa coefficient will also be calculated to measure the agreement. The sensitivity, specificity, 
positive predictive value, and negative predictive value of each testing platform (Super-
ARMS, digital PCR, and NGS) will be calculated with the Cobas test as the reference.  
Descriptive statistics will be used for all variables, as appropriate.  Continuous variables will 
be summarized by the number of observations, mean, standard deviation, median, interquartile 


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range (Q1, Q3), minimum, and maximum. Categorical variables will be summarized by 
frequency counts and percentages for each category.  The 95% confidence interval (CI) will 
be calculated as appropriate. PFS and OS, respectively, will be summarized using Kaplan-
Meier estimates of the median time to event (progression and death) and quartiles together 
with their 95% confidence intervals. The chi-square test will be used to compare the 
sensitivity, specificity, and concordance between any of the two platforms using Cobas as 
reference testing. 
8.5.1 
Analysis of the primary variable (s) 
The concordance of T790M resistance mutation testing between the Cobas test and each of 
other platforms (Spuer-ARMS/digital PCR/NGS). It will be calculated according to the 
following formula: 
Concordance (%)=(number of patients with same T790M mutation status based on 
Cobas and each other platform)/(total number of patients in the FAS with evaluable 
testing results) ×100%. 
PFS will be summarized using Kaplan-Meier (KM) estimates of the median time to 
progression or death and quartiles together with their 95% confidence intervals. KM estimates 
of PFS rate at appropriate time points (to be defined in SAP) will be presented as well. Plot of 
the KM PFS curve will be produced. 
8.5.2 
Analysis of the secondary variable(s) 
The sensitivity, specificity, positive predictive value, negative predictive value of Super-
ARMS/digital PCR/NGS will be calculated according to the following formulae by using 
Cobas as the reference: 
Sensitivity (%)=(number of patients with T790M mutation positive based on Cobas 
and each other platform)/(number of patients with T790M mutation positive based on 
Cobas) ×100% 
Specificity (%)=(number of patients with T790M mutation negative based on Cobas 
and each other platform)/(number of patients with T790M mutation negative based on 
Cobas) ×100% 
Positive predictive value (%)=(number of patients with T790M mutation positive 
based on Cobas and each other platform)/(number of patients with T790M mutation 
positive based on each other platform) ×100% 
Negative predictive value (%)=(number of patients with T790M mutation negative 
based on Cobas and each other platform)/(number of patients with T790M mutation 
negative based on each other platform) ×100% 


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The chi-square test will be used to compare the concordance, sensitivity, and specificity 
between any of the two platforms using Cobas as reference testing in an exploratory manner. 
OS will be summarized using Kaplan-Meier estimates of the median time to death and 
quartiles together with their 95% confidence intervals. KM estimates of OS rate at appropriate 
time points (to be defined in SAP) will be presented as well. Plot of the KM overall survival 
curve will be produced. 
ORR will be summarized with frequency counts and percentages for each category. The 95% 
CI will be provided as appropriate.  
 
8.5.3 
Exploratory analysis  
The proportion of patients with each EGFR mutation (C797S and T790M etc.) as well as other 
genetic and proteomic markers at different time point will be calculated as each EGFR 
mutation or marker divided by total number of patients with evaluable testing results. The data 
will be presented for the overall population (i.e., As-treated analysis set) as well as by 
subgroups such as short-term and long-term survivors.  
- Long-term survivors group (case): EGFR M+ aNSCLC patients who continuously received 
AZD9291 for at least 18 months without evidence of PD 
- Rapid PD group (control): EGFR M+ aNSCLC patients who had undergone PD after AZD9291 
treatment≤3 months  
Testing data of cytological samples (if collected) may be analyzed either separately or 
together with tissue samples. Data of clinical outcomes (ORR, PFS and OS) will be 
described separately for subjects that are negative for T790M mutation in plasma by all 
four platforms but positive in tissue and then receive AZD9291 monotherapy. The 
concordance, sensitivity, specificity, PPV, NPV of EGFR mutation plasma testing by Bio-
rad droplet digital PCR using other plasma tests or tissue test as reference will be 
calculated according to the similar formulas as above. The efficacy of patients who receive 
AZD9291 monotherapy and are T790M positive patient by each of the five platforms, 
respectively, will be analyzed same as above. Details will be specified in SAP.  
8.5.4 
Analysis timing 
Four analyses are planned: 
x The primary analysis of T790M testing concordance of four platforms and other 
testing data at enrollment visit will be conducted after the last patient is enrolled. 
x The primary analysis of PFS data will be conducted after 12-month follow up of the 
last enrolled patients, assuming that 60% of the patients who receive AZD9291 will 
have disease progression or death at this time. 


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x The exploratory analysis of T790M testing concordance and other testing data at 
enrollment visit by Bio-rad droplet digital PCR will be conducted once the data is 
available.  
x The final analysis will be conducted in about Q3 2019 when the last patient is followed 
up for 18 months. 
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 EDC 
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: 
x 
Provide information and support to the Investigator(s) 
x 
Confirm that facilities remain acceptable 
x 
Confirm that the investigational team is adhering to the protocol, that data 
are being accurately and timely recorded in the CRFs, that biological 
samples are handled in accordance with the Laboratory Manual and that 
study drug accountability checks are being performed 
x 
Perform source data verification (a comparison of the data in the 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) 
x 
Ensure withdrawal of informed consent to the use of the subject’s 
biological samples is reported and biological samples are identified and 


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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 
Study sites will maintain source data in accordance with Good Clinical Practice (GCP) or 
local regulations.   
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 enrolled. 
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 Quarter 4 2016 and to end by Quarter 4 2019. 
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. 
9.4 
Data management by AstraZeneca or delegate 
Data management will be performed by AstraZeneca Data Management Centre staff or other 
party, according to the Data Management Plan.  
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. 


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The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  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. 
Data associated with human biological samples 
Data associated with biological samples will be transferred from laboratories internal or 
external to AstraZeneca. 
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 or its representative will not provide patient information to patients, any 
insurance company, any employer, their family members, general physician or to any other 
third party, unless required to do so by law. 
Precautions are taken to preserve confidentiality and prevent data being linked to the identity 
of the patient. Also Regulatory authorities may require access to the relevant files. 
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 , who are authorised by principal 
investigator. 
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.  


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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. 
Before enrolment of any subject into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the site Ethical Committee or a 
notification to the national regulatory authority is done, according to local regulations. 
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements. 
 
10.4 
Informed consent 
The Principal Investigator(s) at each centre will: 
x 
Ensure each subject is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the 
study 
x 
Ensure each subject is notified that they are free to discontinue from the 
study at any time 
x 
Ensure that each subject is given the opportunity to ask questions and 
allowed time to consider the information provided 
x 
Ensure each subject provides signed and dated informed consent before 
conducting any procedure specifically for the study 
x 
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File 
x 
Ensure a copy of the signed Informed Consent Form is given to the 
subject 
x 
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 Principal 
Investigator and AstraZeneca. 


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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 before implementation.  
Local requirements are to be followed for revised protocols. 
AstraZeneca or its representative 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. 
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56 (56) 
Shigematsu, H., Lin, L., Takahashi, T., Nomura, M., Suzuki, M., Wistuba, I.I., Fong, K.M., 
Lee, H., Toyooka, S., and Shimizu, N., et al. Clinical and biological features associated with 
epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005 97, 
339-346. 
 
Song et al., 2016 
Song, H.N., Jung, K.S., Yoo, K.H., Cho, J., Lee, J.Y., Lim, S.H., Kim, H.S., Sun, J.M., Lee, 
S.H., and Ahn, J.S., et al. Acquired C797S Mutation upon Treatment with a T790M-Specific 
Third-Generation EGFR Inhibitor (HM61713) in Non-Small Cell Lung Cancer. J Thorac 
Oncol 2016 11, e45-e47. 
 
Thress et al., 2015 
Thress, K.S., Brant, R., Carr, T.H., Dearden, S., Jenkins, S., Brown, H., Hammett, T., 
Cantarini, M., and Barrett, J.C. EGFR mutation detection in ctDNA from NSCLC patient 
plasma: A cross-platform comparison of leading technologies to support the clinical 
development of AZD9291. Lung Cancer-J Iaslc 2015 90, 509-515. 
 
Vogelstein and Kinzler, 1999 
Vogelstein, B., and Kinzler, K.W. Digital PCR. Proc Natl Acad Sci U S A 1999 96, 9236-
9241. 
 
Weber et al., 2014 
Weber, B., Meldgaard, P., Hager, H., Wu, L., Wei, W., Tsai, J., Khalil, A., Nexo, E., and 
Sorensen, B.S. Detection of EGFR mutations in plasma and biopsies from non-small cell lung 
cancer patients by allele-specific PCR assays. Bmc Cancer 2014 14, 294. 
 
Yu et al., 2013 
Yu, H.A., Arcila, M.E., Rekhtman, N., Sima, C.S., Zakowski, M.F., Pao, W., Kris, M.G., 
Miller, V.A., Ladanyi, M., and Riely, G.J. Analysis of tumor specimens at the time of 
acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. 
Clin Cancer Res 2013 19, 2240-2247. 
 
Yung et al., 2009 
Yung, T.K., Chan, K.C., Mok, T.S., Tong, J., To, K.F., and Lo, Y.M. Single-molecule 
detection of epidermal growth factor receptor mutations in plasma by microfluidics digital 
PCR in non-small cell lung cancer patients. Clin Cancer Res 2009 15, 2076-2084. 
 
Zheng et al., 2016 
Zheng, D., Ye, X., Zhang, M.Z., Sun, Y., Wang, J.Y., Ni, J., Zhang, H.P., Zhang, L., Luo, J., 
and Zhang, J., et al. Plasma EGFR T790M ctDNA status is associated with clinical outcome 
in advanced NSCLC patients with acquired EGFR-TKI resistance. Sci Rep 2016 6, 20913. 
  

SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D5160C00042
Edition Number
2.0
Date
07 Dec 2021
Detect EGFR T790M mutation in ctDNA of Chinese Advanced/Metastatic 
NSCLC Patients by Cobas, Super-ARMS, digital PCR and NGS and 
evaluate clinical outcomes of T790M mutation positive patients who had 
AZD9291 monotherapy


Statistical Analysis Plan  
Study Code D5160C00042 
Edition Number 2.0  
Date 07 Dec 2021 
2 
 
 
 
 
 
 
 
 
 
 
Detect EGFR T790M mutation in ctDNA of Chinese Advanced/Metastatic 
NSCLC Patients by Cobas, Super-ARMS, digital PCR and NGS and 
evaluate clinical outcomes of T790M mutation positive patients who had 
AZD9291 monotherapy 
 
 
Updated by Tigermed Study 
Statistician 
 
 
 
 
Joe Yao 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan  
Study Code D5160C00042 
Edition Number 2.0  
Date 07 Dec 2021 
3 
 
 
 
 
 
 
 
 
 
Detect EGFR T790M mutation in ctDNA of Chinese Advanced/Metastatic 
NSCLC Patients by Cobas, Super-ARMS, digital PCR and NGS and 
evaluate clinical outcomes of T790M mutation positive patients who had 
AZD9291 monotherapy 
 
 
Approved by AstraZeneca Study 
Statistician 
 
 
 
 
Yi Chen 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan  
Study Code D5160C00042 
Edition Number 2.0  
Date 07 Dec 2021 
4 
 
 
 
 
 
 
 
 
 
Detect EGFR T790M mutation in ctDNA of Chinese Advanced/Metastatic 
NSCLC Patients by Cobas, Super-ARMS, digital PCR and NGS and 
evaluate clinical outcomes of T790M mutation positive patients who had 
AZD9291 monotherapy 
 
 
AstraZeneca Product Statistician  
 
 
 
Rosemary Taylor 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan  
Study Code D5160C00042 
Edition Number 2.0  
Date 07 Dec 2021 
5 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ........................................................................................................... 1 
SIGNATURE OF STUDY STATISTICIAN .......................................................... 2 
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN .................................... 3 
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN .................................... 4 
TABLE OF CONTENTS ......................................................................................... 5 
AMENDMENT HISTORY ..................................................................................... 9 
1. 
STUDY DETAILS ................................................................................................. 10 
1.1 
Study objectives ..................................................................................................... 10 
1.1.1 
Primary objective ................................................................................................... 10 
1.1.2 
Secondary objectives ............................................................................................. 10 
1.1.3 
Safety objectives .................................................................................................... 10 
1.1.4 
Exploratory objectives ........................................................................................... 10 
1.2 
Study design ........................................................................................................... 11 
1.3 
Number of subjects ................................................................................................ 11 
2. 
ANALYSIS SETS ................................................................................................. 12 
2.1 
Definition of analysis sets ...................................................................................... 12 
2.2 
Violations and deviations ....................................................................................... 12 
3. 
PRIMARY AND SECONDARY/EXPLORATORY VARIABLES .................... 12 
4. 
ANALYSIS METHODS ....................................................................................... 14 
4.1 
General principles .................................................................................................. 14 
4.2 
Analysis methods ................................................................................................... 15 
4.2.1 
Analysis Timing ..................................................................................................... 15 
4.2.2 
Analysis of the primary variable (s) ....................................................................... 15 
4.2.2.1 
Concordance .......................................................................................................... 15 
4.2.2.2 
PFS ......................................................................................................................... 15 
4.2.3 
Analysis of the secondary variable(s) .................................................................... 16 
4.2.4 
Exploratory analysis ............................................................................................... 17 
4.2.5 
Subject disposition ................................................................................................. 17 
4.2.6 
Demographics and baseline characteristics............................................................ 17 
4.2.7 
Other baseline information collected ..................................................................... 17 
4.2.8 
Treatment exposure ................................................................................................ 18 
4.2.9 
Post-hoc and ad-hoc analysis ................................................................................. 18 
4.2.10 
Data listing ............................................................................................................. 19 
5. 
INTERIM ANALYSES ......................................................................................... 19 


Statistical Analysis Plan  
Study Code D5160C00042 
Edition Number 2.0  
Date 07 Dec 2021 
6 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL ............................................... 19 
7. 
REFERENCES ...................................................................................................... 20 
8. 
APPENDIX ............................................................................................................ 20 
8.1 
Analysis Dataset Specification............................................................................... 20 
8.2 
Table, Figure, and Listing mock-up ....................................................................... 20 
8.3 
Statistical analysis plan for NGS ........................................................................... 20 
 


Statistical Analysis Plan  
Study Code D5160C00042 
Edition Number 2.0  
Date 07 Dec 2021 
7 
List Of Abbreviations 
Abbreviation or 
special term 
Explanation 
ASTRIS  
AccesS to TReatment with AZD9291- International Study  
AE  
Adverse Event  
ADR  
Adverse Drug Reaction  
ALK  
Anaplastic lymphoma kinase  
ALT  
Alanine aminotransferase  
ARMS  
Amplification Refractory Mutation System  
AZ  
AstraZeneca  
aNSCLC  
advanced Non-small Cell Lung Cancer  
BCRP  
Breast Cancer Resistance Protein  
CI  
Confidence Interval  
CRF  
Case Report Form (electronic/paper)  
CRO  
Clinical Research Organisation  
CSA  
Clinical Study Agreement  
CSP  
Clinical Study Protocol  
CSR  
Clinical Study Report  
CT  
Computer tomography  
CTCAE  
Common Terminology Criteria for Adverse Event  
ctDNA  
Circulating Tumor DNA  
cfDNA  
Cell Free DNA  
CYP  
Cytochrome P450  
Digital PCR  
Droplet Digital Polymerase Chain Reaction  
DLT  
Dose limiting toxicity  
DMC  
Data Monitoring Committee  
DNA  
Deoxyribonucleic acid  
DoR  
Duration of Response  
EC  
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)  
ECG  
Electrocardiogram  
eCRF  
Electronic case report form  
EDC  
Electronic Data Capture  
EGFR  
Epidermal Growth Factor Receptor  
EGFRm+  
Epidermal Growth Factor Receptor mutation positive  
EGFR-TKI  
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor  
FFPE  
Formalin-Fixed, Paraffin-Embedded  
FAS  
Full Analysis Set  
FDA  
Food and Drug Administration  
GCP  
Good Clinical Practice  
GMP  
Good Manufacturing Practice  
IB  
Investigator’s Brochure  
ILD  
Interstitial lung disease  
ICH  
International Conference on Harmonisation  
IP  
Investigational Product  
IRB  
Independent Review Board  
IUS  
Intra uterine System  
IVRS  
Interactive Voice Response System  


Statistical Analysis Plan  
Study Code D5160C00042 
Edition Number 2.0  
Date 07 Dec 2021 
8 
Abbreviation or 
special term 
Explanation 
IWRS  
Interactive Web Response System  
LSLV  
Last Subject Last Visit  
NGS  
Next Generation Sequence  
NPV  
Negative Predictive Value  
NSCLC  
Non-small Cell Lung Cancer  
ORR  
Objective Response Rate  
OS  
Overall Survival  
PD  
Progression of Disease  
PPV  
Positive Predictive Value  
PFS  
Progression Free Survival  
PK  
Pharmacokinetics  
qPCR  
Quantitative Polymerase Chain Reaction  
QT  
Interval on the Electrocardiogram Representing the Duration of  
Depolarization and Repolarization of the Heart  
QTc  
The QT Interval Corrected for Heart Rate  
RECIST v1.1  
Response Evaluation Criteria in Solid Tumors version 1.1  
SAE  
Serious Adverse Event  
SAP  
Statistical Analysis Plan  
SOC  
System Organ Class  
SOP  
Standard Operating Procedure  
T790M  
An Amino Acid Substitution at Position 790 in EGFR, from a Threonine 
(T)  to a Methionine (M)  
TKI  
Tyrosine Kinase Inhibitor  
ULN  
Upper Limit of Normal  
Variable  
A Characteristic of a Property of a Subject that may Vary e.g., from Time to 
Time or between Subjects  
WHO  
World Health Organization  
WHO DDE 
WHO Drug Dictionary Enhanced 
 


Statistical Analysis Plan  
Study Code D5160C00042 
Edition Number 2.0  
Date 07 Dec 2021 
9 
AMENDMENT HISTORY 
Version 
Brief description of change 
1.0 
NA 
2.0 
Added the analysis for exploration (Post-hoc/Ad-hoc analysis), removed safety 
analysis  
 


Statistical Analysis Plan  
Study Code D5160C00042 
Edition Number 2.0  
Date 07 Dec 2021 
10 
1. 
STUDY DETAILS 
1.1 
Study objectives 
1.1.1 
Primary objective  
Primary Objectives:  
Outcome Measure:  
To evaluate concordance of An amino acid substitution at 
position 790 in EGFR, from a Threonine to a Methionine 
(T790M) plasma mutation testing between the Cobas test and 
each of the other platforms: Super-ARMS, digital PCR and 
NGS.  
Concordance  
To assess the efficacy of AZD9291 monotherapy by 
assessment of PFS in adult patients with advanced or 
metastatic Non-small Cell Lung Cancer (NSCLC), who have 
received prior Epidermal Growth Factor Receptor Tyrosine 
Kinase Inhibitor (EGFR- TKI) therapy and are T790M 
mutation positive detected by any one of the four plasma 
testing platforms: Cobas/Super-ARMS/digital PCR/NGS.  
PFS using investigator 
assessments according to 
Response Evaluation Criteria in 
Solid Tumors version 1.1 
(RECIST v1.1) 
 
1.1.2 
Secondary objectives  
Secondary Objective:  
Outcome 
Measure:  
To evaluate the sensitivity, specificity, positive predictive value (PPV) and 
negative predictive value (NPV) of Super-ARMS/digital PCR/NGS by using 
Cobas as the reference.  
Testing 
sensitivity, 
specificity, PPV, 
NPV  
To assess the efficacy of AZD9291 monotherapy by assessment of 
Objective Response Rate (ORR) and Overall Survival (OS) in adult patients 
with advanced or metastatic NSCLC, who have received prior EGFR-TKI 
therapy and are T790M mutation positive detected by any one of the four 
plasma testing platforms: Cobas/Super-ARMS/ digital PCR/NGS.  
ORR, OS  
 
1.1.3 
Safety objectives  
N/A  
1.1.4 
Exploratory objectives  
Exploratory objectives:  
Outcome Measure:  
To dynamically monitor EGFR mutations by NGS and 
digital PCR in Circulating Tumor DNA (ctDNA) of patients 
receiving AZD9291 treatment.  
Proportion of patients with each 
EGFR mutation (C797S and 
T790M etc.) at different time 
point.  


Statistical Analysis Plan  
Study Code D5160C00042 
Edition Number 2.0  
Date 07 Dec 2021 
11 
To explore the mechanisms of acquired resistance in 
patients who received AZD9291 treatment by NGS testing 
of tissue and/or blood samples from the collection at 
Progression of Disease (PD) versus baseline.  
Changes of distribution of 
resistance related genes at PD 
compared with baseline.  
To describe the genomic profile of long-term survivors, 
especially to find out potential genomic prognosis and/or 
predictive factors for AZD9291 long-term efficacy as 
compared to rapid PD patients.  
Key genetic and proteomic 
markers including, but not 
limited to, EGFR mutations  
To evaluate concordance, sensitivity, specificity, PPV, 
NPV of EGFR mutation plasma testing by Bio-rad droplet 
digital PCR using other plasma test or tissue test as 
reference, respectively. 
Testing concordance, 
sensitivity, specificity, PPV, 
NPV 
To evaluate the efficacy of patients who receive AZD9291 
monotherapy and are T790M mutation positive detected by 
each of the five platforms, respectively. 
ORR, PFS, OS 
1.2 
Study design 
This is an open-label, multi-center, testing and treatment study in 250 locally advanced or 
metastatic NSCLC patients with a documented EGFR sensitive mutation and progression on a 
previous EGFR-TKI. T790M mutation in plasma ctDNA will be tested by four methods 
including Roche Cobas, Super-ARMS, digital PCR and NGS in order to evaluate the 
concordance of T790M testing in plasma between the Cobas test and each of the other three 
platforms as one of the primary endpoints. Sensitivity, specificity, NPV, and PPV of the 
testing methods are defined as secondary endpoints. 
Patients who are T790M mutation positive via a plasma test by any one of the four platforms 
and meet the eligibility criteria for the treatment period will receive AZD9291 treatment in the 
ASTRIS study. The other primary endpoint for this study is PFS (defined by RECIST v1.1), 
as assessed by the Investigator. Patients may continue to receive AZD9291 as long as they 
continue to show clinical benefit, as judged by the investigator, and in the absence of 
discontinuation criteria (see CSP section 3.11). OS and ORR are defined as secondary 
endpoints. 
1.3 
Number of subjects 
Approximately 250 eligible patients from 9 hospitals are planned to be enrolled into this 
study. Assuming the concordance of each platform of Super-ARMS, digital PCR, and NGS 
with Cobas ranges from 70% to 90%, the precision of estimation (i.e., half-length of 95% 
confidence interval <CI>) will be around 3.7% to 5.7%.  
Platforms  
Possible concordance 
with Cobas  
Precision of estimation  
(i.e., half length of 95% CI)  
Super-ARMS  
70%  
5.7%  
Digital PCR  
80%  
5%  
NGS  
90%  
3.7%  


Statistical Analysis Plan  
Study Code D5160C00042 
Edition Number 2.0  
Date 07 Dec 2021 
12 
 
Assuming that around 40% to 60% (i.e., 100 ~ 150) patients will have a T790M resistance 
mutation and receive AZD9291, the median PFS is around 9 to 11 months, and that disease 
progression or death will be observed for 60% of the patients after 12-months of follow up of 
the last enrolled patient for the primary analysis of PFS data, the 95% CI of estimation of 
median PFS is illustrated in the table below:  
 
 
95% CI of median PFS* 
 
No.  
patients 
No. events Median PFS: 9 months Median PFS: 10 months  Median PFS: 11 months 
100  
60  
7.0 – 11.6  
7.8 – 12.9  
8.5 – 14.2  
125  
75  
7.2 – 11.3  
8.0 – 12.5  
8.8 – 13.8  
150  
90  
7.3 – 11.1  
8.1 – 12.3  
8.9 – 13.5  
*Based on the formula in Collett 1994 (D. Collett et al., 1994).  
2. 
ANALYSIS SETS 
2.1 
Definition of analysis sets 
The full analysis set (FAS) will contain all patients who are eligible for the study and have any 
valid plasma data of T790M mutation status. The FAS will be used for the analysis of 
biomarker data and other data collected at the screening visit. 
The as-treated analysis set will contain all patients who take at least one dose of AZD9291. It 
will be used for the analysis of data collected during the treatment and follow up period. 
As the purpose of analysis, subjects in as-treated analysis set should be positive for T790M 
mutation in plasma by at least one of the four platforms. Subjects who are negative for T790M 
mutation in plasma by all four platforms but positive in tissue and then take at least one dose 
of AZD9291 (Tissue-Positive-Only) will be described separately. 
2.2 
Violations and deviations 
Protocol deviations will be identified by the Medical Monitor team of this project and 
finalized at the Data Review Meeting before the database lock. 
The important protocol deviations will be tabulated and listed.   
3. 
PRIMARY AND SECONDARY/EXPLORATORY VARIABLES 
Primary variables: 
x Concordance estimated by T790M plasma testing results between Cobas and each of 
the other three platforms: Super-ARMS, digital PCR, and NGS. 


Statistical Analysis Plan  
Study Code D5160C00042 
Edition Number 2.0  
Date 07 Dec 2021 
13 
x Progression Free Survival (PFS): PFS is defined as the time from first dose of 
AZD9291 in this study until the date of investigator assessed disease progression 
according to RECIST 1.1 as recorded in CRF or death (by any cause in the absence of 
progression) regardless of whether the subject withdraws from therapy or receives 
another anti-cancer therapy prior to progression. Subjects who have not progressed or 
died at the time of analysis will be censored at the time of the latest date of assessment, 
(or, if no tumor assessments are performed after the baseline visit, at the date of first 
dose date). If death/progression was observed after two or more missing visits (cycle, 6 
weeks + 1 weeks), subject was censored at the last assessment visit before these 
missing visits. 
Secondary variables: 
x Testing sensitivity, specificity, PPV, and NPV estimated by T790M plasma testing 
results by Cobas, Super-ARMS, digital PCR, and NGS. 
x Objective Response Rate: Objective Response Rate is defined as the number (%) of 
patients with measurable disease with at least 1 visit response of CR or PR as assessed 
by investigator according to RECIST 1.1. Data obtained until progression or last 
evaluable assessment in the absence of progression will be included in the assessment 
of ORR. However, any CR or PR which occurred after a further anti-cancer therapy 
will not be included in the numerator for the ORR calculation (where the As-treated 
analysis set will be the denominator). 
x Overall Survival (OS): Overall survival is defined as the time from the date of first 
dose of AZD9291 in this study until death due to any cause. Any subject not known to 
have died at the time of analysis will be censored at the last recorded date on which the 
subject was known to be alive. 
Exploratory variables: 
x Concordance estimated by T790M plasma testing results between Cobas and ddPCR. 
x Testing sensitivity, specificity, PPV, and NPV estimated by T790M plasma testing 
results by Cobas and ddPCR. 
x Percentages of EGFR mutations (C797S and T790M etc., respectively) at different 
time points by NGS and digital PCR, respectively, during dynamic monitoring. 
x Distribution of NGS testing results (contain 295 genes) at baseline and at progressive 
disease. 
x Key genetic and proteomic markers including, but not limited to, EGFR mutations, 
which were different between long-term survivors and rapid PD patients. 


Statistical Analysis Plan  
Study Code D5160C00042 
Edition Number 2.0  
Date 07 Dec 2021 
14 
4. 
ANALYSIS METHODS 
4.1 
General principles 
Descriptive statistics will be used for all variables, as appropriate. Continuous variables will 
be summarized by the number of observations, mean, standard deviation, median, interquartile 
range (Q1, Q3), minimum, and maximum. Categorical variables will be summarized by the 
frequency counts and percentages for each category. The 95% confidence interval (CI) will be 
calculated as appropriate. PFS and OS, respectively, will be summarized using Kaplan-Meier 
estimates of the median time to event (progression and death) and quartiles together with their 
95% confidence intervals. Data will be examined for skewness, outliers, and systematic 
missing data as needed. Transformations will be undertaken as needed. 
Unless otherwise specified, two-sided 95% confidence intervals via exact (Clopper-Pearson 
for percentages) method will be calculated as appropriate. 
The baseline will be the last non-missing assessment before the first dosing date unless 
otherwise specified.  
Time windows will be defined for any presentations that summarise values by visit (such as 
WHO performance status, weight, Ophthalmologic assessment, plasma NGS and digital 
PCR). The following conventions should also apply: 
x 
The time windows should be exhaustive so that data recorded at any time point has the 
potential to be summarized. Inclusion within the time window should be based on the 
actual date and not the intended date of the visit. 
x 
The window for the visits following baseline will be constructed in such a way that the 
upper limit of the interval falls half way between the two visits (the lower limit of the 
first post-baseline visit will be Day 1).  If an even number of days exists between two 
consecutive visits then the upper limit will be taken as the midpoint value minus 1 day.   
x 
If there is more than one value per patient within a time window then the closest value 
should be summarized, or the earlier in the event the values are equidistant from the 
nominal visit date. 
For example, the visit windows for WHO performance status during treatment phase are: 
- 
Week 6 (Day 42), visit window: Day 1 – Day 63 
- 
Week 12 (Day 84), visit window: Day 64 – Day 105 
- 
Week 18 (Day 126), visit window: Day 106 – Day 147 
- 
Etc.  


Statistical Analysis Plan  
Study Code D5160C00042 
Edition Number 2.0  
Date 07 Dec 2021 
15 
In general, no data imputation will be done. The number of subjects with missing data will be 
reported in the statistical description. 
Analyses will be performed by using SAS 9.4.  
4.2 
Analysis methods 
4.2.1 
Analysis Timing  
Two analyses are planned:  
x The primary analysis (analysis 1) of T790M testing concordance and other testing data 
at the enrollment visit will be conducted after the last patient is enrolled and all test 
results at the enrolment visit are obtained.  
x The final analysis (analysis 2) will be conducted in about Q4 2021 after the database is 
locked.  
4.2.2 
Analysis of the primary variable (s) 
4.2.2.1 
Concordance 
The concordance of T790M resistance mutation testing between the Cobas test and each of the 
other platforms (Super-ARMS/digital PCR/NGS) will be calculated according to the 
following formula: 
Concordance (%)=(number of patients with same T790M mutation status <negative or 
positive> based on Cobas and each other platform)/(total number of patients in the FAS with 
evaluable testing results) ×100%. 
According to the analysis purpose defined in section 4.2.1, analysis will be performed on the 
FAS in analysis 1 and only subjects with testing results of both Cobas test and other platform 
(Super-ARMS or digital PCR or NGS) will be included.  
The exact (Clopper-Pearson) confidence limits for this binomial proportion will be calculated.  
As a supportive analysis, the Kappa coefficient and related 95% confidence interval will also 
be calculated to measure the agreement.  
4.2.2.2 
PFS 
According to the analysis purpose defined in section 4.2.1, PFS analysis will be performed on 
the As-treated analysis set in analysis 2. PFS will be summarized using Kaplan-Meier (KM) 
estimates of the median time to progression or death and quartiles together with their 95% 
confidence intervals. KM estimates of PFS rate at appropriate time points (3 months, 6 
months, 9 months, and 12 months and every 6 months afterwards if applicable) will be 
presented as well. Plots of the KM PFS curve will be produced.  


Statistical Analysis Plan  
Study Code D5160C00042 
Edition Number 2.0  
Date 07 Dec 2021 
16 
The definition of censoring for PFS was in section 3 and PFS will be calculated as (the earlier 
of disease progression date or death date or censored date - the first dose date) + 1.  
4.2.3 
Analysis of the secondary variable(s) 
The sensitivity, specificity, positive predictive value, negative predictive value of Super-
ARMS/digital PCR/NGS will be calculated according to the following formulae by using 
Cobas as the reference: 
Sensitivity (%)=(number of patients with T790M mutation positive based on Cobas 
and each other platform)/(number of patients with T790M mutation positive based on 
Cobas) ×100% 
Specificity (%)=(number of patients with T790M mutation negative based on Cobas 
and each other platform)/(number of patients with T790M mutation negative based on 
Cobas) ×100% 
Positive predictive value (%)=(number of patients with T790M mutation positive 
based on Cobas and each other platform)/(number of patients with T790M mutation 
positive based on each other platform) ×100% 
Negative predictive value (%)=(number of patients with T790M mutation negative 
based on Cobas and each other platform)/(number of patients with T790M mutation 
negative based on each other platform) ×100% 
According to the analysis purpose defined in section 4.2.1, analysis will be performed on FAS 
in analysis 1 and only subjects with testing results of both Cobas test and other platform 
(Spuer-ARMS or digital PCR or NGS) will be included.  
OS and ORR analysis will be performed on the As-treated analysis set in analysis 2. OS will 
be summarized using Kaplan-Meier estimates of the median time to death and quartiles 
together with their 95% confidence intervals. KM estimates of OS rate at appropriate time 
points (6 months, 12 months, 18 months, and 24 months and every 6 months afterwards if 
applicable) will be presented as well. Plot of the KM overall survival curve will be produced. 
The definition of censoring for OS was in section 3 and OS will be calculated as (the death 
date or censored date - the first dose date) + 1.  
ORR, as well as the best response of CR, PR, SD, PD, and NE respectively, will be 
summarized with frequency counts and percentages for each category. The exact (Clopper-
Pearson) confidence limits will be provided as appropriate.  
The same analysis for OS and ORR will also be performed on the Tissue-Positive-Only 
subset. 


Statistical Analysis Plan  
Study Code D5160C00042 
Edition Number 2.0  
Date 07 Dec 2021 
17 
4.2.4 
Exploratory analysis  
The concordance of T790M resistance mutation testing between the Cobas test and ddPCR 
will be calculated and analyzed as section 4.2.2.1.  
The sensitivity, specificity, positive predictive value, negative predictive value of Super-
ARMS/digital PCR/NGS against ddPCR will be calculated according to the following 
formulae by using Cobas as the reference. The formulas and analysis methods will be referred 
to section 4.2.3. 
The details methods how to analysis other exploratory variables [Percentages of EGFR 
mutations (C797S and T790M etc., respectively) at different time points by NGS and digital 
PCR, respectively, during dynamic monitoring, Distribution of NGS testing results at baseline 
and at progressive disease, and Key genetic and proteomic markers including, but not limited 
to, EGFR mutations, which were different between long-term survivors and rapid PD patients] 
will be plan in a separated file. 
4.2.5 
Subject disposition 
The frequency counts and percentages of subjects enrolled, included in FAS, included in As-
treated analysis set, undergone each platform test, treated with AZD9291, switching to other 
anti-cancer therapy, undergone disease progression, withdrew, and dead will be calculated and 
presented in analysis 1 and analysis 2. 
Data list on patients with screening failure will be presented. 
4.2.6 
Demographics and baseline characteristics 
Demographics information, such as age, gender, race, weight, and WHO performance status 
will be described according to the general principles in section 4.1. Continuous variables will 
be summarized by the number of observations, mean, standard deviation, median, interquartile 
range (Q1, Q3), minimum, and maximum. Categorical variables will be summarized by the 
frequency counts and percentages for each category. According to the analysis purpose 
defined in section 4.2.1, this analysis will be performed on FAS (analysis 1) and As-treated 
analysis set (analysis 2), respectively. 
4.2.7 
Other baseline information collected 
Other information collected at baseline, such as substance use (Nicotine), previous therapy 
and surgery, relevant medical history (past and current), will be described according the 
general principles in section 4.1. Continuous variables will be summarized by the number of 
observations, mean, standard deviation, median, interquartile range (Q1, Q3), minimum, and 
maximum. Categorical variables will be summarized by the frequency counts and percentages 
for each category. According to the analysis purpose defined in section 4.2.1, this analysis will 
be performed on FAS (analysis 1) and As-treated analysis set (analysis 2), respectively. 
Previous therapy will be coded by the latest version of WHO Drug Dictionary Enhanced 
(WHO DDE) and the frequency counts and percentages of subjects with each preferred term 


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(PT) within each Anatomical-Therapeutic-Chemical classification system (ATC02) will be 
summarized. Relevant medical history and previous surgery (if applicable) will be coded by 
MedDRA (the latest version) and the frequency counts and percentages of subjects with each 
preferred term (PT) within each system organ class (SOC) will be summarized. 
4.2.8 
Treatment exposure 
Duration of exposure, including total exposure and actual exposure, as well as treatment 
compliance will be described according the general principles in section 4.1, i.e., the number 
of observations, mean, standard deviation, median, interquartile range (Q1, Q3), minimum, 
and maximum will be presented. The frequency counts and percentages of subjects with each 
dose adjustment reason within dose adjustment type will be summarized. 
Total Exposure to AZD9291 will be defined as time (days) from the first dose to the last dose: 
x Total exposure = last dosing date where dose > 0 mg – first dosing date where dose > 0 
mg + 1 
Actual exposure to AZD9291 will be time (days) from first dose to last dose, taking into 
account the number of days where no dose was taken. 
x Actual exposure = last dosing date where dose > 0 mg – first dosing date where dose > 
0 mg + 1 – total duration of dose interruption (i.e. number of days with dose = 0 mg)  
Treatment compliance (%) is defined as the number of administered doses of AZD9291 (80 
mg or 40 mg) taken as a proportion of the scheduled expected number of doses. 
Overdose information will be reported as data listing, refer to section 4.2.15. 
According to the analysis purpose defined in section 4.2.1, this analysis will be performed on 
the As-treated analysis set (analysis 2) 
4.2.9 
Post-hoc and ad-hoc analysis 
This section describes additional analysis which was not planned in the protocol. 
 On subjects in the Tissue-Positive-Only subset, the same analysis for PFS (refer to section 
4.2.2.2) will also be performed. 
For T790M plasma positive subjects with different sensitivity mutations testing results (19del 
positive, L858R positive, or other positive) at baseline, the PFS will be analyzed according to 
section 4.2.2.2.   
The ORR (according to section 4.2.3) will be analyzed for subjects with different baseline 
characteristics (T790M resistance mutation test results by 4 platforms, different Digital PCR 
measurement results, different NGS measurement results, T790M and EGFR amplification 
status, mutation other than T790M, T790M tissue status, previous chemotherapy, and previous 
radiotherapy).  


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PFS and ORR of subjects with positive mutations testing (L858R, 19del, G719X, L861Q, 
exon 20 insertion etc. at least one other than T790M) results at baseline will be analyzed 
according to the mutations testing results at different time points, including but not limited to 
progression, visit before progression, week 6, and best response. The PFS will be analyzed 
according to section 4.2.2.2. Time to appearance of resistance related gene alterations, for 
instance C797S etc., will be analyzed.  
For platforms NGS and digital PCR, three different cut off values (0.1%, 0.3% and 0.5%), the 
PFS (HR) and ORR in subjects with values above and below the cut off will be displayed by 
plots.  The cut off at 0.1% will be considered primary and the other cut offs will only be 
explored if 15% subjects change their classification (from below to above the cut off or vice 
versa) when the new cut off is considered.  
For the subgroup analyses on time-to-event data, if there are too few events available (less 
than 20 events across both treatment groups in a level of a subgroup), the survival analyses 
(e.g. KM estimations, HR and CI) will not be produced for that subgroups. In this case, only 
descriptive summaries (e.g. events number and events rate) will be provided.  
If the sub-group contains the majority of the overall population (for example, if the subgroup 
contains 95% of the FAS), the sub-group analysis will not be performed.  
The EGFR T790M mutation status of subjects with chemotherapy or EGFR-TKI as the latest 
therapy, different histology types, and different metastasis status before T790M mutation test 
will be presented separately.  
The duration from previous disease progression to T790M mutation test will be described by 
EGFR T790M mutation status (positive or negative).  
4.2.10 
Data listing 
All data to be analyzed in the sections above will be presented as data listings as well as other 
related information. 
5. 
INTERIM ANALYSES 
No interim analyses are planned. 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL 
Only two analyses would be done according to the decision of study team. The first analysis 
was executed per protocol. The second analysis planned in protocol was cancelled due to 
HGR resubmission. The third analysis planned in protocol is the second formal analysis 
executed actually, which will be conducted after the database is locked. 


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According to the exploration purpose of study team, some post-hoc and ad-hoc analysis will 
also be executed and they were listed in section 4.2.9 (Post-hoc and ad-hoc analysis) besides 
the other ones planned in protocol. 
7. 
REFERENCES 
This SAP is according to CSP version 3.0 (25Aug2017). 
D. Collett et al., 1994 
D. Collett, Chapman & Hall. Modelling Survival Data in Medical Research. London, 1994. 
8. 
APPENDIX 
8.1 
Analysis Dataset Specification 
Refer to file d5160c00042-analysis-datasets-specification.xlsx. 
8.2 
 Table, Figure, and Listing mock-up 
Refer to file d5160c00042-table-figure-listing-toc.xlsx 
Refer to file d5160c00042-table-figure-listing-mock-up.docx 
8.3 
Statistical analysis plan for NGS 
Refer to file d5160c00042-statistical-analysis-plan_NGS.docx