The Efficacy and Safety of Osimertinib With Platinum Plus Pemetrexed Chemotherapy as First-line Treatment in Advanced Non-small Cell Lung Cancer Patients With Uncommon Epidermal Growth Factor Receptor Mutations: A phase2, Open Label, Single Arm, Multicenter, Exploratory Study
Phase: PHASE2
Conditions: Lung Cancer
Sponsor: AstraZeneca

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Clinical Study Protocol
Study Intervention
Osimertinib(TAGRISSO®)
Study Code
D5161C00017
Version
1.0
Date
06-01-2021
The Efficacy and Safety of Osimertinib with Platinum plus 
Pemetrexed Chemotherapy, as First-line Treatment in Recurrent 
or Locally Advanced or Metastatic Non-small Cell Lung Cancer 
(NSCLC) Patients with Uncommon Epidermal Growth Factor 
Receptor Mutations (EGFRm): A phase2, Open Label, Single 
Arm, Multicenter, Exploratory Study
Sponsor Name: China AstraZeneca Marketing Company
Legal Registered Address: AstraZeneca, 
, Shanghai, 
, China
Regulatory Agency Identifier Number(s)Not Applicable
This CSP has been subject to a peer review according to AstraZeneca Standard procedures. The 
CSP 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 Number:
Amendment Number: None
Study Intervention: osimertinib 
Study Phase: Phase 2
Short Title: Osimertinib plus chemotherapy in uncommon EGFRm NSCLC
Acronym: MINAURA
Medical Monitor Name and Contact Information will be provided separately
National co-ordinating investigator:
 
, Chengdu, China

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date of Issue
Original Protocol
30-Jul-2020

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3
TABLE OF CONTENTS ...................................................................................................... 4
LIST OF FIGURES .............................................................................................................. 6
LIST OF TABLES ................................................................................................................ 6
1
PROTOCOL SUMMARY .................................................................................. 8
1.1
Synopsis ............................................................................................................. 8
1.2
Schema............................................................................................................. 13
1.3
Schedule of Activities ....................................................................................... 13
2
INTRODUCTION............................................................................................ 19
2.1
Study Rationale ................................................................................................ 21
2.2
Background ...................................................................................................... 22
2.3
Benefit/Risk Assessment................................................................................... 26
2.3.1
Risk Assessment ............................................................................................... 26
2.3.1.1
Osimertinib....................................................................................................... 26
2.3.1.2
Chemotherapy................................................................................................... 28
2.3.1.3
Safety data from studies of chemotherapy with EGFR TKI therapies ................ 29
2.3.1.4
Potential for osimertinib and chemotherapy overlapping toxicity ...................... 29
2.3.2
Benefit Assessment........................................................................................... 31
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 32
3
OBJECTIVES AND ENDPOINTS................................................................... 33
4
STUDY DESIGN ............................................................................................. 35
4.1
Overall Design.................................................................................................. 35
4.2
Scientific Rationale for Study Design ............................................................... 36
4.2.1
Rationale for primary and secondary endpoint .................................................. 36
4.2.2
Testing for uncommon EGFR mutations ........................................................... 36
4.3
Justification for Dose........................................................................................ 37
4.3.1
Osimertinib....................................................................................................... 37
4.3.2
Platinum and pemetrexed regimen .................................................................... 37
4.4
End of Study Definition.................................................................................... 37
5
STUDY POPULATION.................................................................................... 38
5.1
Inclusion Criteria .............................................................................................. 38
5.2
Exclusion Criteria ............................................................................................. 40
5.3
Lifestyle Considerations ................................................................................... 42
5.3.1
Pregnancy......................................................................................................... 42
5.3.2
Meals and Dietary Restrictions ......................................................................... 43
5.4
Screen Failures ................................................................................................. 43

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5.5
Procedures for handling incorrectly enrolled patients........................................ 44
6
STUDY INTERVENTION ............................................................................... 44
6.1
Study Intervention Administered....................................................................... 44
6.1.1
Investigational Product ..................................................................................... 44
6.1.2
Dosing instructions ........................................................................................... 45
6.2
Preparation/Handling/Storage/Accountability of Interventions.......................... 46
6.3
Study Intervention Compliance......................................................................... 46
6.4
Concomitant Therapy........................................................................................ 47
6.4.1
Background medications................................................................................... 47
6.4.2
Restricted and prohibited concomitant medications........................................... 49
6.4.3
Antiemetic therapy............................................................................................ 52
6.4.4
Other concomitant treatment............................................................................. 55
6.4.5
Prior immune-oncology therapy........................................................................ 55
6.5
Dose Modification ............................................................................................ 55
6.6
Intervention after the End of the Study.............................................................. 55
6.7
Labelling .......................................................................................................... 55
6.8
Storage ............................................................................................................. 56
6.9
Accountability .................................................................................................. 56
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 56
7.1
Discontinuation of Study Intervention............................................................... 56
7.1.1
Follow-up of Participants Post Discontinuation of Study Intervention............... 57
7.1.2
Follow-up for Survival...................................................................................... 57
7.2
Intervention through progression....................................................................... 58
7.3
Participant Withdrawal from the Study.............................................................. 58
7.4
Lost to Follow-up ............................................................................................. 59
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 60
8.1
Efficacy Assessments........................................................................................ 60
8.1.1
Imaging Tumour Assessments........................................................................... 60
8.2
Safety Assessments........................................................................................... 62
8.2.1
Physical Examinations...................................................................................... 62
8.2.2
Vital Signs ........................................................................................................ 62
8.2.3
Electrocardiograms........................................................................................... 63
8.2.4
Clinical Safety Laboratory Assessments............................................................ 63
8.2.5
Echocardiogram/Multigated Acquisition Scan................................................... 64
8.2.6
ECGO/WHO Performance Status ..................................................................... 65
8.3
Collection of Adverse Events and Serious Adverse Events................................ 65
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 65
8.3.2
Follow-up of AEs and SAEs ............................................................................. 66
8.3.3
Adverse event data collection............................................................................ 66
8.3.4
Causality Collection.......................................................................................... 67
8.3.5
Adverse Events Based on Signs and Symptoms ................................................ 67

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8.3.6
Adverse Events Based on Examinations and Tests ............................................ 68
8.3.7
Disease Progression.......................................................................................... 68
8.3.8
Disease Under Study......................................................................................... 69
8.3.9
New Cancers..................................................................................................... 69
8.3.10
Deaths .............................................................................................................. 69
8.3.11
Safety Data to be Collected Following the Final Data Cut off of the Study........ 69
8.4
Safety reporting and medical management........................................................ 70
8.4.1
Reporting of Serious Adverse Events................................................................ 70
8.4.2
Pregnancy......................................................................................................... 70
8.4.2.1
Maternal Exposure............................................................................................ 71
8.4.2.2
Paternal Exposure............................................................................................. 71
8.4.3
Overdose .......................................................................................................... 72
8.4.4
Medication Error............................................................................................... 73
8.4.5
Management of study intervention-related toxicities ......................................... 73
8.4.5.1
General dose adjustments for adverse events..................................................... 73
8.4.5.2
Dose adjustment information for osimertinib .................................................... 74
8.5
Biomarkers and exploratory research ................................................................ 76
8.5.1
Collection of samples........................................................................................ 76
8.5.2
Determination of exploratory analysis............................................................... 77
8.5.3
Storage and destruction of samples ................................................................... 77
9
STATISTICAL CONSIDERATIONS................................................................ 77
9.1
Statistical Hypotheses....................................................................................... 77
9.2
Sample Size Determination............................................................................... 77
9.3
Populations for Analyses................................................................................... 78
9.4
Statistical Analyses ........................................................................................... 78
9.4.1
General Considerations..................................................................................... 78
9.4.2
Efficacy ............................................................................................................ 78
9.4.2.1
Primary Endpoint(s).......................................................................................... 78
9.4.2.2
Secondary Endpoint(s)...................................................................................... 79
9.4.2.3
Exploratory Endpoint........................................................................................ 81
9.4.3
Safety ............................................................................................................... 82
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ........................................................................................ 82
11
REFERENCES............................................................................................... 118
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 13
LIST OF TABLES
Table 1
Schedule of Activities (SoA).................................................................... 14

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Table 2
Objectives and Endpoints......................................................................... 33
Table 3
Investigational Products........................................................................... 44
Table 4
Background Medications ......................................................................... 49
Table 5
Restricted, prohibited and allowed concomitant medications.................... 49
Table 6
QT/TdP risk category for antiemetic therapies ......................................... 53
Table 7
Laboratory Safety Variables..................................................................... 64
Table 8
Dose Modifications for Study Treatments................................................ 74
Table 9
Dose adjustment information for adverse reactions .................................. 74
Table 10
Summary of Imaging Modalities for Tumour Assessment........................ 95
Table 11
RECIST 1.1 Evaluation of Target Lesions ............................................. 102
Table 12
RECIST 1.1 Evaluation of Non-Target Lesions ..................................... 103
Table 13
RECIST 1.1 Overall Visit Response ...................................................... 103
Table 15
Highly Effective Methods of Contraception (<1% Failure Rate) ............ 106
Table 16
Drugs known to be inhibitors of CYP3A4/5........................................... 109
Table 17
Exposure, Pharmacological Action, and Toxicity May be Increased by 
Osimertinib............................................................................................ 111
Table 18
Drugs with a Known Risk of Torsades de Pointes.................................. 112
Table 19
Restricted medications/therapies............................................................ 113
Table 20
Prohibited medications/therapies............................................................ 113
Table 21
Supportive medications/therapies........................................................... 113
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 83
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 88
Appendix C
Handling of Human Biological Samples .................................................. 93
Appendix D
Guidelines for Evaluation of Objective Tumour Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumours).... 95
Appendix E
Contraception Requirements.................................................................. 105
Appendix F
Concomitant Medications ...................................................................... 108
Appendix G
Calculated Creatinine Clearance ............................................................ 115
Appendix H
Abbreviations ........................................................................................ 116

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: The Efficacy and Safety of Osimertinib with Platinum plus Pemetrexed 
Chemotherapy, as First-line Treatment in Recurrent or Locally Advanced or Metastatic Non-
small Cell Lung Cancer (NSCLC) Patients with Uncommon Epidermal Growth Factor Receptor 
Mutations (EGFRm): A phase2, Open Label, Single Arm, Multicenter, Exploratory Study
Short Title: Osimertinib plus chemotherapy in uncommon EGFRm NSCLC
Rationale:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Objectives
Endpoints
To further describe the efficacy signals of 
osimertinib with platinum plus pemetrexed as 
first-line treatment

PFS (progression free survival) defined as time 
from first dose of study intervention until 
progression (PD) per RECIST 1.1 as assessed by 
the investigator or death due to any cause prior to 
PDOS (overall survival) defined as the time from 
first dose of study intervention until the date of 
death due to any cause;

DoR (duration of response), defined as time from 
first occurrence of a response to a documented PD 
per RECIST 1.1 as assessed by the investigator or 
death of any cause;

Depth of response, defined as maximum response
of target lesions per RECIST 1.1 as assessed by 
the investigator;

DCR (disease control rate)), defined as the 
percentage of participants who achieved CR, PR 
or stable disease (SD) based on RECIST 1.1 as 
assessed by the investigator;

Time to treatment failure (TTF), defined as the 
time from first dose of study intervention to 
earlier of the date of last study intervention
administration or death due to any cause;

Time to first subsequent treatment (TFST), 
defined as the time from first dose of study 
intervention to the earlier of the date of anti-
cancer therapy start date following study 
intervention discontinuation or death due to any 
cause;
To describe the safety and tolerability of 
osimertinib with platinum plus pemetrexed as 
first-line treatment

All Adverse events (AEs) graded by CTCAE v5

Incidence of ≥grade 3 AE/Serious AE (SAE);

Incidence of all ADR;

Discontinuation rate due to AEs;

Clinical chemistry, haematology and urinalysis;

Vital signs (pulse and blood pressure); physical 
examination; weight; LVEF; ECG parameters;

ECOG/WHO Performance Status.
For exploratory objectives and endpoints, see Section 3 of the protocol.
Overall Design Disclosure Statement: 
This is a Phase 2, open-label, single arm, multicentre study assessing the efficacy and safety of 
osimertinib plus platinum-based doublets chemotherapy in advanced NSCLC participants with 
uncommon EGFRm

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Follow-up of participants post discontinuation of study intervention:
After study intervention discontinuation, all participants will undergo an end-of-treatment visit 
(within 10 days of discontinuation) and will be followed up for safety assessments for 28 days 
after their last dose of study intervention (ie, the safety follow-up visit).
Participants who have discontinued study intervention in the absence of RECIST 1.1-defined
radiological progression which is confirmed by investigator assessment will be followed up 
with tumour
assessments according to the Schedule of Activities (SoA)
until 
RECIST 1.1-defined progressive disease (PD) or death regardless of whether or not the 
participant start a subsequent anticancer therapy, unless they have withdrawn all consent of 
study-related assessments.
In addition, all participants will be followed up for survival status after intervention 
discontinuation every 12 weeks (±1 week) from the date of last dose until death, withdrawal of 
consent, or the end of the study (sufficient maturity achieves for OS events), as per the SoA.
See Section 6.6 for a detailed description of assessments following study cut-offs (DCOs).
Statistical methods
All statistical analyses will be completed using SAS version 9.4 or later. The efficacy analyses 
will be based on the Full Analysis Set (FAS), which includes all participants who have taken at 
least one dose of study intervention. 
The Data Cut-off (DCO) date of the primary outcome endpoint, ORR, will be when all 
participants have completed at least two follow-up assessments based on Investigator 
assessment according to RECIST 1.1. In order to allow max time for response to be observed, 
the DCO date for primary analysis for ORR will be at 24 weeks after last subject in (LSI). 
Objective response is defined as a patient achieving a complete response (CR) or partial 
response (PR) as their best overall response based on Response Evaluation Criteria in Solid 
Tumours (RECIST) 1.1 as assessed by the investigator. ORR is defined as the proportion of 
patients achieving an objective response and will be presented as a percentage with 
accompanying 95% Clopper-Pearson confidence interval. Participants who discontinue the 
intervention without progression or who, receive a subsequent anti-cancer therapy and then 
respond will not be considered as responders in the calculation of ORR.
The secondary outcomes, PFS will be analysed when approximately 21 progression events have 
been achieved in the 35 participants (approximately 60% maturity). The Kaplan-Meier method 
will be used to estimate the median PFS (mPFS) and its 95% confidence interval. A KM curve 
will be provided as well. Other time-to-event endpoints (OS and DoR) will be summarized by 
same method. 

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Table 1
Schedule of Activities (SoA)
Procedure
Screening 
Intervention Period 
Follow-up Period
For details see 
protocol 
section
Visit
1
2
3
4
5
6
7
8+
a
Treatmen
t 
discontin
uation
Safety 
Follow-up 
(28 Days 
After Last 
Dose) 
b
Progression 
Follow-up 
c
Survival 
Follow-up d
Day (visit window ±days) 
-28 to -1
1(+/
-3)
22(+
/-3)
43(+
/-3)
64(+
/-3)
85(+
/-3)
106(
+/-
3)
127+
(+/-
3)
+10
+7
+/-7
+/-7
Informed consent 
e
X
Section 5.1
Inclusion and exclusion criteria
X
Section 5.1
and 5.2
Diagnostic clinical procedures
Record documented
uncommon EGFR mutation
results by an accredited
laboratory through ARMS, 
Super-ARMS, and NGS 
testing f
X
Section 5.1
and 5.2
Optional provision of tumour 
sample (sufficient amount)
allowed for central 
confirmation of the EGFR 
mutation status by Cobas®
testing 
X
Section 4.2.2
Routine clinical procedures
g
Demography and smoking 
history h
X
Section 5.1

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Procedure
Screening 
Intervention Period 
Follow-up Period
For details see 
protocol 
section
Visit
1
2
3
4
5
6
7
8+
a
Treatmen
t 
discontin
uation
Safety 
Follow-up 
(28 Days 
After Last 
Dose) 
b
Progression 
Follow-up 
c
Survival 
Follow-up d
Physical examination and 
weight
X
X
X
X
X
X
X
X
X
Section 8.2.1
Height
X
Section 8.2.1
Medical history
X
Sections 5.1
and 5.2
ECOG/WHO performance 
status 
X
Xi
X
X
X
X
X
X
X
X
Section 8.2.6
Routine safety measurements
g
Serum or urine pregnancy test 
(WOCBP only)j
X
As clinically indicated. Serum pregnancy test performed at screening 
and urine pregnancy tests performed thereafter. 
Sections 5.1, 
5.2 and 8.2.4
Clinical safety laboratory 
assessments (clinical 
chemistry, haematology, 
urinalysis)
X
Xi
X
X
X
X
X
X
X
X
Section 8.2.4
Creatinine clearance 
calculation
X
Xi
X
X
X
X
X
X
X
X
Appendix G
12-lead ECG k
X
Xi
X
X
X
X
X
X
X
X
Section 8.2.3
Echocardiogram/MUGA 
X
At Week 12 (± 4 week), Week 24 (± 4 week) and then 
every 12 weeks (± 4 weeks) relative to first dose and as 
clinically indicated 
X
l
Section 8.2.5
Vital signs
X
X
X
X
X
X
X
X
X
X
Section 8.2.2

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Procedure
Screening 
Intervention Period 
Follow-up Period
For details see 
protocol 
section
Visit
1
2
3
4
5
6
7
8+
a
Treatmen
t 
discontin
uation
Safety 
Follow-up 
(28 Days 
After Last 
Dose) 
b
Progression 
Follow-up 
c
Survival 
Follow-up d
AE
X
=============================
At every visit and may be conducted by phone if not 
tied to a visit.
X
Xm
Xm
Section 8.3
Concomitant medication 
X
=============================
At every visit and may be conducted by phone if not 
tied to a visit
X
X
X
Section 6.4
Anti-cancer and surgical 
treatments n
X
==========================================================================
All will be collected throughout the study
Sections 
Error! 
Reference 
source not 
found., 5.1, 
and Error! 
Reference 
source not 
found.
Study treatment administration g, o
Osimertinib treatment  
dispensed (
)
X
X
X
X
X
X
X
Sections 6
and 7
Background treatment administration o
Platinum plus pemetrexed 
followed by pemetrexed 
maintenance treatment
stability
X
X
X
X
Xo
Xo
X
Sections 6
and 7
Efficacy measurements g

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k
A 28-day follow-up assessment will be required if an on-treatment assessment was abnormal at the time of discontinuation of study intervention to confirm 
reversibility of the abnormality.
l
If a participant had a MUGA or echocardiogram performed within 30 days prior to intervention discontinuation, the discontinuation visit Echo/MUGA scan 
is not required unless clinically indicated.
m
AEs will be collected from time of signature of informed consent form until 28 days after last dose of study intervention or until the end of study, 
whichever occurs earlier. If the participant discontinues study intervention prior to disease progression, SAEs considered related to study intervention 
and/or study procedures will be collected until disease progression or end of study.
n
All prior anti-cancer and surgical therapies will be collected at screening and throughout the study as indicated.   
o
Osimertinib and chemotherapy dosing should begin on the same day. Pemetrexed plus carboplatin or cisplatin should be used for 4-6 cycles followed by 
pemetrexed maintenance.
p
The baseline radiological assessments should be performed during the 28-day screening period and preferably as close as possible to and prior to the date of 
enrolment. Baseline assessments include (i) CT (preferred) or MRI chest/abdomen (including liver and adrenal glands) plus any other sites where disease is 
suspected or known at baseline and (ii) Brain imaging - MRI is preferred unless contraindicated.  Follow-up scans of anatomy imaged at baseline (as well as 
other sites where disease is suspected or known) are to be performed using the same modality as at baseline, after 6 weeks (±7 days), 12 weeks (±7 days), 
18 weeks (±7 days), 24 weeks (±7 days) and then every 9 weeks (±1 week) subsequently, relative to first dose, until radiological disease progression as per 
RECIST 1.1, even if dose is delayed due to toxicity or a participant discontinues intervention prior to progression or receives other anti-cancer treatment.
Following RECIST 1.1 defined progression, PFS assessment will be performed by the Investigator and defined according to local standard practice and may 
involve any of the following: objective radiological imaging (preferred), symptomatic progression, or death. 
q
Brain scans using the same modality as at baseline will be performed as part of each RECIST tumour assessment visit in participants with brain metastases 
or a history of brain metastases until RECIST 1.1-defined disease progression. In participants without brain metastases or a history of brain metastases at 
baseline, brain scans will be performed only when there is a suspected CNS progression and at the point of RECIST 1.1 defined extracranial progression. 
Note: All assessments on treatment days are to be performed prior to study intervention administration, unless otherwise indicated. Data collection following study analysis until 
the end of the study is described in Section 8.
AE=adverse event; C=cycle; CSP=Clinical Study Protocol; CTCAE=Common Terminology Criteria for Adverse Events; CV=cardiovascular; ECG=electrocardiogram; E/D=Early 
Study Intervention/Discontinuation; ICF=informed consent form; IV=intravenous; MUGA=multigated acquisition; PFS=time to progression or death; qXXw=every X weeks; 
RECIST 1.1=Response Evaluation Criteria in Solid Tumours, Version 1.1; SoC=standard of care; ECGO= eastern cooperative oncology group. 

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2
INTRODUCTION
Lung cancer is the most frequently occurring forms of malignancy worldwide (estimated at 
~11.6% of all new cancer cases from GLOBOCAN 2018) [8, 9]. Non-small cell lung cancer 
(NSCLC) is the most common type in histology, which accounts for 80% to 90% of all lung 
cancers [1, 10]. NSCLC is also a leading cause of cancer related death in worldwide (~25.3% 
of all deaths from cancer) [9]. Among NSCLC, adenocarcinoma is the most common subtype 
and also additionally the most frequent histological type in female [11]. Chinese patients with
lung cancer have increased rapidly in recent years. In China, the estimated new lung cancer 
cases and deaths were about 787,000 and 631,000 in 2015 from National Center Cancer Registry
[12,13]. According to GLOBOCAN estimation, China accounted for 37.0% of annual lung 
cancer incidence and 39.2% of lung cancer mortality [9]. Consistent with global condition, 
NSCLC remains the predominant form of the lung cancer in China, with majority of patients 
being diagnosed as adenocarcinoma. Meanwhile, a retrospective analysis suggested that the 
percentage of adenocarcinomas increased significantly (from 36.4% to 53.5%; P < 0.001), with 
a decrease in squamous cell carcinomas (from 45.4% to 34.4%; P < 0.001) in recent years [14].
Lung cancer is a major disease burden in the whole world. And the financial burden appears to 
be mainly influenced by stage of disease, with healthcare costs increasing as the disease 
progresses. Despite a lot of new therapies were available in the several years, the prognosis of 
metastatic NSCLC patients remains poor with a mean 5-year survival rate of approximately 5% 
worldwide [10]. Similar to those in other countries, a majority of lung cancer in China are 
diagnosed at an advanced stage. A study from a tertiary hospital in east China showed that over 
half of lung cancer patients were diagnosed at an advanced stage [13]. A comprehensive analysis 
of several large-scale statistical results from 2000 to 2009 in China showed that the 5-year 
survival rate of stage I in NSCLC patients is about 70%, stage II is about 50%, stage III is about 
15%, and stage IV is only about 5% [14]. The prognosis of lung cancer is still poor among most 
Chinese patients. Systemic treatment for NSCLC has advanced significantly with several new, 
effective agents available within recent years. Developing some more effective medication 
regimens to achieve long‐term declines in death rates was one of the strategies to further 
reduce the burden of disease.
Numerous gene mutations or alterations have been identified as molecular therapeutic targets 
that impact the choice of therapy. These mutations/alterations are generally not overlapping, 
although 1% to 3% of NSCLC tumours may harbor concurrent alterations [1]. Since it was 
identified in 1980s, EGFR aberrant activation has been shown to be prognostic in NSCLC, 
which provided a solid rationale for the development of EGFR-targeting strategies. Overall, the 
activating EGFRm have been found to be more frequent in never-smokers, in patients with the 
adenocarcinoma histological subtype and in women. Besides those, the prevalence of the EGFR 
mutations is also higher in East Asian patients than in Caucasian patients. Activating mutations 
in exons 18-21 of the kinase domain of EGFR are found in approximately 15% of patients with 

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lung cancer in the US [15], 10% of patients with lung cancer in the European Economic Area 
[16-19], and 30% to 50% of patients with lung cancer in Asia [20-23]. In Chinese NSCLC 
patients, genetic alterations are consistently more frequent than in western countries [24]. 
According to PIONEER (NCT01185314), a prospective genetic analysis of advanced lung 
adenocarcinoma, it suggested the prevalence of activating EGFRm in Chinese patients is 50.2%
and is as large as 59.6% of people who have never smoked [21, 25].
Even though two major EGFR-activating mutations of ex19Del and L858R account for over 
85% of all EGFRm, the remaining less than 15% patients acquire uncommon mutations of 
EGFR [26]. They are a heterogeneous group of molecular alterations and often detected as co-
occurance with classic mutations which called complex or compound mutations in NSCLC [27]. 
It is estimated that over 75,000 worldwide and 28, 000 NSCLC patients in China have
uncommon EGFRm. The largest study which investigated the epidemiology of common and 
uncommon EGFR mutations in a cohort of Chinese NSCLC patients reported that uncommon 
mutations comprised 11.9% of all EGFRm in this cohort, which is comparable with the 
prevalence reported in previous studies [28]. 
EGFR-TKIs have become the established first-line treatment in patients with advanced NSCLC 
harboring EGFR ex19del or L858R substitution mutations. Among them, osimertinib seemed 
to be the most effective and other candidates included erlotinib, afatinib, gefitinib, or 
dacomitinib [1]. Patients with advanced EGFRm NSCLC who receive EGFR-TKIs have a 
median OS of more than 2 years which in contrast to the survival of unselected NSCLC patients 
receiving platinum-based chemotherapy with approximately 1 year [29]. In NSCLC patients 
with activating EGFRm, response rates reached 50% to 80% under first-line EGFR-TKI 
treatment, compared with 15% to 34% in patients receiving platinum-doublet chemotherapy as 
first-line therapy [30-32].  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2.1
Study Rationale
Uncommon EGFRm are defined as all mutations excluding ex19del and L858R in exons 18-21. 
The number of NSCLC patients with uncommon EGFRm is relatively small and they represent
a heterogeneous group of molecular alterations. Due to the complicated genotypes and limited 
number of cases, few prospective clinical trials examined the clinical benefits of systemic 
therapy likes chemotherapy or EGFR-TKIs in patients with uncommon EGFRm. 
The NCCN 2020 guidelines include pemetrexed in combination with cisplatin or carboplatin as 
category 1 first-line systemic therapy options for patients with adenocarcinoma of non-
sensitizing EGFR mutation (Error! Reference source not found.).  ESMO 2019 guidelines 
recommend pemetrexed in preference to gemcitabine or docetaxel for use in combination with 
platinum-based chemotherapy in patients with nonsquamous tumours (level II, Grade A) [33].  
Per the ASCO guideline, platinum/pemetrexed combinations are acceptable options for patients 
with stage IV NSCLC [34]. Moreover, international guidelines recommend pemetrexed 
maintenance. ESMO 2019 guidelines recommend 4 cycles of platinum-based doublets followed 
by less toxic maintenance monotherapy as first-line treatment of NSCLC without actionable 
oncogenic driver regardless of programmed death ligand 1 (PD-L1) status [33]. It also appears 
that there are no prospective studies that have assessed whether pemetrexed maintenance is 
superior to no maintenance treatment (or placebo) specifically in patients with EGFRm disease 
who have been treated with 6 cycles of platinum-pemetrexed therapy. In hence, pemetrexed 
plus carboplatin or cisplatin for 4-6 cycles, followed by pemetrexed maintenance has been 
widely accepted as a standard of care or standard chemotherapy for nonsquamous NSCLC 
patients in current clinical practise.
 
 
 
 
.
 
 
 
 
 
 

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2.2
Background
The accurate landscape and frequency of uncommon EGFRm in NSCLC are still controversial. 
A previous study of genomic signatures by target next-generation sequencing (NGS) in Chinese 
NSCLC patients showed that uncommon EGFRm sites include but not limited to several 
patterns likes G719X/S768I/L861X, exon 20 insertion, de novo T790M, complex ones and 
others [35]. A comprehensive view of uncommon EGFR mutations from five studies 
demonstrated that the G719X mutation in exon 18 was the most frequent point mutation, 
representing approximately 26% of uncommon EGFR mutations, followed by L861Q mutation 
in exon 21 (17%) and S768I mutation in exon 20 (9%). Then various exon 20 insertions 
accounted for 19% of uncommon EGFR mutations. In these data, complex mutations were not 
listed alone and were included as part of the other mutations [36]. Meanwhile, another study in 
Chinese patients reported the most frequent uncommon EGFRm was exon 20 insertion (30.7%), 
followed by G719X mutation (21.1%), compound L858R mutation (17.0%) and T790M 
mutation (13.8%) [28]. Compared with previous EGFR-TKIs, the improved efficacy of third 
generation EGFR-TKI, osimertinib in patients with acquired T790M has been confirmed. 
However, the efficacy of osimertinib in patients with de novo T790M-positive cases as the 
primary treatment is still under investigating through AZENT phase II trial (NCT02841579). It 
also appeared that around 40-50% of uncommon EGFRm were at least dual mutation positivity, 
which account for approximately 3–14% of all EGFRm NSCLC patients. And the clinical 
parameters analysis showed that uncommon EGFRm were more frequent in men, never-
smokers, and adenocarcinomas[36, 37].
In addition, there was a significant heterogeneity in the response of these mutation sites to 
EGFR-TKIs. There are at least two subgroups such as major uncommon EGFRm or EGFR-
TKIs sensitizing ones include G719X/L861Q/S768I, exon 19 insertion, A763_Y764insertion, 
as well as rare uncommon EGFRm include exon 20 insertion except A763_Y764insertion, pre-
treatment de novo T790M and other uncommon mutations [1]. In a retrospective study in Asian
patients where 28 NSCLC patients harbouring various uncommon EGFRm, first or second 
generation EGFR-TKIs therapy showed greater benefits for OS than platinum-doublet 
chemotherapy [38]. Another retrospective study from China suggested that in patients with 

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G719X mutations following EGFR-TKI monotherapy, positive efficacy was observed with a 
median PFS of 11.6 months (95% CI: 3.6-19.6) which was comparable to median PFS observed 
in patients with sensitizing EGFRm [39]. In contrast, T790 M and exon 20 insertion were 
associated with disease control deficiency, with median PFSs of 1.0 month (95% CI: 0.0-2.2) 
and 3.0 months (95% CI: 1.3-4.7) respectively [28]. In addition, compound mutations of 
uncommon EGFRm (G719X+ L861Q and G719X+ S768I) with or without co-occurring 
classical mutations may generally have the favourable survival outcomes [37, 39]. Controversy 
over the treatment of uncommon EGFRm NSCLC patients still remains despite some completed 
and ongoing clinical trials have been conducted. 
A lot of clinical studies suggested that the majority of uncommon EGFRm in populations
studied showed decreased sensitivity to EGFR-TKIs or chemotherapy when compared with 
common EGFRm [28]. In a post-hoc analysis of North East Japan Study Group (NEJ) 002 study, 
among the patients with uncommon EGFRm likes G719X/L861Q who were treated with 1st 
generation EGFR-TKI, gefitinib at any treatment line, the survival outcome of patients with 
uncommon EGFRm was greatly worse than that of patients with common EGFRm (11.9 months 
vs. 29.3 months, p < 0.001) [40]. Among 161 patients with stage IIIB/IV lung adenocarcinoma 
bearing G719X/S768I/L861Q mutations enrolled in a study from Taiwan, China, it also 
exhibited a significantly inferior tumour response rate than patients with common mutations in 
the controlled group (41.6% vs. 66.5%; P<0.001) and median PFS (7.7 vs. 11.4 months; 
P<0.001) after receiving EGFR-TKIs treatment [41]. Another retrospective analysis showed a 
significantly shorter mPFS in uncommon and complex EGFRm after EGFR-TKIs therapy when
compared with ex19del and L858R mutations (4.0 (0.0-8.2) months and 8.6 (0.0-18.4) months 
vs. 14.0 (12.2-15.8) months and 13.0 (10.7-15.3) months) [42]. These results mainly indicated 
that single uncommon or complex EGFRm generally confers inferior efficacy of EGFR-TKIs 
treatment to the classic mutations. However, when comparing uncommon EGFRm with 
common EGFRm subgroups in patients receiving platinum doublet chemotherapy, slightly 
decrease but no significance of survival time was observed (22.8 vs. 28.0 months; p= 0.358) 
[40]. 
Several studies have preliminarily explored the efficacy of EGFR-TKIs in Chinese NSCLC 
patients with uncommon EGFRm. Zhang et al reported the ORR of 1st generation EGFR-TKIs 
was 20.0% and mPFS was 6.4 (95% CI: 4.8-7.9) months [43]. Consistently, Chen et al observed 
the ORR of 28.8% and a median PFS of 4.8 (95% CI: 3.5-6.1) months of uncommon EGFRm 
after EGFR-TKIs therapy [44]. For those treated with 1st generation EGFR-TKIs or platinum-
based chemotherapy, Shi et al identified that median PFS was similar (7.1 vs. 6.1 months, 
P=0.893) in the uncommon EGFRm group [45]. Meanwhile, for the first-line treatment efficacy 
between 1st generation EGFR-TKIs and platinum-based chemotherapy, it showed no difference 
in ORR (33% vs. 27.1% P=0.499), but a superior median PFS of EGFR-TKIs therapy was 
measured in significance (7.2 months vs. 4.9 months, P = 0.0088) [44]. In terms of safety and 
improving the quality of life of patients, with fewer adverse reactions and better tolerance, 

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EGFR-TKIs show important signals of efficacy and safety in NSCLC patients with uncommon 
EGFRm.
With the development of molecular diagnostic techniques and detailed mutated gene profile, for 
the first-line treatment of NSCLC with uncommon EGFRm, EGFR-TKIs can be used in patients 
with sensitizing uncommon EGFRm likes G719X/L861Q/S768I, A763_Y764insertion, while 
others without sensitizing EGFRm should not be treated with EGFR-TKIs in any line of therapy
and platinum-based chemotherapy remains the mainstream of treatment options [1]. Some data 
from Chinese patients also support the opinion. In patients with EGFR G719X/L861Q 
mutations, the longer median PFS was observed in the first-line EGFR-TKIs treatment group 
than in the chemotherapy group, but the difference was not statistically significant (G719X: 8.2 
vs. 5.8 months, P=0.061; L861Q: 7.6 vs. 4.1 months, P=0.872) [46]. For more details, Xu et al 
ascertained that the EGFR-TKI therapy was effective in Chinese patients with G719X/L861Q 
mutations while less effective in patients with exon 20 insertion/T790M (median PFS: 8.90 
months (95% CI: 4.47-13.34) / 5.98 months (95% CI: 1.53-10.42) vs. 2.00 months (95% CI: 
0.00-5.41) / 1.94 months (95% CI: 0.00-4.43)) [39]. A real-world study conducted in patients 
with exon 20 insertion mutations showed better outcome in those received first-line platinum-
based chemotherapy compared to a promising antitumor activity of 1st generation and all 
generation EGFR-TKIs (ORR 19.2% vs. 0% and 8.7%; mPFS 6.4m vs. 2.0m and 2.9m) [47].
Given the history of the first-line treatment options in common EGFRm NSCLC patients, a
similar trend of promoted efficacy was observed especially in sensitizing uncommon EGFRm 
NSCLC patients. A previous retrospective study showed that the ORR and median PFS from 
platium-based doublet chemotherapy, and 1st generation EGFR-TKI, gefitinib were around 
46.7% and 4.6 months, as well as 23.3% and 7.1 months in patients with G719X/S768I/L861Q 
EGFRm respectively [46]. Additionally, the second generation EGFR-TKI, afatinib has been 
approved to treat three uncommon EGFRm likes G719X/S768I/L861Q through FDA in 2018. 
The data from LUX-Lung 2,3,6 trials (NCT00525148, NCT00949650, NCT01121393) showed 
ORR and median PFS for afatinib treatment in G719X/L861Q/S768I were 71.1% and 10.7 
months, but less effective in T790M, and exon 20 insertion mutations (ORR: 14.3%, 8.7%; 
mPFS: 2.9 months, 2.7 months) [2]. Osimertinib, as the first approved third generation EGFR-
TKI in worldwide, there is a lack of comparable data from controlled trials currently. In China, 
Chinese Society of Clinical Oncology (CSCO) guidelines adopted the post-hoc analysis data to 
support the usage of afatinib in patients with G719X/L861Q/S768I mutations while 
chemotherapy as first-line treatment mainly for the rest NSCLC patients with other uncommon 
EGFRm [48].
Based on the FLAURA study, osimertinib has emerged as standard first-line treatment for 
patients with metastatic EGFRm NSCLC. The study assessed treatment with osimertinib 
compared to standard of care EGFR-TKI (erlotinib or gefitinib) and showed the clinically 
meaningful and statistically significant mPFS (18.9m vs. 10.2m, HR 0.46) and OS (38.6m vs. 

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31.8m, HR 0.799) benefit [6-7]. However, the study did not include those with simple 
uncommon EGFRm. A recent phase II, single arm study from Korea (NCT03424759) showed 
that the ORR and mPFS was 50% and 8.2 months of osimertinib in both first- and subsequent-
line treatment of patients with G719X/L861Q/S768I EGFRm [3]. Interestingly, the latest 
research has indicated a promising antitumor activity of osimertinib with ORR 66.7% and mPFS 
6.2m for 6 patients with certain exon 20 insertion mutation [49]. Moreover, in the phase II 
ECOG-ACRIN 5162 trial (NCT03191149), patients with exon 20 insertion of EGFRm 
receiving
showed ORR was 24%, and mPFS was 9.6 months (95% 
CI: 4.1-10.7) [50]. Compared with osimertinib as a first-line treatment for patients with common 
EGFRm, the therapeutic advantage from available data in major uncommon EGFRm population 
is limited. Therefore, there is a great unmet need in the treatment of NSCLC patients with 
uncommon EGFRm. As a highly mixed but small subpopulation of EGFR-positive NSCLC 
patients, it requires more optimal choices of therapy besides EGFR-TKIs monotherapy because 
of insufficient evidence to date from randomized clinical trials.. 
The hypothesis that the addition of platinum and pemetrexed chemotherapy to osimertinib could 
extend the benefit of osimertinib therapy is supported by NEJ 009 study. In this study 344 
patients with newly diagnosed stage III/IV/ recurrent NSCLC harbouring an EGFR activating 
mutation (ex19del or L858R) were randomized 1:1 to receive gefitinib 
 
 in combination with carboplatin AUC5 and pemetrexed 
 followed by pemetrexed maintenance. Median PFS was 
statistically significantly longer in the gefitinib in combination with chemotherapy arm than that 
in the gefitinib monotherapy arm (20.9 months (95% CI: 18.0-24.2) vs. 11.2 months (95% CI: 
9.0-13.4), respectively). The HR was 0.49 (95% CI: 0.390, 0.623; p<0.001). Second mPFS (the 
period from randomization to PD of the second-line therapy or death, whichever occurred first 
in the gefitinib monotherapy arm, but the same as the PFS in the combination group) was similar 
in both arms, with a median of 20.9 months (95% CI: 18.0, 24.2) in the gefitinib in combination 
with chemotherapy arm vs. 21.1 months (95% CI:1 7.9, 24.9) in the gefitinib monotherapy arm 
(HR= 0.891 (95% CI: 0.708, 1.122); p = 0.806). Overall survival was longer in the gefitinib in 
combination with chemotherapy arm than in the gefitinib monotherapy arm, with a median OS 
of 52.2 months (95% CI: 41.8, 62.5) vs. 38.8 months (95% CI: 31.1, 47.3), respectively (HR = 
0.70 (95% CI: 0.58, 0.95); p = 0.013) [4, 5].
In addition, data from 5 prospective studies (3 randomized, 2 single arm) of gefitinib in 
combination with pemetrexed monotherapy or platinum/pemetrexed doublet therapy followed 
by pemetrexed maintenance and a retrospective study of erlotinib with chemotherapy 
(predominantly platinum/pemetrexed) further support the concept of adding chemotherapy to 
EGFR-TKI therapy in the first-line treatment for patients with advanced EGFRm NSCLC [51-
56]. These results showed that for the patients with EGFRm, the combination strategy (EGFR-
TKIs plus chemotherapy) could provide superior ORR (over 80%), mPFS and/or OS compared
to those of 1st generation EGFR-TKI alone while the combination treatment was tolerable and 

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safe. 
Considering the similar molecular pathogenesis of uncommon and common EGFRm in 
NSCLC, it is supposed a combination therapy may improve clinical responses and bring the 
improved clinical benefit of patients with uncommon EGFRm. The combination treatment 
strategy is promising due to its potential synergistic anti-cancer effect through induction of 
cellular apoptosis, suppressing mitogenic and anabolic signalling, as well as restricting the 
development of drug tolerance [57]. It is evident that heterogeneous mechanisms are responsible 
for acquired resistance to first-line osimertinib, and detailed mechanisms of acquired resistance 
to first-line osimertinib is limitedly understood. Platinum doublet chemotherapy is currently 
recommended following systemic progression on osimertinib. So concurrent treatment of 
osimertinib and chemotherapy may guarantee that patients can receive chemotherapy during 
their treatment journey. On the other hand, not all patients who progress on first-line EGFR-
TKI therapy subsequently receive platinum doublet chemotherapy or single-agent 
chemotherapy as second- or later-line therapy because of poor physical condition. Given that 
patients in the proposed trial are required to have a PS of 0 or 1, all the participants will fit 
enough to receive platinum/pemetrexed chemotherapy.
 
 
 
 
 
 
 
 
A detailed description of the chemistry, pharmacology, mechanism of action, efficacy, and safety 
of osimertinib is provided in the Investigator's Brochure (IB). A detailed description of the 
pharmacology, pharmacokinetics, efficacy, and safety of cisplatin or carboplatin and 
pemetrexed are provided in the respective prescribing information.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
osimertinib plus cisplatin or carboplatin and pemetrexed may be found in the IB, Patient
Information Leaflet, Package Insert, Development Safety Update Report (DSUR).
2.3.1
Risk Assessment
2.3.1.1
Osimertinib

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The tolerability profile of osimertinib when given as monotherapy is well characterized and 
suitable for long term dosing. In a pooled dataset that incorporated data from 1142 patients with 
EGFR mutation-positive NSCLC who received 
 osimertinib in all lines of therapy (first-
, second-, and ≥thirdline) in Phase I-III studies (FLAURA, AURA Phase I, AURA extension, 
AURA2, and AURA3), the median duration of osimertinib therapy was 12.9 months (mean, 
13.9 months; range, <0.1 – 40.1 months). In the FLAURA trial based on a data cut-off of June 
25th 2019, the median duration of treatment exposure was 20.7 months (range, 0.1 to 49.8) in 
the osimertinib group. The number of patients who were continuing to receive the assigned trial 
drug at the time of the data cutoff was 61 (22%) in the osimertinib group.
In the above pooled dataset that incorporated data from of 1142 patients treated with osimertinib 
, most adverse drug reactions (ADRs) were Common Terminology Criteria 
for Adverse Events (CTCAE) Grade 1 or 2 in severity. The most commonly reported ADRs 
were diarrhea (49%) and rash (47%). Other typical EGFR-TKI ADRs include dry skin, pruritis, 
paronychia and stomatitis. CTCAE Grade 3 and Grade 4 adverse reactions occurred in 9.7% 
and 0.9% of patients, respectively. Dose reductions due to ADRs occurred in 2.1% of the 
patients and discontinuations due to ADR in 4.3% of patients. 
Interstitial Lung Disease (ILD) or ILD-like ADRs (eg, pneumonitis) were reported in 3.9% and 
were fatal in 0.4% (n=5) of the 1142 patients who received osimertinib 
 in the FLAURA 
and AURA studies. The incidence of ILD was 10.4% in patients of Japanese ethnicity, 1.8% in 
patients of non-Japanese Asian ethnicity and 2.8% in non-Asian patients. The median time to 
onset of ILD or ILD-like adverse reactions was 2.8 months. 
Of the 1142 patients in FLAURA and AURA studies treated with osimertinib 
, 0.9% were 
found to have a corrected QT interval (QTc) greater than 500 msec and 3.6% of patients had an 
increase from baseline QTc greater than 60 msec. No QTc-related arrhythmia events were 
reported in the FLAURA or AURA studies. A pharmacokinetic/pharmacodynamic analysis with 
osimertinib predicted a drug-related QTc interval prolongation at
 of 14 msec with an 
upper bound of 16 msec (90% CI).
Decreases from baseline in median values for platelets, neutrophils and leucocytes were 
observed early in treatment with osimertinib. Median values appear to stabilize after the initial 
drop with the majority of patients experiencing a single grade change or no change in CTCAE 
grade. As would be expected with the small magnitude of these changes, no clinically significant 
sequelae in the population have been observed.  
AEs of leukopenia, lymphopenia, neutropenia and thrombocytopenia have been reported, most 
of which were mild or moderate in severity and did not lead to dose interruptions.
Keratitis was reported in 0.7% of the 1142 patients treated with osimertinib in the FLAURA 
and AURA studies.

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Across clinical trials, left ventricular ejection fraction (LVEF) decreases greater than or equal 
to 10% and a drop to less than 50% occurred in 3.9% of patients treated with osimertinib who 
had baseline and at least one follow-up LVEF assessment. Based on the available clinical trial 
data, a causal relationship between effects on changes in cardiac contractility and osimertinib 
has not been established.
Further details on the clinical safety profile of osimertinib including guidance on management 
of ADRs is available in the Investigator’s Brochure.
2.3.1.2
Chemotherapy
In this study, the background treatment included only pemetrexed plus cisplatin or carboplatin
regimen. The safety profile of pemetrexed as monotherapy and in combination with cisplatin or
carboplatin is well defined.
In a Phase III study of cisplatin and pemetrexed administered up to 6 cycles (but without 
pemetrexed maintenance), Grade 3 or 4 drug-related hematological toxicities occurred in the 
following:  neutropenia (15% of patients), anemia (6%), and thrombocytopenia (4%). Drug-
related Grade 3 or 4 non-haematological toxicities occurred in the following:  nausea (7.2%), 
vomiting (6.1%), fatigue (6.7%), and febrile neutropenia (1.3%). In addition, alopecia of any 
grade was reported in 11.9% of patients and dehydration in 3.6% of patients [58].
In a placebo-controlled Phase III study of pemetrexed maintenance following completion of 4 
cycles of cisplatin and pemetrexed in patients with EGFR unselected NSCLC, the most common 
Grade 3 or 4 ADRs included anemia (4.8% of patients), neutropenia (3.9%), fatigue (4.5%), 
nausea (0.3% )and mucositis/stomatitis (0.3%). In this study the median number of cycles of 
pemetrexed maintenance was 4; 47% of patients received ≥6 cycles and 28% received ≥10 
cycles [59].
It should be noted that the present study of osimertinib with platinum/pemetrexed chemotherapy 
is estimated to explore an median PFS around 13 months. Assuming 5 months for the first 6
cycles of carboplatin/pemetrexed doublet therapy, this equates to a median duration of 
pemetrexed of 8 months (ie, approximately 11 cycles assuming patients receive pemetrexed 
maintenance and do not discontinue for reasons other than disease progression); thus, the 
average duration of pemetrexed treatment is anticipated to be shorter than has been observed in 
previous studies in which the median PFS was 18.3-20.9 months [60, 5]. Gefitinib in 
combination with platinum/pemetrexed with pemetrexed maintenance was generally well 
tolerated in these studies which provides reassurance for the present study.
There is evidence of cumulative nephrotoxicity in patients receiving pemetrexed therapy [61, 
62]. With this in mind, in order to help maximize the potential to administer prolonged 
pemetrexed maintenance, patients will be required to have a screening creatinine clearance of ≥
60 mL/min. Careful monitoring of renal function will be carried out during administration of 

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study medication plus background treatment in the present study. The background treatment 
may be interrupted by investigator if creatinine clearance is <45 mL/min and permanently 
discontinued .
Platinum agents, most notably cisplatin, are associated with nephrotoxicity, ototoxicity and 
neuropathy; therefore, careful monitoring will be carried out.
2.3.1.3
Safety data from studies of chemotherapy with EGFR TKI therapies.
In Phase III studies of platinum-based chemotherapy (cisplatin/gemcitabine and 
carboplatin/paclitaxel) with or without EGFR-TKIs in patients with EGFR unselected NSCLC, 
there is no clear evidence that combination treatment increases the incidence of hematological 
toxicity or non-hematological toxicity other than the expected EGFR-TKI toxicities of rash and 
diarrhea [63-66].
In studies of EGFR-TKIs with or without pemetrexed-based chemotherapy in patients with 
EGFR mutation positive NSCLC, including the Phase III study of gefitinib with or without 
carboplatin/pemetrexed chemotherapy [5, 55], Phase III study of osimertinib with 
cisplatin/carboplatin and pemetrexed (FLAURA2) and Phase II studies [51-54, 56, 60], 
hematological toxicities were more common in patients receiving combination therapy 
compared with EGFR-TKI therapy alone. In safety run-in part of FLAURA2 study, no dose 
reductions due to a haematological AE were reported for any study treatment. In another study 
2/127 (1.6%) patients receiving pemetrexed and gefitinib died as a result of AEs that were 
considered related to IP (pneumonitis and interstitial lung disease) [51]. However, across studies 
combination therapy was not clearly associated with a marked increased incidence of severe 
ILD. Overall, the safety profile of first-line EGFR-TKI therapy in combination with 
platinum/pemetrexed chemotherapy is manageable.
2.3.1.4
Potential for osimertinib and chemotherapy overlapping toxicity
The theoretical potential for overlapping toxicity between osimertinib and platinum/pemetrexed 
chemotherapy exists and includes the potential for additive hematological toxicity.  
Decreases from baseline in median values for platelets, neutrophils, lymphocytes and 
leukocytes have been observed early in treatment with osimertinib. Median values appear to 
stabilize after the initial decrease with the majority of patients experiencing a single CTCAE 
grade change or no grade change.
The FLAURA and AURA studies suggested the incidence of CTCAE all grade shifts and 
CTCAE ≥Grade 3 shifts in laboratory values of patients treated with osimertinib 
 includes 
the following: leukocytes decreased all grades 68% and ≥Grade 3 1.5%; neutrophils decreased 
all grades 35% and ≥Grade 3 4.1%; lymphocytes decreased all grades 67% and ≥Grade 3 7.2%; 
and platelet count decreased, all grades 54% and ≥Grade 3 1.6%. Dose reductions due to AEs 

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of neutropenia and thrombocytopenia were reported in 0.4% and 0.3% of patients, respectively
[6, 7]. 
Platinum agents and pemetrexed are associated with myelosuppression. Carboplatin is 
associated with a higher incidence of severe thrombocytopenia than cisplatin [67].
Other potential overlapping toxicities include but are not limited to rash, diarrhea, stomatitis 
and ILD. In clinical trials, cases of interstitial pneumonitis with respiratory insufficiency, 
sometimes fatal, have been reported uncommonly in patients treated with pemetrexed 
(Pemetrexed SmPC). Interstitial lung disease has also been observed in patients receiving 
carboplatin (Carboplatin SmPC).
There is also the potential for overlapping toxicity with respect to effects on fertility. Based on 
studies in animals, male fertility and female fertility may be impaired by treatment with 
osimertinib. For further details see the osimertinib IB. Gonadal suppression resulting in 
amenorrhea or azoospermia may occur in patients receiving antineoplastic therapy and such 
effects may be irreversible. Moreover, chemotherapy can have genetically damaging effects.  
Guidance on contraception requirements and sperm donation is provided in Section 5.3 and 
Appendix E. 
Due to the possibility of platinum-based chemotherapy and pemetrexed treatment causing 
irreversible infertility, men allocated to receive osimertinib and chemotherapy are advised to 
seek counselling on sperm storage before starting treatment. 
A Japanese Phase II open-label, randomized study of osimertinib alone vs. osimertinib plus 
carboplatin/pemetrexed for patients with locally-advanced or metastatic NSCLC whose disease 
has progressed with previous EGFR-TKI therapy and whose tumours harbour a T790M 
mutation within the EGFR gene is ongoing (TAKUMI Study LOGIK1604/NEJ032A; 
UMINCTR: UMIN). An interim safety review was conducted based on data from the first cycle 
in 24 patients (12 on monotherapy and 12 on combination therapy). One ≥Grade 3 AE was 
reported in the osimertinib arm (Grade 3 decreased neutrophil count); whereas, in the 
combination arm, 4 episodes each of Grade 3 or 4 decreased white blood cell count, decreased 
neutrophil count, decreased platelet count, and anemia; 2 episodes of Grade 3 skin rash, and 1 
episode each of Grade 3 bronchial infection, oral mucositis, hypertension, and hypokalemia 
were reported.  The authors stated that “The event frequency in the combination arm was similar 
to that in previous studies of carboplatin/pemetrexed. Exaggeration of AEs by osimertinib or 
previously unobserved events were not apparent in the combination arm.” The authors 
concluded “The combination treatment was safe in the selected patient population” [68] and the 
Safety Review Committee for the study recommended that the study continue to enroll patients.
In a retrospective analysis of patients with advanced EGFRm NSCLC treated off-label with 
concurrent chemotherapy and osimertinib, 18 patients received 25 chemotherapy regimens in 

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combination with osimertinib, including 10 platinum doublets (8 on carboplatin/pemetrexed) 
and 15 monotherapy regimens (6 on pemetrexed) [50].  All patients had progressed on third-
generation EGFR-TKI monotherapy before the addition of chemotherapy. One Grade 4 
neutropenia (pemetrexed) and 5 Grade 3 neutropenia (1 carboplatin/pemetrexed; 2 pemetrexed; 
1 gemcitabine; 1 carboplatin/nab-paclitaxel) were reported; 3 patients received support with 
granulocyte colony stimulating factors. Other Grade 3 toxicities were rare and all were 
reversible: 1 aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) elevation 
(carboplatin/pemetrexed), 1 thrombocytopenia (carboplatin/pemetrexed), and 1 anemia 
(carboplatin/pemetrexed). Adverse events led to treatment delay in 5 patients, osimertinib dose-
reduction in 2 patients, and discontinuation of regimen in 2 patients. There were no cases of 
pneumonitis. The authors concluded that osimertinib does not appear to add significant toxicity 
to the various chemotherapy regimens.
The FLAURA2 study is currently underway, which is a global Phase III study of osimertinib, 
with cisplatin/carboplatin and pemetrexed in patients with locally-advanced or metastatic 
EGFRm NSCLC who have not received any prior therapy for advanced disease. Of the 43 
patients enrolled in the safety run-in period, 13 patients did not receive treatment, resulting in 
30 patients (15 patients in the osi-carbo-pem cohort and 15 patients in the osi-cis-pem cohort) 
who received at least one dose of study intervention.The overall incidence of SAEs and CTCAE 
Grade 3 or higher AEs were 20.0% (6/30 patients) and 36.7% (11/30 patients), respectively. The 
proportion of patients who were reported with an AE leading to death was low (1 patient; 3.3%), 
which was considered unrelated to study intervention (osi-carbo-pem) by the reporting 
investigator, and was also attributed to the disease under study. AEs infrequently led to the 
permanent discontinuation of any study treatment (7/30 patients overall [23.3%]). Dose 
modifications (interruption and/or reduction) of any study intervention due to AEs were 
reported in the minority of patients (4/15 patients [26.7%] in the osi-carbo-pem cohort, and 2/15 
patients [13.3%] in the osi-cis-pem cohort).Following the review of all available data, the Safety 
Review Committee concluded that there were no new safety signals with osimertinib when used 
in combination with chemotherapy, and recommended that the FLAURA2 study progress to the 
randomised period with no additional safety measures required. The safety data from 
FLAURA2 safety run-in period provide sufficient confidence in the safety of osimertinib with 
carboplatin/pemetrexed treatment in this study.
2.3.2 Benefit Assessment
Although there can be no certainty of clinical benefit to patients, the positive efficacy data for 
osimertinib from FLAURA, supported by the Phase III NEJ 009 study and several other studies 
of 1st generation EGFR-TKIs in combination with pemetrexed or carboplatin/pemetrexed in 
patients with EGFR mutation-positive NSCLC, provide supportive evidence for evaluation of 
osimertinib with cisplatin/carboplatin plus pemetrexed as first-line treatment for locally 
advanced or metastatic or recurrent NSCLC patients with uncommon EGFRm.

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2.3.3 Overall Benefit: Risk Conclusion
Based on a review of the potential benefits and risks, it is considered to be reasonable and 
appropriate to investigate the concurrent use of osimertinib and standard chemotherapy 
(platinum plus pemetrexed therapy followed by pemetrexed maintenance) in the first-line 
treatment for participants with locally-advanced or metastatic or recurrent uncommon EGFRm 
NSCLC.

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4
STUDY DESIGN
4.1
Overall Design
This is a phase II, open-label, single-arm,  multicenter, exploratory study to assess the efficacy 
and safety of osimertinib plus standard chemotherapy in locally advanced or metastatic or 
recurrent NSCLC participants with uncommon EGFRm (single or multiple mutations of 
G719X/L861Q/S768I/de novo T790M without other EGFR mutations including ex19del and 
L858R). The main assumption is that osimertinib plus chemotherapy could further enhance the 
ORR in these patients.
Locally advanced or metastatic or recurrent NSCLC patients with uncommon EGFRm who are 
untreated or received previous adjuvant/neoadjuvant chemotherapy that was completed at least 
6 months prior to the development of recurrent disease will be enrolled into the study. Patients 
should have at least one lesion that can be accurately measured at baseline of study enrolment 
according to RECIST 1.1. Meanwhile, their mutation status must be confirmed through one of 
ARMS, Super-ARMS or NGS analysis, of which test method and product were reviewed and 
approved by the Chinese regulatory authority, to reduce waiting time. 
Considering the low prevalence of uncommon EGFRm in Chinese newly diagnosed NSCLC 
patients, as well as other reasons for potential screen failure, participants with locally confirmed 
uncommon EGFRm report would be recruited so it’s estimated that around 10% screen failure 
rate would be appropriate. Thus, a total of 40 patients across 10 sites will be screened over 12 
months, with approximately 35 participants anticipated to be enrolled. Platinum based doublet 
chemotherapy as standard of care for the participants is considered as background treatment in 
this study. The participants will be treated with osimertinib (
plus
standard 
chemotherapy which composed of cisplatin or carboplatin and pemetrexed i.v. for 4 to 6 cycles 
(dose , method and detail information, please see Section 6.1), followed by pemetrexed 
maintenance therapy. The osimertinib will be used to treat participants till treatment 
discontinuation criteria achieved such as inadequate cycles of platinum and pemetrexed 
treatment, or discontinuation of pemetrexed maintenance, unacceptable or irreversible toxicities, 
or confirmed objective disease progression as defined by RECIST 1.1, or symptomatic 
progression requiring urgent medical intervention (eg, CNS metastases, respiratory failure, 
spinal cord compression), or death, or study completion, or consent withdrawal.
Following treatment discontinuation, subsequent therapy will be at the discretion of the 
Investigator. Patients will be followed till death, or study completion after subsequent 
treatments for survival analysis. 
Baseline evaluation consists of demography, physical examination, weight, height, medical 
history, smoking history, ECOG/WHO performance status, brain enhanced MRI, chest and 

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abdomen enhanced CT imaging, concomitant medication, ECG, echocardiogram/MUGA, as 
well as clinical chemistry, haematology, and urinalysis testing.
Patients will undergo the efficacy assessments based on RECIST 1.1 assessment criterion at 
week 6 , 12, 18, 24 and later every 9 weeks, until objective disease progression. The survival 
follow-up will be repeated every 12 weeks after disease progression until study complete. 
There will be 3 analyses planned for this study. The data cut-off (DCO) date for primary analysis 
for ORR will be at 24 weeks after last subject in (LSI). The second analysis DCO for median 
PFS will be at the point when approximately 21 progression events (60% of maturity of PFS 
events) achieved. The final OS analysis will be performed when at approximately 21 death
events (60% maturity of OS events) achieved.  
What’s more, participants will undergo the safety assessment in the whole treatment period and 
28-day safety follow-up visit after discontinued osimertinib for any reason or study complete.
All adverse events and laboratory abnormalities will be graded according to NCI-CTCAE 5.0.
To evaluate the potential molecular resistance mechanism at disease progression after 
osimertinib plus chemotherapy treatment by plasma analysis, as well as the correlation between 
these genomic changes and clinical efficacy, plasma samples will be collected at the baseline 
and the disease progression in enrolled patients. And then the resistance profiling of molecular 
alterations including but not limited to mutations in, amplifications and expression of relevant 
pathway genes would be detected by NGS analysis.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for primary and secondary endpoint
The primary endpoint of this study is ORR, which on tumour imaging is one intuitive end point 
for single-arm trial design given its historical role in drug development. ORR is a rather 
convincing measure of anti-tumour activity more directly from treatment as for most tumours.
The secondary endpoints include PFS, which has been widely accepted as a surrogate endpoint 
for clinical benefit in studies of patients with advanced NSCLC. PFS also represents a direct 
effect of the efficacy of osimertinib with platinum plus pemetrexed chemotherapy as it is not 
confounded by the efficacy of different subsequent therapies used after disease progression. 
Other time to event measurements (Duration of response and overall survival) will be also 
evaluated as a secondary endpoint, as well as disease control rate, depth of response and OS.
4.2.2
Testing for uncommon EGFR mutations
Only 
participants 
with 
NSCLC 
with
one 
or 
multiple
EGFR
mutations
of
G719X/L861Q/S768I/de novo T790M and without other EGFR mutations including ex19del

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The study may be terminated at individual study sites if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment process is slow. The 
study may be terminated due to futility. AstraZeneca may also terminate the entire study 
prematurely if concerns for patient safety arise within this study or in any other study with 
osimertinib.
A participant is considered to have completed the study when he/she has completed his/her last 
scheduled visit or last scheduled assessment shown in the Schedule of Assessments (SoA) 
(Table 1).
The study may be stopped if, in the judgment of AstraZeneca, study participants are placed at 
undue risk because of clinically significant findings.
After the study is completed, study results will be disseminated as outlined in the guidelines in 
Appendix A 6.
See Section 0 for details on participant management following the final OS analysis as well as 
following study completion.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each subject should must 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. Participants who 
do not meet the entry requirements are screen failures, refer to Section 5.4. 
For procedures for withdrawal of incorrectly enrolled patients see Section 7.3
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Informed consent
1. Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
2. Provision of signed and dated, written informed consent form prior to any mandatory study-
specific procedures, sampling, and analyses. 
The ICF process is described in Appendix A3.
Age
3. Male or female, at least 18 years of age.

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Type of participants and disease characteristics
4. Pathologically confirmed nonsquamous NSCLC 
5. Newly diagnosed locally advanced (clinical stage IIIB, IIIC) or metastatic NSCLC (clinical 
stage IVA or IVB) or recurrent NSCLC (per Version 8 of the International Association for 
the Study of Lung Cancer [IASLC] Staging Manual in Thoracic Oncology), not amenable 
to curative surgery or radiotherapy.
6. The tumour harbors at least 1 of the 4 uncommon EGFR mutations (G719X/L861Q/S768I/ 
T790M), either alone or in combination, which not include other EGFR mutations including 
ex19del /L858R, assessed by one of ARMS, Super-ARMS or NGS analysis on the basis 
of tumour tissue or plasma testing from accredited laboratories approved by the Chinese 
regulatory authority. 
7. Participants must be considered suitable by investigator and about to receive standard of 
care which composed of pemetrexed plus carboplatin or cisplatin for 4 to 6 cycles followed 
by pemetrexed maintenance.
8. Participants must have untreated advanced NSCLC not amenable to curative surgery or 
radiotherapy. Prior adjuvant and neo-adjuvant therapies (chemotherapy, radiotherapy, 
immunotherapy, 
biologic 
therapy, 
investigational 
agents), 
or 
definitive 
radiation/chemoradiation with or without regimens including immunotherapy, biologic 
therapy, investigational agents, are permitted as long as treatment was completed at least 6 
months prior to the development of recurrent disease.
9. Stable CNS metastases participants will be allowed.
10. ECOG/WHO PS of 0 to 1 at screening with no clinically significant deterioration in the 
previous 2 weeks.
11. Life expectancy >12 weeks at Day 1.
12. At least 1 lesion, not previously irradiated 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 CT or MRI, and that is suitable for accurate repeated measurements. If only 1 
measurable lesion exists, it is acceptable to be used (as a target lesion) as long as it has not 
been previously irradiated and as long as it has not been biopsied within 14 days of the 
baseline tumour assessment scans. 
Reproduction
13. Female must be using highly effective contraceptive measures, must not be breast feeding, 
and must have a negative pregnancy test prior to first dose of study intervention or must 
have evidence of non-child-bearing potential by fulfilling 1 of the following criteria at 
screening:
-
Post-menopausal, defined as more than 50 years of age and amenorrhoeic for at least 
12 months following cessation of all exogenous hormonal treatments
-
Women under 50 years old would be considered as postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 

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treatments and have luteinizing hormone (LH) and follicle-stimulating hormone (FSH) 
levels in the post-menopausal range for the institution
-
Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation.
Further information is available in Appendix E (Definition of Women of Childbearing 
Potential and Acceptable Contraceptive Methods).
14. Male participants must be willing to use barrier contraception (see Section 5.3).
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical conditions
1
Spinal cord compression; symptomatic and unstable brain metastases, except for those 
participants who have completed definitive therapy, are not on steroids, and have a stable 
neurological status for at least 2 weeks after completion of the definitive therapy and 
steroids. Participants with asymptomatic brain metastases can be eligible for inclusion if in 
the opinion of the Investigator immediate definitive treatment is not indicated.  
2
Past medical history of ILD, drug-induced ILD, radiation pneumonitis that required steroid 
treatment, or any evidence of clinically active ILD.
3
Any evidence of severe or uncontrolled systemic diseases, including uncontrolled 
hypertension and active bleeding diatheses, which in the Investigator’s opinion makes it 
undesirable for the participant to participate in the trial or which would jeopardize 
compliance with the protocol, or active infection including any patients receiving treatment 
for infection but not limited to hepatitis B, hepatitis C and human immunodeficiency virus 
(HIV). Screening for chronic conditions is not required.
4
Any of the following cardiac criteria: 
!
Mean 
resting 
corrected 
QT 
interval 
(QTc) 
>470 msec, 
obtained 
from 
3 electrocardiograms (ECGs), using the screening clinic ECG machine-derived QTcF 
value;
!
Any clinically important abnormalities in rhythm, conduction, or morphology of 
resting ECG; eg, complete left bundle branch block, third-degree heart block, second-
degree heart block;
!
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as electrolyte abnormalities including serum/plasma potassium*, magnesium* 
and calcium* below the lower limit of normal (LLN), heart failure, congenital long QT 
syndrome, family history of long QT syndrome, or unexplained sudden death under 40 
years of age in first-degree relatives or any concomitant medication known to prolong 
the QT interval and cause Torsades de Pointes. See Section 6.4 and Appendix F.

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* correction of electrolyte abnormalities to within normal ranges can be performed 
during screening
5
Inadequate bone marrow or organ function reserve as demonstrated by any of the following 
laboratory values: 
!
Absolute neutrophil count below the LLN *
!
Platelet count below the LLN*
!
Hemoglobin <90 g/L*
*The use of granulocyte colony stimulating factor support, platelet transfusion and 
blood transfusions to meet these criteria is not permitted.
!
ALT >2.5 x the upper limit of normal (ULN) if no demonstrable liver metastases or >5 
x ULN in the presence of liver metastases
!
AST >2.5 x ULN if no demonstrable liver metastases or >5 x ULN in the presence of 
liver metastases
!
Total bilirubin >1.5 x ULN if no liver metastases or >3 x ULN in the presence of 
documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver
metastases
!
Creatinine clearance <60 mL/min calculated by Cockcroft and Gault equation (refer to 
Appendix G for appropriate calculation)
6
Any concurrent and/or other active malignancy that has required treatment within 2 years 
of first dose of study intervention (osimertinib, carboplatin and pemetrexed).
7
Any unresolved toxicities from prior therapy (eg, adjuvant chemotherapy) greater than 
CTCAE Grade 1 at the time of starting study treatment, with the exception of alopecia and 
Grade 2 prior platinum-therapy related neuropathy.
8
Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the 
formulated product, or previous significant bowel resection that would preclude adequate 
absorption of osimertinib.
Prior/concomitant therapy
9
Prior treatment with any systemic anti-cancer therapy for advanced NSCLC not amenable 
to curative surgery or radiation including chemotherapy, biologic therapy, immunotherapy, 
or any investigational drug. Prior adjuvant and neo-adjuvant therapies (chemotherapy, 
radiotherapy, 
biologic 
therapy, 
investigational 
agents), 
or 
definitive 
radiation/chemoradiation with or without regimens including biologic therapies, 
investigational agents are permitted as long as treatment was completed at least 6 months 
prior to the development of recurrent disease. 
10 Prior treatment with an EGFR-TKI or immune-oncology (IO) therapy.

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11 Major surgery within 4 weeks of the first dose of study intervention. Procedures such as 
placement of vascular access, biopsy via mediastinoscopy or biopsy via video assisted 
thoracoscopic surgery (VATS) are permitted.
12 Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of 
radiation within 4 weeks of the first dose of study intervention.
13 Current use of (or unable to stop use prior to receiving the first dose of study treatment) 
medications or herbal supplements known to be strong inducers of cytochrome P450 
(CYP) 3A4 (at least 3 weeks prior) (Appendix F). All patients must try to avoid 
concomitant use of any medications, herbal supplements and/or ingestion of foods with 
known inducer effects on CYP3A4.
Prior/concurrent clinical study experience
14 Participation in another clinical study with an investigational product during the 4 weeks 
prior to Day 1. Participants in the follow-up period of an interventional study are permitted.
Other exclusions
15 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and staff at the study site).
16 Judgment by the Investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions and requirements.
17 Previously enrolled in the present study. 
18 Currently pregnant (confirmed with positive pregnancy test) or breast-feeding.
19 History of hypersensitivity to active or inactive excipients of study intervention or drugs 
with a similar chemical structure or class to study intervention.
20 In addition, the following conditions are considered criteria for exclusion:
!
Prior allogeneic bone marrow transplant
!
Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample 
collection.
5.3
Lifestyle Considerations
5.3.1
Pregnancy
The following restrictions apply while the participant is receiving study treatment and for the 
specified times before and after:
1
Female participants of child-bearing potential must use highly effective methods of 
contraception from screening until at least 6 weeks after discontinuing study treatment. 
Acceptable methods are provided in Appendix E (Definition of Women of Childbearing 
Potential and Acceptable Contraceptive Methods).

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2
Male participants must use barrier contraceptives (condoms) during sex with a female 
partner of child-bearing potential (including a pregnant partner) from the start of dosing 
until at least 6 months after discontinuing chemotherapy or at least 4 months after 
discontinuing osimertinib. In addition, participants must refrain from donating sperm from 
the start of dosing until at least 6 months after discontinuing chemotherapy or at least 4
months after discontinuing osimertinib.
5.3.2
Meals and Dietary Restrictions
Once enrolled all patients must try to avoid concomitant use of medications, herbal supplements 
and/or ingestion of foods that are known to be strong inducers of CYP3A4 whenever feasible.
If medically feasible, participants taking regular medication, with the exception of strong 
inducers of CYP3A4, should be maintained on their regular medication throughout the study 
period. Participants may receive any medication that is clinically indicated for treatment of 
adverse events. Such drugs must have been discontinued for an appropriate period before they 
enter screening and for a period of 3 months after the last dose of osimertinib.
Participants taking concomitant medications whose disposition is dependent upon BCRP and/or 
P-glycoprotein (Pgp) with 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 osimertinib. Guidance on medications to avoid, medications that require close 
monitoring and on washout periods is provided (see Appendix F).
Participants taking rosuvastatin should have creatine phosphokinase levels monitored (due to 
BCRP-mediated increase in exposure). If the participant experiences any potentially relevant 
AEs suggestive of muscle toxicity including unexplained muscle pain, tenderness, or weakness, 
particularly if accompanied by malaise or fever, rosuvastatin must be stopped and any 
appropriate further management should be taken.
The use of any natural/herbal products, as well as use of all vitamins, nutritional supplements, 
and all other concomitant medications should be recorded in the eCRF.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently initiated on study intervention. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened a single time. However, rescreening should be documented so that its effect on study 

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results, if any, can be assessed. All assessments must be repeated for rescreening unless they are 
within the 28-day screening period..
Participants who initially fail to qualify for the study based on safety laboratory test results (ie, 
clinical chemistry [including creatinine clearance] hematology and urinalysis) or ECG results 
may have their laboratory value and ECG assessment retested 1 time within the 28-day 
screening period at the discretion of the Investigator. Retesting within the 28-day screening 
period does not constitute rescreening; however, if retesting falls outside of the 28-day screening 
period, it should be considered a rescreen.
5.5
Procedures for handling incorrectly enrolled patients
Participants who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled to receive any study intervention.  There can be no exceptions to this rule.  Where a 
participant does not meet all the eligibility criteria but is 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 participant from treatment. The Study Physician should ensure 
all decisions are appropriately documented. The Investigator should make documentation in the 
medical record as appropriate.
6
STUDY INTERVENTION
Study intervention in this study refers to osimertinib. Participants would be given osimertinib 
as an add-on treatment to standard chemotherapy which was defined as background treatment.
Osimertinib and standard chemotherapy dosing should begin on the same day.
6.1
Study Intervention Administered
6.1.1
Investigational Product
AstraZeneca will supply osimertinib. Dose modifications are described in Section 0.
Table 3
Investigational Products
ARM Name
Osimertinib plus standard chemotherapy
Intervention Name
osimertinib 
Type 
drug
Dose Formulation
osimertinib: tablet
Dosage Level(s)
 
Dosage formulation, dose reduction
 

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Route of Administration
osimertinib: 
Use
experimental
IMP and NIMP
IMP 
Sourcing
Osimertinib: AstraZeneca
Packaging and Labelling
Osimertinib will be provided in blisters packed in cartons 
containing. Each carton will be labelled in accordance with 
GMP Annex 13 and per country regulatory requirement.
6.1.2
Dosing instructions
Osimertinib will be supplied as tablets for oral administration as 
 
 
Each box will contain sufficient osimertinib treatment for 21 days. 
 will be 
supplied as needed upon request. 
Osimertinib will be dispensed to participants at Cycle 1 Day 1 only after all study procedures 
and assessments have been performed and all eligibility criteria have been met. All the 
eligibility criteria are met as confirmed by the Investigator. It should be documented in the 
medical records in a proper manner.
Sufficient osimertinib treatment for 3 weeks will be distributed at each dispensing visit. 
 Tablets 
should be taken whole with water, with or without food. The tablet should not be crushed, split 
or chewed.
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.
Every effort should be made to minimize the time between enrolment and starting study 
treatment. Pre-treatment should be started as soon as possible and will take place prior to the 
start of study intervention (osimertinib). It is recommended that participants commence study 
treatment, standard chemotherapy or chemotherapy pre-treatment as soon as possible after 
enrolment and whenever possible within 1 day.  
To allow for management of study intervention-related toxicities, the initial dose of osimertinib 
 can be reduced to 
 (see Section 8.4). Once the dose of osimertinib 

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is reduced to 
, the participant will remain on the reduced dose until 
termination from study intervention. Re-challenge 
 not allowed in this study.
Doses should be taken approximately 24 hours apart at the same time each day. Doses should 
not be missed. If a participant misses taking a scheduled dose, it is acceptable to take the dose 
within a window of 12 hours. If it is more than 12 hours after the scheduled dose time, the 
missed dose should not be taken, and the participant should be instructed to take the next dose 
at the next scheduled time. If a participant vomits after taking the osimertinib, he/she should not 
make up for this dose, but should take the next dose at the scheduled time.
The reason for any missed dose and any change from dose interruptions, or dose reductions 
must be recorded in the medical record, the source document and the electronic Case Report 
Form (eCRF).
Additional information about osimertinib may be found in the Investigator’s Brochure.  
6.2
Preparation/Handling/Storage/Accountability of Interventions
1
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2
Only participants enrolled in the study may receive study intervention and only authorised 
site staff may supply or administer study intervention. All study intervention must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the investigator and 
authorised site staff.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, dispensing, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).
4
Used/unused study intervention will be disposed based on local procedures. The 
Investigator(s) is responsible for ensuring that the participant has returned all unused study 
intervention. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date, and time if applicable, of dose 
administered in the site will be recorded in the source documents and recorded in the eCRF. The 
dose of study intervention and study participant identification will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
intervention.
Any change and the reason for changing the dose interruption, dose delay, dose reduction, dose 
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The study intervention should be completely reconciled with supportive evidence provided in 
the source document such as drug accountability log or study drug diary or equivalent 
documents.
The delegated site staff is responsible for managing the study intervention from receipt by the 
study site until the destruction or return of all unused study interventions. The Investigator(s) or 
designee(s) is responsible for ensuring that the participant has returned all unused study 
interventions.
6.4
Concomitant Therapy
Any concomitant treatment, procedure, or other medication considered necessary by the 
investigator for the participant’s safety and wellbeing, or vaccine including over-the-counter or 
prescription medicines, vitamins, and/or herbal supplements or other specific categories of 
interest that the participant is receiving within 4 weeks prior to the first dose of study 
intervention or receives during the study including the 28-day follow-up period following the 
last dose of study intervention must be recorded in the eCRF along with:
!
Reason for use.
!
Dates of administration including start and end dates.
!
Dosage information including dose and frequency.
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
If any concomitant therapy is administered due to new or unresolved AE, it should be recorded.
Participants must be instructed not to take any medications, including over-the-counter 
products, without first consulting with the investigator.
Restricted, prohibited, and permitted concomitant medications/therapies are described in more 
detail in Appendix F 2.
Guidance regarding potential interactions with concomitant medications is provided in 
Appendix F 1.
6.4.1
Background medications
Standard chemotherapy defined as background medications in this study are described in the 
table below. The cisplatin or carboplatin plus pemetrexed regimen will be locally sourced. Full 
details on cisplatin, carboplatin and pemetrexed can be found in the local prescribing 
information for these products. Osimertinib and standard chemotherapy dosing should begin on 
the same day. Participants may receive pre-treatment and concomitant treatment (eg, 

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antiemetics) as recommended by the approved label for pemetrexed, cisplatin or carboplatin as 
clinically indicated by the Investigator.
Pemetrexed
Pemetrexed 
will be administered as 
as per 
local practice and labels until RECIST1.1-defined progression or another discontinuation 
criterion is met (see Section 7.1).
To reduce the severity of hematologic and gastrointestinal toxicity of pemetrexed toxicity, 
participants treated with pemetrexed may receive vitamin supplementation containing folic 
acid and vitamin B12. Furthermore, a corticosteroid may be given to reduce the incidence and 
severity of skin reactions. All these pre-treatment can be implicated according to clinical 
practice.
Cisplatin
Cisplatin 
will be administered as an IV infusion according to local practice and labels 
and should be 
immediately preceded and followed by hydration.
Participants who are receiving cisplatin are at increased risk of developing nephrotoxicity, 
ototoxicity, neuropathy, myelosuppression and nausea and vomiting and should be carefully 
monitored in accordance with local standards of care.
Carboplatin
Carboplatin 
 will be administered 
 
 according to local clinical practice and labels.
Carboplatin dose is calculated using the Calvert formula. The carboplatin dose is not to exceed 
Calvert Formula
 
 
 
 
 
 
 
 
 
 
 
 

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Subjects who are receiving carboplatin are at increased risk of developing myelosuppression 
nephrotoxicity and allergic reactions. In addition, ototoxicity and neuropathy have been 
observed. Participants should be carefully monitored in accordance with local standards of care
Table 4
Background Medications
Type 
Background medications
Dose Formulation
pemetrexed: ampule
cisplatin: ampule
carboplatin: ampule
Dosage Level(s)
pemetrexed 
plus carboplatin 
 
or cisplatin
 
 
Dosage formulation, dose reduction
Refer to the local drug instruction 
Route of Administration
pemetrexed: IV infusion
cisplatin/carboplatin: IV infusion
Use
Stand of care
IMP and NIMP
NIMP
Sourcing
Sourced locally
Packaging and Labelling
Sourced locally
6.4.2
Restricted and prohibited concomitant medications
Restricted and prohibited concomitant medications are described in the table below.  For 
questions related to specific medications, contact the Study Physician of sponsor. Guidance on 
medications to avoid, medications that require close monitoring, and on washout periods are 
provided in Appendix F.  
Table 5
Restricted, prohibited and allowed concomitant medications
Prohibited Medication/Class of drug:
Usage:
Other anti-cancer agents, investigational 
agents except cisplatin or carboplatin or 
pemetrexed and non-palliative 
radiotherapy
Should not be given while the participant is on 
study intervention.
Restricted Medication/Class of drug:
Usage:

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Strong inducers of CYP3A4. See 
Appendix F for a list of drugs.
Once enrolled all participants must try to avoid 
concomitant use of medications, herbal 
supplements and/or ingestion of foods that are 
known to be strong inducers of CYP3A4 
whenever feasible. Such drugs must have been 
discontinued for an appropriate period before the 
patient enters screening and for a period of 3 
months after the last dose of osimertinib.  
Patients may receive any medication that is 
clinically indicated for treatment of AEs. 
Medications whose disposition is
dependent upon the Breast Cancer 
Resistance Protein (BCRP) and/or P-
glycoprotein (P-gp) with a narrow 
therapeutic index. See Error! Reference 
source not found. for a list of drugs. 
Rosuvastatin
Closely monitor for signs of changed tolerability 
as a result of increased exposure to the 
concomitant medication while receiving 
osimertinib.
Patients taking rosuvastatin should have creatine 
phosphokinase levels monitored (due to BCRP-
mediated increase in exposure). If the patient 
experiences any potentially relevant AEs 
suggestive of muscle toxicity including 
unexplained muscle pain, tenderness, or 
weakness, particularly if accompanied by 
malaise or fever, rosuvastatin must be stopped 
and any appropriate further management should 
be taken.
Nonsteroidal Anti-Inflammatory Drugs
Subjects taking nonsteroidal anti-inflammatory 
drugs (NSAIDs) or salicylates will not take the 
NSAID or salicylate (other than an aspirin dose 
≤1.3 grams per day) for 2 days before, the day of, 
and 2 days after receiving pemetrexed.  Subjects 
taking NSAIDs or salicylates with a long half-
life (for example, naproxen, piroxicam, 
diflunisal, or nabumetone) will not take the 
NSAIDs or salicylates for 5 days before, the day 
of, and 2 days after pemetrexed. 

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Warfarin or other anticoagulant
Due to the possibility of an interaction between 
oral anticoagulants and anti-cancer 
chemotherapy, there is requirement to monitor 
International Normalized Ratio (INR) frequently, 
if it is decided to treat the patient with oral anti-
coagulants.
Participants taking warfarin or other 
anticoagulant with pemetrexed should be 
monitored regularly for changes in prothrombin 
time or INR.
Colony stimulating factors (CSFs)
Granulocyte colony stimulating factors (G-CSF) 
should not be used prophylactically during Cycle 
1. Following first cycle chemotherapy, growth 
factors may be used in accordance with the 
American Society of Clinical Oncology Clinical 
Practice Guideline Update on the use of WBC 
Growth factors [69] or in accordance with local 
standards of care.
Antiemetic therapy
See Section 6.4.3
Drugs that prolong the QT interval
Detailed guidance is provided in Appendix F and 
additional specific guidance regarding anti-
emetic drugs that can prolong the QT interval is 
provided in Section 6.4.3
Allowed Medication/Class of drug:
Usage:
Pre-medication will be allowed for subjects 
receiving osimertinib plus standard 
chemotherapy.  
To be administered as directed by the 
Investigator. This includes management of 
diarrhoea, nausea and vomiting.
Calcium folinate/folinic acid 
The use of calcium folinate/folinic acid in the 
management of pemetrexed overdose should be 
considered.

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Leukocyte-depleted blood transfusions
Participants can have blood transfusions during 
the study treatment. However, patients aren’t 
allowed to receive blood transfusions or platelet 
transfusions in order meet the inclusion criteria 
of the study.
Corticosteroids /bisphosphonates/Rank-
ligand inhibitors
Please see Section 6.1.2 for details relating to 
corticosteroid pre-medication for subjects 
receiving standard chemotherapy. 
Corticosteroids can be used for the management 
of bone metastases.
Regular, concomitant use of bisphosphonates and 
RANK-L inhibitors for management of bone 
metastases is permitted if therapy is initiated 
prior to first dose of study therapy. Initiation of 
therapy after enrollment is permitted in 
participants with no evidence of overall clinical 
or radiographic progression per RECIST 1.1. or 
in patients in survival follow-up.
Palliative local therapy-radiotherapy and 
surgical resection
Palliative local therapy, including radiation 
therapy and surgical resection for non-target 
lesions is permitted in participants with no 
evidence of overall clinical or radiographic 
progression per RECIST 1.1 or in patients in 
survival follow-up.
Vaccines
Vaccines can be administered in accordance with 
local labels.
6.4.3
Antiemetic therapy
In principle, antiemetic premedication should be administered according to local standards of 
care. QTc interval prolongation has been observed in participants treated with osimertinib, 
however no QTc-related arrhythmias were reported in the FLAURA or AURA studies. Given 
that some antiemetic therapies have been associated with QT interval prolongation with or 
without Torsades de Pointes (TdP), caution is required with respect to co-administration of 
osimertinib with antiemetics in this study given.  

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The 
Arizona 
Centre 
for 
Education 
and 
Research 
on 
Therapeutics 
(https://www.crediblemeds.org/) is a website that categorizes drugs based on the risk of causing 
QT prolongation or TdP. Information on these categories and antiemetic therapies is provided 
in Table . The list of drugs may not be exhaustive; moreover the information regarding drugs in 
the table below is subject to change as new information on drugs becomes available.  As such 
investigators should review the up-to-date website.
Table 6
QT/TdP risk category for antiemetic therapies
QT/TdP risk Category
Definition
Antiemetic therapies
Known risk of TdP
These drugs prolong the QT 
interval AND are clearly 
associated with a known risk of 
TdP, even when taken as 
recommended
domperidone
droperidol
haloperidol
levomepromazine
levosulpiride
ondansetron
Possible risk of TdP
These drugs can cause QT 
prolongation BUT currently lack 
evidence for a risk of TdP when 
taken as recommended.
dolasetron
granisetron 
palonosetron
tropisetron

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QT/TdP risk Category
Definition
Antiemetic therapies
Conditional Risk of TdP
These drugs are associated with 
TdP BUT only under certain 
conditions of their use (eg, 
excessive dose, in patients with 
conditions such as hypokalemia, 
or when taken with interacting 
drugs) OR by creating 
conditions that facilitate or 
induce TdP (eg, by inhibiting 
metabolism of a QT-prolonging 
drug or by causing an electrolyte 
disturbance that induces TdP).
metoclopramide
An additional risk category applies to Drugs to Avoid in Congenital Long QT Syndrome 
(cLQTS); however, participants with congenital long QT syndrome are not permitted to enroll 
in this study.
In the light of this information, the following guidance is given:At screening participants are 
required to have serum electrolytes ≥LLN; ie, potassium, magnesium and calcium in the 
normal range. If during screening participants have electrolyte levels <LLN, measures can be 
taken to bring these into the normal range and retesting would be conducted. During study 
treatment, electrolyte levels should be maintained in the normal range.
Investigators should review guidance that applies to all drugs (ie, not just anti-emetics) with the 
potential for interaction with osimertinib regarding QTc interval prolongation (see Appendix 
F). 
In this study it is strongly recommended that antiemetic drugs from the known risk of TdP 
category 
are 
not 
given, 
ie, 
ondansetron, 
domperidone, 
droperidol, 
haloperidol, 
levomepromazine, or levosulpiride. If it is considered essential to give a 5-HT3 receptor-
antagonist, one of the following agents should be given if available: granisetron, dolasetron, 
tropisetron or palonosetron. However, as these drugs are categorized as having a possible risk 
of TdP, careful monitoring of ECGs and electrolytes is recommended. If it is essential to give a 
5-HT3 receptor- antagonist and ondansetron is the only available 5-HT3 receptor- antagonist, 
careful monitoring with ECGs and electrolytes is recommended.

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Note neurokinin-1 receptor (NK-1) antagonists such as aprepitant are not associated with QTc 
interval prolongation.
6.4.4
Other concomitant treatment
Other medication other than that described above, that is considered necessary for the 
participant’s safety and wellbeing may be given at the discretion of the Investigator and 
recorded in the appropriate sections of the eCRF.
6.4.5
Prior immune-oncology therapy
Participants who were treated with immune oncology (IO) drug prior to study enrolment 
are prohibited to participate in this study. Immune-oncology therapies are prohibited 
during the study.
6.5
Dose Modification
Dose modifications are permitted in the management of study intervention-related toxicities as 
described in Section 8.4.
6.6
Intervention after the End of the Study
After the final OS analysis for this study, AstraZeneca will not provide any of the study 
intervention free of charge for participants even if the investigator judges that the participant
can still benefit from that. All participants may continue on treatments which follow local 
clinical practice.
If a roll-over or safety extension study is available at the time of the final OS analysis and 
database closure, participants currently receiving treatment with osimertinib and standard 
chemotherapy may be transitioned to such a study, and the current study would reach its end. 
The roll-over or extension study would ensure treatment continuation with visit assessments per 
its protocol, as applicable. Any participant who would be proposed to move to such a study 
would be given a new informed consent, as applicable.
6.7
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfil GMP Annex 13 requirements for labelling. Label 
text will be translated into local language.
Osimertinib will be relabelled to indicate “clinical use only”, and also will include study number 
site number and subject number etc.

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6.8
Storage
All study drugs should be kept in a secure place under appropriate storage conditions (sealed, 
below 30 ° C). The osimertinib label on the boxesspecify the appropriate storage.
As an investigational drug, the osimertinib 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).
6.9
Accountability
The osimertinibd 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 participant.
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 study intervention.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention (osimertinib) for the situations listed below. If study intervention are
permanently discontinued, regardless of the reason, the participant will be identified as having 
permanently discontinued treatment and continue in follow-up per the protocol. The investigator 
should instruct the participant to contact the site before or at the time if any study intervention 
is stopped. A participant that decides to discontinue study intervention will always be asked 
about the reason(s) and the presence of any AEs. The reason for discontinuation should be 
documented in the source document and the appropriate section of the eCRF.
Participants who have permanently discontinued from further receipt of study intervention will 
need to return all study intervention at their next on-site study visit or unscheduled visit.
Participants may be discontinued from study intervention in the following situations. 
!
RECIST 1.1-defined radiological progression (refer to Appendix D) (notes: participants 
can still receive osimertinib at their own expenses if clinical benefits exists).
!
Investigator determination that the participant is no longer benefiting from study 
intervention.
!
Inadequate (less than 4 times totally) doublet chemotherapy cycles of platinum plus
pemetrexed before pemetrexed maintenance.

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!
Permanently discontinuation of pemetrexed maintenance.
!
An AE that, in the opinion of the investigator or AstraZeneca, contraindicates further 
dosing.
!
Any AE that meets criteria for discontinuation defined in the dose modification guidelines 
for management of study intervention-related toxicities (see Section 8.4)
!
Participant decision. The participant is at any time free to discontinue treatment, without 
prejudice to further treatment. A participant who discontinues treatment is normally 
expected to continue to participate in the study (eg, for safety and survival follow-up) 
unless they specifically withdraw their consent to all further participation in any study 
procedures and assessments (see Section 7.2).
!
Severe non-compliance with the CSP as judged by the investigator or AstraZeneca.
!
Pregnancy or intent to become pregnant.
!
Initiation of subsequent anticancer therapy, including another investigational agent.
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study.
7.1.1
Follow-up of Participants Post Discontinuation of Study Intervention
All participants who discontinue the study intervention will be followed up for safety 
assessments 28 days (+7 days) after their last dose of study intervention. Additional assessments 
to be performed at the time of the discontinuation (+10 days) are detailed in the SoA. 
Participants who have discontinued study intervention for the reason other than objective 
RECIST 1.1-defined radiological progression prior to the DCO for PFS analysis, regardless of 
whether or not they have commenced subsequent anticancer therapy, will be followed up with 
tumour assessments as indicated in the SoA until RECIST 1.1-defined PD or the DCO for PFS 
analysis, whichever occurs first, regardless of whether or not the participant started a subsequent 
anticancer therapy, unless they have withdrawn all consent to study-related assessments. After
PD or the DCO for PFS analysis, participants will continue to be followed for progression 
defined as per local clinical practice. Investigator assessment of response/progression will be 
collected up to disease progression or until the final OS analysis. SAEs considered related to 
study intervention and/or study procedures will be collected until disease progression or end of 
study, whichever occurs earlier.
7.1.2
Follow-up for Survival
Participants will be followed up for survival status as indicated in the SoA until death, 
withdrawal of consent, or the end of the study. Survival information may be obtained via 
telephone contact with the participant or the participant’s family, or by contact with the 
participant’s current physician. Additional assessments to be performed at the time of survival 
follow-up are detailed in the SoA.

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7.2
Intervention through progression
At the Investigator’s discretion, study intervention may continue for as long as a patient 
continues to derive clinical benefit after RECIST 1.1 progression in the absence of any 
discontinuation criteria before the end of the study. However, if the patient is deemed to have 
clinically significant, unacceptable or irreversible toxicities, rapid tumor progression, or 
symptomatic progression requiring urgent medical intervention (eg, CNS metastases, 
respiratory failure, spinal cord compression) study intervention must be discontinued. 
Participants who continue on study intervention following progression should maintain the 
schedule of assessments as shown below:
!
Routine safety measurements (AEs, safety laboratory assessments [clinical chemistry, 
haematology and urinalysis], and creatinine clearance calculation);
!
Routine clinical procedures (physical exam, ECOG/WHO PS, vital signs, ECGs, Echo/ 
MUGA [every 12 weeks relative to first dose ], and concomitant medications).
In addition, patients who continue on treatment following progression will continue to be 
followed up for survival status every 12 weeks until death, withdrawal of consent, or the final 
OS analysis as per the survival follow-up column shown in the SoA (Table 1). 
7.3
Participant Withdrawal from the Study
!
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural,
compliance, or administrative reasons. This is expected to be uncommon.
!
A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options to ensure the collection of endpoints and 
safety information including new AEs and follow-up on any ongoing AEs and concomitant 
medications (eg, telephone contact at 28 days (+7 days) after study intervention is 
discontinued, a contact with a relative or treating physician, or information from medical 
records).
!
At the time of withdrawal from the study, if possible, an Early Study Intervention 
Discontinuation visit should be conducted, as shown in the SoA. See SoA for data to be 
collected at the time of study withdrawal and follow-up and for any further evaluations that 
need to be completed.
∀
The participant will discontinue the study intervention and be withdrawn from the 
study at that time.
!
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

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!
If a participant withdraws from the study, it should be confirmed if he/she is still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried in line with what was stated in the informed consent and local regulation. The 
investigator must document the decision on use of existing samples in the site study records
and inform the Study Team.
7.4
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and no contact has been established by the time the study is completed (see 
Section 4.4), such that there is insufficient information to determine the participant’s status at 
that time.
Participants who decline to continue participation in the study, including telephone contact, 
should be documented as “withdrawal of consent” rather than “lost to follow-up.” Investigators 
should document attempts to re-establish contact with missing participants throughout the study 
period. If contact with a missing participant is re-established, the participant should not be 
considered lost to follow-up and evaluations should resume according to the protocol.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
!
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.
!
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. Should the participant continue to be unreachable, he/she will be 
considered to have been lost to follow-up from the study and censored at the latest follow-
up contact.
!
Site personnel will attempt to collect the vital status of the participant during survival 
follow-up within legal and ethical boundaries for all participants. Public sources may be 
searched for vital status information. If vital status is determined as deceased, this will be 
documented and the participant will not be considered lost to follow-up. Sponsor personnel 
will not be involved in any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.

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8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA (Table 1). Data collection 
following study analysis until the end of the study is described below. 
!
Protocol waivers or exemptions are not allowed.
!
The Investigator ensures the accuracy and completeness of the eCRFs including legibility 
and timeliness of the data recorded and of the provision of answers to data queries according 
to the Clinical Study Agreement. The Investigator will sign the completed eCRF and a copy 
will be archived at the study site.
!
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
!
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
!
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
8.1
Efficacy Assessments
8.1.1
Imaging Tumour Assessments 
Tumour assessments use images from CT (preferred) or MRI, with IV contrast, of the chest and 
abdomen, collected during screening/baseline and at 6 weeks (±1 week), 12 weeks (±1 week), 
18 weeks (±1 week), 24 weeks (±1 week), and then every 9 weeks (±1 week) relative to first 
dose of study intervention until radiological disease progression. Any other areas of disease 
involvement should be additionally imaged at screening based on known metastasis sites or by 
the signs and symptoms of individual participants. Tumour assessments of the brain will be part 
of the RECIST 1.1 assessment for Investigators (recorded as non-target lesions), using images 
from contrast-enhanced T1 MRI (preferred over CT) that are collected at screening and at 
progression for all participants. In addition, participants with brain metastases or a history of 
brain metastases at screening should be followed up with repeated imaging assessments using 
the same frequency as the extracranial scans to allow whole-body RECIST assessments until 
progression. If brain metastases are not detected (within 28 days prior to enrolment), or if the 
participant does not have a history of brain metastases, the participant is not required to undergo 
further imaging of the brain unless metastases are suspected by the Investigator, or until 

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(extracranial) PD is assessed with RECIST 1.1 by the Investigator. Once PD is assessed in 
participants without brain metastases or without a history of brain metastases, a brain scan 
should be performed within 4 weeks, but preferably as soon as possible, to allow the assessment 
of new lesions in the brain. 
If participants are contraindicated to CT contrast agents, a non-contrast CT otherwise MRI will 
be acceptable. In those participants who are contraindicated to contrast agents based on 
gadolinium-diethylenetriamine penta-acetic acid (Gd-DTPA), a non-contrast MRI would be 
sufficient. In those participants with a contraindication to MRI, a (contrast-enhanced) CT of the 
brain would be sufficient. The imaging modality used for baseline tumour assessment, CT/MRI
for chest and abdomen and MRI for brain, should be kept the same consistently at each 
subsequent follow-up assessment throughout the study if possible. It is important to follow the 
tumour assessment schedule as closely as possible (refer to the SoA) relative to first dose. 
Screening/baseline imaging should be performed no more than 28 days before start of study 
intervention and ideally should be performed as close as possible to and prior to the start of 
study intervention. Treatment continues until RECIST 1.1-defined radiological progression 
(refer to Appendix D), and scanning/tumour assessments continue throughout treatment until 
RECIST 1.1-defined radiological progression by Investigator assessment. If an unscheduled 
assessment is performed (eg, to investigate clinical signs/symptoms of progression) and the 
participant has not progressed, every attempt should be made to perform the subsequent 
assessments at the next scheduled visit. 
The baseline assessment is part of the screening procedures and ideally should be performed as 
close as possible to and prior to the first dose of treatment. Scans obtained prior to first dose of
treatment do not need to be repeated and are acceptable to use as baseline evaluations, if the 
following criteria are met:
!
the scan is obtained within 28 days before the first dose of study intervention;
!
the scan is performed using the method requirements outlined in RECIST 1.1 (contrast-
enhanced CT is recommended for imaging the chest and abdomen, including liver and 
adrenal glands, whereas contrast-enhanced MRI is recommended for brain scans);
!
the same technique/modality can be used to follow identified lesions throughout the trial 
for a given participant; 
!
appropriate documentation indicating that these radiographic tumour assessments were 
performed as standard of care is available in the participant’s source notes.  
Participants with a CT scan of the brain obtained prior to the first dose of treatment will not be 
required to have an MRI brain scan during screening if the criteria above are met.
The RECIST 1.1 assessments of baseline images identify target lesions (TLs; defined as 
measurable) and non-target lesions (NTLs). On-study images are evaluated for TLs and NTLs 

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chosen at baseline, and for new lesions (NLs) when they appear. This allows determination of 
follow-up TL response, NTL lesion response, the presence of unequivocal NLs, and overall time 
point responses (complete response [CR], partial response [PR], stable disease [SD], PD, or not 
evaluable [NE]). Data obtained up until progression, or the last evaluable assessment in the 
absence of progression, will be included in the assessment of ORR. Participants who 
discontinue study intervention without progression, receive a subsequent therapy, and then 
respond will not be included as responders in the analysis of ORR.
If the Investigator is in doubt as to whether progression has occurred, particularly with response 
on NTLs or the appearance of a NLs, it is advisable to continue treatment until the next 
scheduled assessment (or sooner assessment, if clinically indicated) and reassess the 
participant’s status. If repeat scans confirm progression, then the date of the initial scan should 
be declared as the date of progression.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1
Physical Examinations
Physical examination will be performed and include assessments of the following; general 
appearance, skin, head and neck (including ears, eyes, nose and throat), respiratory,
cardiovascular, abdomen, lymph nodes, thyroid, musculoskeletal (including spine and 
extremities) and neurological systems. 
Height will be measured during screening only.  Physical examination, and assessment of 
weight, will be performed at timelines as specified in the SoA; investigators should pay special 
attention to clinical signs related to previous serious illnesses, new or worsening abnormalities 
may qualify as AEs, see Section 8.3.6 for details.
8.2.2
Vital Signs
Vital signs will be performed at timelines as specified in the SoA.
Vital signs (to be taken before blood collection for laboratory tests) will be measured in a supine 
position after 5 minutes rest for the participant in a quiet setting without distractions (eg, 
television, cell phones) and will include systolic and diastolic blood pressure, temperature and 
pulse rate. Three readings of blood pressure and pulse will be taken. The first reading should be 
rejected. The second and third readings should be averaged to give the measurement to be 
recorded in the eCRF.
Changes in vital signs as compared to baseline may qualify as an AE, see Section 8.3.

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8.2.3
Electrocardiograms
Twelve-lead ECG will be performed at the visit indicated in the SoA (Table 1).
8.2.4
If there is a clinically significant abnormal ECG finding during the 
Treatment period, this should be recorded on the AE eCRF, according 
to standard adverse events collection and reporting processes. A 28-day 
follow-up assessment will be required if an on-treatment assessment was 
abnormal at the time of discontinuation of study therapy, to confirm 
reversibility of the abnormality.Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the visits indicated in the SoA (Table 1).
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date, time of collection and results (values, units and reference ranges) will be 
recorded on the appropriate eCRF.
Clinical chemistry, haematology, and urinalysis assessments that have been performed within 
14 days prior to starting study treatment do not have to be repeated on Cycle 1 Day 1 if the 
participant's condition has not changed.
The clinical chemistry, haematology and urinalysis will be performed at a central laboratory.
Other safety laboratory tests include assessment for pregnancy (serum at screening and urine 
thereafter). Pregnancy tests may be performed at the site using a licensed test (urine or serum 
pregnancy test). Abnormal clinically significant laboratory results should be repeated as soon 
as possible (preferably within 24 to 48 hours).
The following laboratory variables will be measured.

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Table 7
Laboratory Safety Variables
Haematology/Haemostasis (Whole Blood)
Clinical Chemistry (Serum or Plasma)
Haemoglobin
Albumin
Leukocyte count
Alanine transaminase (ALT)
Leukocyte differential count (absolute count)
Aspartate transaminase (AST)
Platelet count
Alkaline phosphatase (ALP)
Absolute neutrophil count
Bilirubin, total
Absolute lymphocyte count
Calcium, total
Absolute monocytes count
Creatinine
Absolute basophils count
Glucose
Absolute eosinophils count
Lactate dehydrogenase (LDH) a
Total white blood cell count
Magnesium
Total red blood cell count
Potassium
Haematocrit
Sodium
Reticulocytes
Urea/Blood Urea Nitrogen
Urinalysis
Haemoglobin/Erythrocytes/Blood 
Protein/Albumin 
Glucose 
ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase;
INR=international normalised ratio; PTT=partial thromboplastin time.
a
LDH is an additional variable collected during screening.
b
The value is to be provided as percentage of the leukocyte count if the absolute leukocyte differential counts are not 
available.
The investigator should assess the available results with regard to clinically relevant 
abnormalities in documentation. Any clinically significant abnormal laboratory values should 
be repeated as clinically indicated and recorded on the eCRF. Situations in which laboratory 
safety results should be reported as AEs are described in Section 8.3.6.
All participants with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from study intervention must be followed and have further tests performed until the laboratory 
values have returned to Grade 1 or 2, unless these values are not likely to improve because of 
the underlying disease.
8.2.5
Echocardiogram/Multigated Acquisition Scan 
An echocardiogram or MUGA scan to assess LVEF will be performed at the visits as shown in 
SoA (Table 1). The modality of the cardiac function assessments must be consistent for a given 
participant (ie, if echocardiogram is used for the screening assessment for a given participant, 
then echocardiogram should also be used for subsequent scans for that participant). The 

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participants should also be examined using the same machine and operator whenever possible, 
and quantitative measurements should be taken.
If a participant has had an echocardiogram or MUGA performed within 4 weeks prior to 
treatment discontinuation, the discontinuation visit echocardiogram/MUGA scan is not required 
unless clinically indicated. A 28-day follow-up assessment will be required if an on-treatment 
assessment was abnormal at the time of discontinuation of study intervention, to confirm 
reversibility of the abnormality.
Situations in which echocardiogram or MUGA results should be reported as AEs are described 
in Section 8.3.6.
8.2.6
ECGO/WHO Performance Status
ECOG/WHO performance status will be assessed at the times specified in the SoA (Table 1)
based on the following:
0
Fully active; able to carry out all usual activities without restrictions.
1
Restricted in strenuous activity, but ambulatory and able to carry out light work or work of 
a sedentary nature (eg, light housework or office work).
2
Ambulatory and capable of self-care, but unable to carry out any work activities; up and 
about more than 50% of waking hours.
3
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours.
4
Completely disabled; unable to carry out any self-care and totally confined to bed or chair.
5
Dead.
Any significant change from baseline or screening must be reported as an AE.
8.3
Collection of Adverse Events and Serious Adverse Events
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorised representative). 
The investigator and any designees are responsible for detecting, documenting, recording, and 
reporting events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
AEs will be collected from time of signature of informed consent form until 28 days after last 

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dose of study intervention or until the end of study follow-up (death, loss of follow-up, 
withdrawal of consent, end of study), whichever occurs earlier.
If the patient discontinues study intervention prior to disease progression, SAEs considered
related to study intervention and/or study procedures will be collected until disease progression 
or end of study, whichever occurs earlier. All SAEs will be recorded and reported to the sponsor 
or designee within 24 hours, as indicated in Error! Reference source not found..  The 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of the data being 
available.
Investigators are not obligated to actively seek AE or SAE in former study patients. However, 
if the Investigator learns of any SAE, including a death, at any time after a patient’s last visit 
and he/she considers the event to be reasonably related to the study treatment or study 
participation, the Investigator may notify the Sponsor.
The methods of recording, evaluating, and assessing causality of AE and SAE are provided in 
Error! Reference source not found..
If an Investigator learns of any SAEs, including death, at any time after a patient has 
discontinued study treatment (plus 28-day follow-up), and he/she considers there is a reasonable 
possibility that the event is causally related to osimertinib, the Investigator should notify 
AstraZeneca (see Section 8.4).  
8.3.2
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow up on each 
participant at subsequent visits/contacts. Any new or unresolved AE observed at 28-day follow-
up should be followed until the event resolves, stabilizes, or is otherwise explained, or the 
participant is lost to follow-up.  
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the Investigator for as long as medically indicated, but without further recording in the 
eCRF. AstraZeneca retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
8.3.3 Adverse event data collection
The following variables will be collected for each AE;
!
AE (verbatim)
!
The date when the AE started and stopped
!
Maximum CTCAE grade
!
Whether the AE is serious or not (Appendix B)

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!
Investigator causality rating against the study intervention(s) (yes or no)
!
Action taken with regard to study intervention(s)
!
AE caused participant’s withdrawal from study (yes or no)
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for SAE
!
Date Investigator became aware of SAE
!
Seriousness criteria
!
Date of hospitalisation
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed (yes or no)
!
Causality assessment in relation to study procedure(s) (yes or no)
!
Causality assessment to other medication (yes or no)
!
Description of SAE
The grading scales found in the National Cancer Institute CTCAE v5 will be utilised for all 
events with an assigned CTCAE grading. For those events without assigned CTCAE grades, 
the recommendation in the CTCAE criteria that converts mild, moderate, and severe events into 
CTCAE grades should be used. A copy of the CTCAE can be downloaded from the Cancer 
Therapy Evaluation Program website (http://ctep.cancer.gov).
8.3.4 Causality Collection
The Investigator should assess causal relationship between study intervention and each AE, and
answer “yes” or “no” to the question “Do you consider that there is a reasonable possibility that 
the event may have been caused by the investigational product?”
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as “yes”.
A guide to the interpretation of the causality question is found in Appendix B to the CSP.
8.3.5 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 

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from the study site staff: “Have you/the child had any health problems since the previous 
visit/you were last asked?”, or revealed by observation will be collected and recorded in the 
eCRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms. However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately.
8.3.6 Adverse Events Based on Examinations and Tests
The results from the CSP-mandated laboratory tests, vital signs, physical examinations, ECGs, 
and echocardiogram/MUGA scans will be summarised in the Clinical Study Report (CSR). 
Deterioration as compared with baseline in protocol-mandated laboratory values, vital signs 
ECG, or echocardiogram/MUGA scan should therefore only be reported as AEs if they fulfil 
any of the SAE criteria, are the reason for discontinuation of treatment with the study 
intervention or are considered to be clinically relevant as judged by the investigator (which may 
include but not limited to consideration as to whether treatment or non-planned visits were 
required or other action was taken with the study intervention, eg, dose adjustment or study 
intervention interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator uses 
the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally related 
to the disease under study.
8.3.7 Disease Progression
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the study intervention is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The 
development of new, or progression of existing metastasis to the primary cancer under study
should be considered as disease progression and not an AE. Events, which are unequivocally 
due to disease progression , should not be reported as an AE during the study.
Progression of the malignancy under study, including signs and symptoms progression, should 

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not be reported as an SAE. Hospitalization due to signs and symptoms of disease progression 
should not be reported as an SAE.
8.3.8 Disease Under Study
Symptoms of the disease-under study are those that might be expected to occur as a direct result 
of locally advanced or metastatic or recurrent NSCLC. Events which are unequivocally due to 
disease under study should not be reported as an AE during the study unless they meet SAE 
criteria or lead to discontinuation of the study intervention.
8.3.9
New Cancers
The development of a new cancer should be regarded as an AE and will generally meet at least 
one of the serious criteria. New primary cancers are those that are not the primary reason for 
the administration of study intervention and are identified after the participant’s inclusion in 
this study. They do not include metastases of the original cancer.
8.3.10
Deaths
All deaths that occur during the study intervention period, or within the protocol-defined 
follow-up period after the administration of the last dose of study intervention, must be reported 
as follows:
!
Death clearly resulting from disease progression should be documented in the eCRF in the 
Statement of Death page. It should not be reported as an SAE.
!
Where death is not due (or not clearly due) to disease progression of the disease under 
study, the AE causing the death must be reported as an SAE within 24 hours. It should also 
be documented in the Statement of Death page in the eCRF. The report should contain a 
comment regarding the co-involvement of disease progression, if appropriate, and should 
assign the main and contributory causes of death.
!
Deaths with an unknown cause should always be reported as an SAE and documented in 
the Statement of Death page in the eCRF, but every effort should be made to determine 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 should be forwarded to AstraZeneca Patient 
Safety or its representative within the usual time frames.
Deaths occurring after the protocol-defined follow-up period after the administration of the last 
dose of study intervention should be documented in the Statement of Death page. If the death 
occurred as a result of an event that started after the defined follow-up period and the event is 
considered to be due to a late-onset toxicity to study intervention, then it should also be reported 
as an SAE.

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8.3.11
Safety Data to be Collected Following the Final Data Cut off of the Study
AEs and SAEs will be collected from time of signature of ICF until 28 days after last dose of 
study intervention or until the end of study, whichever occurs earlier. For participants continuing 
to receive osimertinib after the final OS analysis, AEs related to osimertinib spontaneously will 
be reported to the AstraZeneca-designated mailbox.
8.4
Safety reporting and medical management
8.4.1
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedure(s). All SAEs will be recorded in the eCRF.
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.
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs 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 immediately but no 
later than 24 hours of when he or she becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative. If the EDC system 
is not available, then the investigator or other study site staff reports a SAE to the appropriate 
AstraZeneca representative by telephone followed by completion of a investigator-signed paper 
SAE form whose scanned copy should be emailed to AZ Data Entry Site immediately but no 
later than 24 hours of awareness. The AstraZeneca representative will advise the 
Investigator/study site staff how to proceed. 
Contact information of AZ Data Entry Site: 
E-mail: 
.
For further guidance on the definition of a SAE, see Appendix B of the CSP.  
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy with conception dates following the first date of 

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study intervention or within 6 weeks of the last dose of study intervention, including pregnancy 
in the partner of male participants, should be reported to AstraZeneca.
The investigator/site staff must inform the Study Representative immediately but no later than 
24 hours after he/she becomes aware of a pregnancy. The Study Representative will ensure the 
pregnancy is reported to AZ Data Entry Site (DES) within 30 calendar days of awareness.
Pregnancy in itself is not considered to be an AE or SAE unless there is a suspicion that the IP 
may have interfered with the effectiveness of a contraceptive medication. However, events of 
congenital abnormality/birth defect, spontaneous miscarriage or ectopic pregnancy, or any 
complications in the subject which meet the criteria for serious should also be reported as SAEs. 
Elective abortions without complications are not considered to be SAEs.
Pregnancy occurring in study subjects will be reported via the Pregnancy Case Record Form 
(CRF) module. However, a Pregnancy Form may be used in situations where EDC system is 
not utilized or when the pregnancy CRF modules are not available/appropriate, for example, if 
the pregnancy occurred in the partner of the study subject.
8.4.2.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, study intervention should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
participant was discontinued from the study.
If any pregnancy occurs during the study or within 6 weeks of the last dose of study intervention, 
then the investigator or other site personnel informs the appropriate AstraZeneca representatives 
within 1 day (ie, immediately but no later than 24 hours) of when he or she becomes aware of 
it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.4 ) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
8.4.2.2
Paternal Exposure 
Non-sterilised male participants who intend to be sexually active with a female partner of 

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For participants received standard chemotherapy over any dose higher than pemetrexed 
 
, or cisplatin 
, or carboplatin 
 
(see Section 6.4), please refer to the local prescribing information 
for treatment of cases of overdose. If any overdose is associated with an AE or SAE please 
record the AE/SAE diagnosis or symptoms in the relevant AE modules only of the eCRF.
8.4.4
Medication Error
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day (ie, immediately 
but no later than 24 hours) of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-threatening or follow-up 
Fatal/Life-threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3) and within 30 days for all other 
medication errors.
The definition of a medication error can be found in Appendix B.
8.4.5
Management of study intervention-related toxicities
All adverse events will be managed per standard local practice.
8.4.5.1
General dose adjustments for adverse events   
Osimertinib is the standard of care for participants with treatment-naïve sensitizing EGFR 
mutation NSCLC. And chemotherapy is the standard of care for participants without driver gene 
mutation NSCLC. In this study, osimertinib is considered as an investigational treatment and 
standard chemotherapy (cisplatin or carboplatin plus pemetrexed) as background treatment. As 
such, in order to maintain the dose intensity of the study intervention, it is recommended that if 
clinically appropriate, and where osimertinib interruption is not mandated, for the management 
of potential overlapping toxicities, dose interruption/dose reduction of chemotherapy in 
accordance with local practice/guidelines by the Investigating site is prioritized above dose 
interruption/dose reduction of osimertinib.
If appropriate, the Investigator may attribute each toxicity event to  osimertinib alone, or to 
standard chemotherapy alone, or to a combination of osimertinib and standard chemotherapy
and use a stepwise dose modification according to Table and Error! Reference source not 
found.. Dose modification can be implemented for the study treatment components depending 
upon the Investigator’s assessment of causality. If, in the opinion of the Investigator, a toxicity 
is considered to be due predominantly to the study intervention (osimertinib) and the dose is 
delayed or modified in accordance with the guidelines below, the standard chemotherapy may 

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be administered if there is no contraindication. If a participant experiences several toxicities and 
there are conflicting recommendations for those toxicities, the most conservative dose 
adjustment recommended should be followed (dose reduction appropriate to the most severe 
toxicity). Dose modifications for toxicities must be based on the maximum toxicity experienced 
during a cycle. Toxicity must resolve to CTCAE Grade ≤1 or baseline prior to resumption of 
study treatment.
Only 1 dose reduction is permitted for osimertinib treatment. If a participant experiences a 
toxicity associated with osimertinib that would cause a second dose reduction, osimertinib must 
be discontinued. If a dose reduction for toxicity occurs with osimertinib, the dose of osimertinib
may not be re-escalated. Moreover, osimertinib may be interrupted for a maximum of 3 weeks.
Participants may discontinue osimertinib and continue on standard chemotherapy alone if 
appropriate. The standard chemotherapy may be interrupted for a maximum of 3 weeks (ie, 6 
weeks since the last dose of chemotherapy).
Reasons for dose modifications or delays, the supportive measures taken, and the outcomes are 
to be documented in the participant's chart and recorded on the eCRF.
Table 8
Dose Modifications for Study Treatments
Initial dose
Dose reduction 1
Dose reduction 2
Osimertinib
Discontinue
8.4.5.2
Dose adjustment information for osimertinib
If a participant experiences a CTCAE Grade 3 or higher and/or unacceptable toxicity not 
attributable to the disease or disease-related processes under investigation, not covered by the 
specific guidance below, where the investigator feels that there is a reasonable possibility of a 
causal relationship with osimertinib, dosing of osimertinib will be interrupted and supportive 
therapy administered as required in accordance with local practice/guidelines. If the toxicity 
does not resolve to ≤CTCAE grade 2 after 3 weeks of withholding osimertinib, osimertinib must 
be permanently discontinued. If the toxicity resolves or reverts to ≤CTCAE Grade 2 within 
3 weeks of onset, treatment with osimertinib may be restarted at the same dose 
 or a 
lower dose (osimertinib 
) using the rules below for dose modifications (Table 9) and 
at the discretion of the Investigator. Following restart of treatment, the participant should be 
closely monitored for recurrence. There will be no individual modifications to dosing schedule 
in response to toxicity, only potential dose reduction or dose interruption. Further guidance is 
provided in Table and text below.
Table 9
Osimertinib dose adjustment information for adverse reactions
Target Organ
Adverse reaction*
Dose modification
Pulmonary
ILD/Pneumonitis
Permanently discontinue osimertinib

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Keratitis
Participants presenting with signs and symptoms suggestive of keratitis such as acute or 
worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red 
eye should be referred promptly to an ophthalmology specialist.
Changes in cardiac contractility
.An Echocardiogram or MUGA scan to assess LVEF will be performed at screening (prior to 
first dose of osimertinib) and at least every 16 weeks throughout the treatment period. The 
modality of the cardiac function assessments must be consistent within a patient i.e. if 
echocardiogram is used for the screening assessment then echocardiogram should also be used 
for subsequent scans. The patients should also be examined using the same machine and 
operator whenever possible, and quantitative measurements should be taken. A 28-day follow-
up assessment will be required if an on-treatment assessment was abnormal at the time of 
discontinuation of study intervention, to confirm reversibility of the abnormality.
Erythema Multiforme and Stevens-Johnson syndrome 
Case reports of Erythema multiforme (EM) and Stevens-Johnson syndrome (SJS) have been 
uncommonly and rarely reported, respectively, in association with osimertinib treatment. Before 
initiating treatment, participants should be advised of signs and symptoms of EM and SJS. If 
signs and symptoms suggestive of EM develop, close participant monitoring and drug 
interruption or discontinuation of osimertinib should be considered. If signs and symptoms 
suggestive of SJS appear, osimertinib should be interrupted or discontinued immediately.
Permanent discontinuation due to toxicity
Patients experiencing Interstitial Lung Disease (ILD/pneumonitis) or QTc prolongation with 
signs/symptoms of serious arrhythmia will not be permitted to restart study treatment.
8.5
Biomarkers and exploratory research
8.5.1
Collection of samples
The subject’s consent to the use of donated biological samples for research is mandatory during 
treatment period and at disease progression in the SoA (Table 1). Biological samples will be 
collected and may be used for central tesing of the EGFR mutation status resistance mechanisms 
analysis and biomarkers of response. 
Blood samples (approx. 10 mL) will be taken at the baseline and disease progression or study 
intervention discontinuation whichever occurs earlier and are presented in the SoA (Table 1).
An unstained, archival tumour tissue or cellular sample from a fresh biopsy or surgical 
specimens in a quantity sufficient to allow for retrospective central confirmation of the EGFR 
mutation status with the cobas® EGFR Mutation Test v2 at the time of screening will be 

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collected as an option. Central confirmation will not be mandated before enrolment for 
participants with a positive tissue EGFR test result obtained from a locally accredited 
laboratory. The central testing of EGFR mutations will be used to assess concordance with 
local test results.
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual. 
8.5.2
Determination of exploratory analysis 
Blood samples to generate plasma samples will be collected from all participants. These samples 
will be used for the extraction and analysis of circulating tumour deoxyribonucleic acid 
(ctDNA). Genetic profiles will be analysed by the central lab NGS testing, and then used to 
explore the relationship between changes in biomarkers and response to treatment. In addition, 
innate and acquired resistance mechanisms may be explored. The analytical method will be 
used is described in Section 9.4.2.3.
8.5.3
Storage and destruction of samples
The processes adopted for the coding and storage of samples for genetic analysis are important 
to maintain subject confidentiality. Sample storage and destruction will be performed according 
to the central labs’ policy and China HGR regulations. DNA is a finite resource that may be 
used up during experiments. The results of any further analyses will be reported either in the 
Clinical Study Report itself or as an addendum, or separately in a scientific report or publication.
All genetic testing and analysis in resistance mechanisms assessment and exploratory biomarker 
analysis will be performed after China HGR approved. Mutation testing residual plasma 
samples collected will be destroyed. The remaining tissue sections will be returned to the 
subjects.
9
STATISTICAL CONSIDERATIONS
Statistical analyses will be performed by AstraZeneca or its representatives.
A comprehensive SAP will be prepared with final amendments completed prior to database 
lock.
9.1
Statistical Hypotheses
There is no statistical hypothesis associated with the study objectives. As such, no statistical 
tests will be performed. The analyses of efficacy, safety and tolerability will primarily be 
descriptive.
9.2
Sample Size Determination
Approximately 40 participants will be screened to enrol 35 subjects into the study. With the 

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assumption of expected ORR as 60%, the sample size of 35 subjects will provide the 95% 
confidence interval estimation as [42.2%, 78.2%], assuming a potential dropout rate for loss to 
follow-up as 10%.
9.3
Populations for Analyses
The full analysis set (FAS) will include all enrolled participants who have received at least 1 
dose of study intervention. The FAS will be used for all efficacy analyses and safety analyses
unless specified otherwise.
9.4
Statistical Analyses
The SAP will be finalised prior to database lock and it will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of the most important endpoints including primary and key 
secondary endpoints. Any deviations from this plan will be reported in the CSR.
9.4.1
General Considerations
All statistical analyses will be conducted using SAS version 9.4 or later. For continuous 
variables, the summarization will include number, mean, median, standard deviation, minimum 
and maximum. For categorical variables, this will include frequency counts and percentages at 
each category. Results of all statistical analyses will be summarized with descriptive statistics 
and presented with a 95% confidence interval estimate if applicable. Missing data will be 
assumed missing at random or missing completely at random. In general, no imputation will be 
applied unless otherwise specified.
9.4.2
Efficacy
Investigator RECIST 1.1-based assessments
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations. All assessment results will be utilized to determine the endpoints of ORR, PFS and 
DoR. For detailed description of RECIST 1.1 please refer to section 8.1.1.. 
At each visit, participants will be programmatically assigned a RECIST 1.1 visit response of 
CR, PR, SD, PD, or NE depending on the status of their disease compared with baseline and 
previous assessments. Baseline status will be assessed within the 28 days prior to the first dose 
of study intervention. The tumour response endpoints (PFS, ORR, and duration of response 
[DoR]) will then be derived from the baseline scan dates and overall visit responses dates.
9.4.2.1
Primary Endpoint(s)
Objective Response Rate
ORR (per RECIST 1.1 using Investigator assessments) is defined as the proportion of 
participants who achieved a complete or partial response as their best overall response based on 

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RECIST 1.1 as assessed by the investigator, where the response must be confirmed by a later 
scan conducted at least 4 weeks after the initial response is observed. Data obtained up until 
progression, or the last evaluable assessment in the absence of progression, will be included in 
the assessment of ORR. Participants who discontinue treatment without progression, or who
receive a subsequent therapy and then respond will not be included as responders in the ORR 
calculation, where the denominator will always be the total number of participants in FAS.
ORR will be presented as s percentage, with the corresponding 95% confidence interval using
the Clopper-Pearson (exact) method.
Subgroup Analysis
Subgroup analyses will be conducted using same method as described above, in the following 
subgroups of the FAS (but not limited to) as applicable:
!
ECOG/WHO PS (0 vs. 1)
Other baseline variables may also be assessed if there is clinical justification. The purpose of 
the subgroup analyses is to assess the consistency of treatment effect across expected prognostic 
and/or predictive factors.
9.4.2.2
Secondary Endpoint(s)
9.4.2.2.1
Progression-Free Survival
PFS will be defined as the time from first dose of study intervention until progression per 
RECIST 1.1 as assessed by the investigator or death due to any cause prior to PD. 
Participants who have not progressed or died at the time of analysis will have PFS right-
censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 
assessment. However, if the participant progresses or dies after 2 or more consecutive missed 
visits,  PFS will be censored at the time of the latest evaluable RECIST 1.1 assessment prior to 
the 2 missed visits. (Note: NE visit is not considered as missed visit).
If the participant has no evaluable visits or does not have baseline data, PFS will be censored at 
Day 1, unless they die within 2 visits of baseline in which case their date of death will be used 
as an event.
PFS will always be derived based on scan/assessment dates and not visit dates.
RECIST 1.1 assessments/scans contributing toward a particular visit may be performed on 
different dates. The following rules will be applied:
!
For investigator assessments, the date of progression will be determined based on the 
earliest RECIST assessment/scan dates of the component that indicates progression.

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!
When censoring PFS, right-censoring will be at the latest of the scan dates contributing to 
a particular overall visit assessment.
Analysis Methods
The analysis of secondary endpoint, PFS, (based on Investigator assessment) will occur when 
approximately 21 progression events have been observed in the 35 participants (approximately 
60% PFS maturity). Kaplan-Meier method will be used to estimate the median PFS and its 95% 
confidence interval. 
Kaplan-Meier plots of PFS will be presented. Summaries of the number and percentage of 
participants experiencing a PFS event and the type of event (RECIST 1.1 PD or death) will be 
provided.
9.4.2.2.2
Overall Survival
OS is defined as the time from the first dose of treatment to the date of death, regardless of the 
actual cause of the subject’s death. For participants who are still alive at the time of data analysis 
or who are lost to follow up, OS will be right-censored at the last recorded date that the 
participant is known to be alive prior to or at the data cut-off date for the analysis.
The efficacy analysis of OS will be performed on the FAS. 
The analysis of OS will occur when approximately 21 death events have been observed in the 
35 participants (approximately 60% maturity). Results will be analysed with the same method 
as PFS. 
9.4.2.2.3
Analysis of duration of response
DoR is defined as the time from the date of first documented response until the date of 
documented progression or death in the absence of disease progression. The end of response 
should coincide with the date of progression or death from any cause used for the PFS endpoint.  
The time of the initial response will be defined as the latest of the dates contributing toward the 
first visit response of PR or CR. If a participant does not progress following a response, then 
his/her duration of response will use the PFS censoring time as the end point for their DoR 
calculation.
The analysis of DoR will be based on the responding patients. Analysis method of DoR will 
be same as PFS.
9.4.2.2.4
Analysis of disease control rate
DCR is defined as the percentage of subjects who have a best overall response of CR or PR or 
SD by RECIST 1.1 as assessed by the Investigator. For participants with a best overall response 
of SD, a RECIST assessment of SD must have been observed at least 6 weeks following 
enrolment to be included in the numerator of the calculation for disease control rate. This is to 

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enable sufficient follow-up to establish SD. 
Disease Control Rate will be summarized and presented as percentage, with 95% confidence 
interval estimated using Clopper-Pearson exact method.
9.4.2.2.5
Analysis of depth of response
Depth of response (ie, tumour shrinkage / change in tumour size) by Investigator is defined as 
the relative change in the sum of the longest diameters of RECIST target lesions at the nadir in 
the absence of NLs or progression of NTLs when compared to baseline. The best absolute 
change in target lesion tumour size from baseline, and best percentage change in target lesion 
tumour size from baseline will be summarized using descriptive statistics. The best change in 
tumour size will include all assessments prior to progression or start of subsequent anti-cancer 
therapy.
9.4.2.2.6
Analysis of time to treatment failure or death
Time to treatment failure (TTF) or death is defined as defined as the time from first dose of 
study intervention (osimertinib) to earlier of the date of last study intervention administration 
or death due to any cause. Any participant not known to have permanently discontinued study 
intervention and not known to have died at the time of the analysis will be censored at the last 
known time on which the participant was known to be alive. Kaplan-Meier method will be used 
to estimate the median TTF and its 95% confidence interval.
9.4.2.2.7
Analysis of time to first subsequent therapy or death
Time to first subsequent therapy (TFST) or death is defined as the time from first dose of study 
intervention to the earlier of the date of anti-cancer therapy (except cisplatin or carboplatin or 
pemetrexed) start date following study intervention discontinuation or death due to any cause. 
Any participant not known to have had a subsequent therapy or not known to have died at the 
time of the analysis will be censored at the last known time to have not received subsequent 
therapy. Kaplan-Meier method will be used to estimate the median TFST and its 95% 
confidence interval.
9.4.2.3
Exploratory Endpoint
9.4.2.3.1
 
 
 
 
 
 

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9.4.3
Safety
Safety and tolerability will be assessed in terms of AEs, deaths, laboratory data, vital signs 
(pulse and BP), ECG, LVEF, and ECOG PS. These will be collected for all enrolled participants 
and will be summarized per descriptive analysis.
Adverse events (coded both in terms of Medical Dictionary for Regulatory Activities 
[MedDRA] preferred terms and CTCAE grade) will be listed individually by participant. Any 
AE occurring before treatment with IP will be included in the data listings but will not be 
included in the summary tables of AEs.  Any AE occurring within 28 days of discontinuation of 
study intervention and prior to start of a new anti-cancer treatment will be included in the AE 
summaries. Any events in this period that occur after a participant has received further therapy 
for cancer (following discontinuation of study intervention) will be flagged in the data listings.
The AE/SAE incidence rate, ≥grade 3 AE/SAE incidence rate (AE/SAE graded by CTCAE v5), 
related AE incidence rate, and discontinuation rate due to AE will be summarized by MedDRA 
system organ class and preferred term.
The clinical chemistry, hematology, urinalysis results, vital signs (pulse and blood pressure); 
physical examination; weight; LVEF; ECG parameters and ECOG PS will be summarized by 
visit if applicable. The abnormalities with above measurement will be summarized by visit as 
well. 
SAE reconciliation between AZ global safety database and clinical study database must be 
performed monthly, and a final reconciliation performed prior to database lock to ensure that all 
SAEs have been received by AZ global safety database. Data Management Manager is 
accountable for performing the reconciliation.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS

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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with the following:
∀
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines
∀
Applicable ICH GCP Guidelines
∀
Applicable laws and regulations
!
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg,
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.
!
Any amendments to the protocol will require IRB/IEC and applicable Regulatory Authority
approval before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.
!
AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
Contract Research Organisation but the accountability remains with AstraZeneca.
Regulatory Reporting Requirements for Serious Adverse Events
!
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.
!
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. 
The sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and investigators.
!
For all studies except those utilising medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
!
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the [IB or state other documents] and will notify the IRB/IEC, if 
appropriate according to local requirements.
A 2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 

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responsible for providing information on financial interests during the course of the study and 
for 1 year after completion of the study.
A 3
Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorised representative and answer all questions regarding the study.
Participants must be informed that their participation is voluntary and they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the study. 
Participants or their legally authorised representative will be required to sign a statement of 
informed consent that meets the requirements of 21 Code of Federal Regulations 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act requirements, 
where applicable, and the IRB/IEC or study centre.
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorised person obtaining the informed consent must also sign the ICF.
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorised 
representative.
Participants who are rescreened are required to sign a new ICF.Data Protection
!
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred.
!
The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use of 
their data must also be explained to the participant in the informed consent 
!
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Unless previously specified, the biomarker data will have unknown clinical significance and 
AstraZeneca will not provide biomarker assessment results to participants, their family 
members, any insurance company, any employer, a clinical study investigator, a general 
physician, or any other third party, unless required to do so by law. 
The participant’s samples will not be used for any purpose other than those described in the 
study protocol.
A 5
Committees Structure

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The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to investigators.
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the study results when they are available. 
The clinical study and/or summary of study results may also be available on other websites 
according to the regulations of the countries in which the study is conducted.
A 7
Data Quality Assurance
!
All participant data relating to the study will be recorded on the CRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.
!
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
!
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory authority inspections and provide direct access to source data documents.
!
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.
!
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
!
The sponsor assumes accountability for actions delegated to other individuals (eg,
Contract Research Organisations).
!
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
!
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years from the end of the study unless local regulations 
or institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor.

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A 8
Source Documents
!
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
!
Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants. The first act of recruitment is the first site open.
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines
!
Inadequate recruitment of participants by the investigator
!
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any Contract Research 
Organisation(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy
!
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 

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submission. This allows the sponsor to protect proprietary information and to provide 
comments.
!
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a co-ordinating investigator will be designated by mutual agreement.
!
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence (other than progression of the 
malignancy under evaluation) in a participant or clinical study participant administered a study 
intervention and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavourable and unintended sign (eg, an abnormal laboratory finding), 
symptom (for example nausea, chest pain), or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the study intervention. 
The term AE is used to include both serious and non-serious AEs and can include a deterioration 
of a pre-existing medical occurrence. An AE may occur at any time, including run-in or washout 
periods, even if no study intervention has been administered.
B 2
Definitions of Serious Adverse Event
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-
up), that fulfils one or more of the following criteria:
!
Results in death.
!
Is immediately life-threatening.
!
Requires in-participant hospitalisation or prolongation of existing hospitalisation.
!
Results in persistent or significant disability or incapacity. 
!
Is a congenital abnormality or birth defect.
!
Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above.
Life threatening
“Life-threatening” means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
participant’s death. “Life-threatening” does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the participant was enrolled in the study, provided that it did not deteriorate in an unexpected 
way during the study.

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Important medical event or medical treatment
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the participant or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse
Adverse Events (AEs) for malignant tumours reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgement on an individual 
event basis should be applied to clarify that the malignant tumour event should be assessed and 
reported as a Non-Serious AE. For example, if the tumour is included as medical history and 
progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfil the attributes for being assessed as 
Serious, although reporting of the progression of the malignant tumour as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalization, may be assessed as Non-Serious; 
examples include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone 
biopsy.
The above instruction applies only when the malignant tumour event in question is a new 
malignant tumour (i.e., it is not the tumour for which entry into the study is a criterion and that 
is being treated by the IP under study and is not the development of new or progression of 
existing metastasis to the tumour under study). Malignant tumours that – as part of normal, if 
rare, progression – undergo transformation (e.g., Richter's transformation of B cell chronic 
lymphocytic leukemia into diffuse large B cell lymphoma) should not be considered a new 
malignant tumour.

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Intensity rating scale:
The grading scales found in the revised National Cancer Institute CTCAE latest version 5.0 will 
be utilised for all events with an assigned CTCAE grading. For those events without assigned 
CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate and 
severe events into CTCAE grades should be used. A copy of the CTCAE can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable 
version of CTCAE should be described clearly.
Intensity is assessed according to the following scale:
!
Grade 1
Mild - asymptomatic or mild symptoms or clinical or diagnostic observations 
only or intervention not indicated;
!
Grade 2
Moderate - minimal, local or non-invasive intervention indicated or limiting age-
appropriate instrumental activities of daily living;
!
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated or disabling or limiting self-care 
activities of daily living;
!
Grade 4
Life-threatening consequences or urgent intervention indicated;
!
Grade 5
Death related to AE.
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe intensity need 
not necessarily be considered serious. For example, nausea that persists for several hours may 
be considered severe nausea, but not a SAE unless it meets the criteria shown in Appendix B 2. 
On the other hand, a stroke that results in only a limited degree of disability may be considered 
a mild stroke but would be a SAE when it satisfies the criteria shown in Appendix B 2.
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a “reasonable possibility” that an AE may have been caused by the drug.
!
Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?
!
Consistency with known drug profile. Was the AE consistent with the previous knowledge 
of the suspect drug (pharmacology and toxicology) or drugs of the same pharmacological 
class? Or could the AE be anticipated from its pharmacological properties?
!
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

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!
No alternative cause. The AE cannot be reasonably explained by another aetiology such as 
the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.
!
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognised feature of overdose of the drug?
!
Is there a known mechanism?
Causality of “related” is made if following a review of the relevant data, there is evidence for 
a “reasonable possibility” of a causal relationship for the individual case. The expression 
“reasonable possibility” of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as “not related”.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 4
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error:
!
occurred.
!
was identified and intercepted before the participant received the drug.
!
did not occur, but circumstances were recognised that could have led to an error.
Examples of events to be reported in clinical studies as medication errors:

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!
Drug name confusion.
!
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant.
!
Drug not administered as indicated, for example, wrong route or wrong site of 
administration.
!
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a solid 
tablet.
!
Drug not stored as instructed eg, kept in the fridge when it should be at room temperature.
!
Wrong participant received the medication.
!
Wrong drug administered to participant.
Examples of events that do not require reporting as medication errors in clinical studies:
!
Participant accidentally missed drug dose(s) eg, forgot to take medication.
!
Accidental overdose (will be captured as an overdose).
!
Participant failed to return unused medication or empty packaging.
!
Errors related to background and rescue medication, or standard of care medication in open 
label studies, even if an AstraZeneca product.
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.

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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site.
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 record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.If required, AstraZeneca will ensure that remaining 
biological samples are returned to the site according to local regulations or at the end of the 
retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
AstraZeneca ensures that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the informed consent.
If a participant withdraws consent specifically to the subsequent use of donated biological 
samples, the samples will be disposed of/destroyed/repatriated, and the action documented. If 
samples are already analysed, AstraZeneca is not obliged to destroy the results of this research.
The participant will be presented with the option to opt out of the subsequent use of the donated 
samples during the withdrawal process. If the participant decides to opt out, then the donated 
samples will be disposed of. If the participant withdraws consent without opting out for the 
subsequent use of the donated samples, then the samples will be used as per protocol.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:
!
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.

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!
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.
!
Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented and study site notified.
C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
IATA
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx
) 
classifies 
infectious substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.
Category A pathogens are infectious substances meeting these criteria which cause disease in 
humans or both in humans and animals. They must be assigned to UN 2814. Infectious 
substances which cause disease only in animals must be assigned to UN 2900.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, for example, Hepatitis A, C, D, and E 
viruses. They are assigned the following UN number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.
!
Clinical study samples will fall into Category B or exempt under IATA regulations.
!
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 
650 
compliant 
packaging.
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).
!
Biological samples transported in dry-ice require additional dangerous goods specification 
for the dry-ice content.

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Appendix D
Guidelines for Evaluation of Objective Tumour Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumours)
Introduction
This appendix details the implementation of RECIST 1.1 guidelines [1]. Investigator 
assessments will use the RECIST 1.1 guidelines described in this appendix.
Imaging modalities and acquisition specifications for RECIST 1.1
A summary of the imaging modalities that can be used for tumour assessment of TLs, NTLs
and NLs is provided in Table 10.
Table 10
Summary of Imaging Modalities for Tumour Assessment
Target Lesions 
Non-Target Lesions
New Lesions
CT
MRI
CT
MRI
Plain X-ray
Chest X-ray
CT
MRI
Plain X-ray
Chest X-ray
Bone scan (Scintigraphy)
18F-fluoro-deoxyglucose-PET/CT
CT=computed tomography; PET/CT=positron emission tomography/CT; MRI=magnetic resonance imaging.
Computed Tomography and Magnetic Resonance Imaging
CT with IV contrast is the preferred imaging modality (although MRI with IV contrast is 
acceptable if CT is contraindicated) to generate reproducible anatomical images for tumour
assessments (ie, for measurement of TLs, assessment of NTLs, and identification of NLs). It is 
essential that the same correct imaging modality, image acquisition parameters (eg, anatomic 
coverage, imaging sequences, etc), imaging facility, tumour assessor (eg, radiologist), and 
method of tumour assessment (eg, RECIST 1.1) are used consistently for each participant
throughout the study. The use of the same scanner for serial scans is recommended, if possible.
It is important to follow the image collection/tumour assessment schedule as closely as possible 
(refer to the SoA), and this on-study imaging schedule MUST be followed regardless of any 
delays in dosing or missed imaging visits. If an unscheduled assessment is performed (eg, to 
investigate clinical signs/symptoms of progression) and the participant has not progressed, 
every attempt should be made to perform the subsequent scan acquisitions at the next scheduled 
imaging visit.
Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice. Body 
scans should be performed with breath-hold scanning techniques, if possible. Therefore, CT of 
the chest is recommended over MRI due to significant motion artefacts (eg, heart, major blood 
vessels, breathing) associated with MRI. MRI has excellent contrast and spatial and temporal 

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resolutions; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. The modality used at follow-up should be the same as 
was used at baseline, and the lesions should be measured/assessed on the same pulse sequence.
In general, local oncology diagnostic imaging parameters are applied for scan acquisition. It is 
beyond the scope of this appendix to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.
The most critical CT and MRI image acquisition parameters for optimal tumour evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumours is the 
chest-abdomen (-pelvis). Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may be 
involved based on signs and symptoms of individual participants. Because a lesion later 
identified in a body part not scanned at baseline would be considered as a NL representing PD, 
careful consideration should be given to the extent of imaging coverage at baseline and at 
subsequent follow-up time points. This will enable better consistency not only of tumour
measurements but also identification of new disease.
Required anatomical regions to be imaged for assessment of tumour burden (TLs and/or NTLs) 
at baseline and follow-up visits vary according to the study, and these time points are specified 
in the SoA. Examples include the following:
!
IV contrast-enhanced CT of chest-abdomen (including the entire liver and both adrenal 
glands) (-pelvis).
!
Non-contrast CT of chest and IV contrast-enhanced abdomen (including the entire liver and 
both adrenal glands) (-pelvis).
!
IV contrast-enhanced CT or MRI of the head and neck.
!
IV contrast-enhanced MRI (preferred) or CT of the brain.
For chest-abdomen (-pelvis) imaging, the following are scanning options in decreasing order of 
preference, with additional options (2 to 4) for consideration when participants have sensitivity 
to IV contrast or have compromised renal function:
1
Chest-abdomen (-pelvis) CT with IV CT contrast (most preferred).
2
Chest CT without IV-contrast + abdomen (-pelvis) MRI with IV MRI contrast, if CT IV 
contrast (iodine based) is medically contraindicated at any time during the study.
3
Chest-abdomen (-pelvis) CT without IV contrast, if both IV CT and MRI contrast are 
medically contraindicated or the participant has compromised renal function.

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4
Chest-abdomen (-pelvis) MRI with IV MRI contrast, if CT cannot be performed at any time 
during the study.
b. IV contrast administration: Optimal visualisation and measurement of metastases in solid 
tumours require consistent administration (dose and rate) of IV contrast as well as timing of 
scanning. An adequate volume of a suitable contrast agent should be given so that the tumour
lesions are demonstrated to best effect and a consistent method is used on subsequent 
examinations for any given participant. Oral contrast is recommended to help visualise and 
differentiate structures in the abdomen and pelvis.
c. Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) slices with ≤5 mm thickness throughout the entire 
anatomic region of interest for optimal lesion measurements. Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses >5 mm. If this occurs, 
the minimum size of measurable lesions at baseline should be twice the slice thickness of the 
baseline scans.
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered. When measuring lesions, the 
TL should be measured on the same window setting for repeated examinations throughout the 
study.
Chest X-ray
Chest X-ray assessment will not be used for the assessment of TLs. Chest X-ray can, however, 
be used to assess NTLs and to identify the presence of NLs. However, there is preference that a 
higher resolution modality, such as CT, be used to confirm the presence of NLs.
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTLs and to identify the presence 
of new bone lesions.
Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray at baseline should be recorded as NTLs and followed by the same method per baseline 
assessment (CT, MRI, or X-ray).
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits. NLs may be recorded in case positive hot-spots appear on a 
bone scan that were not present on a previous bone scan; however, a newly observed equivocal 
hot-spot on a bone scan that cannot be verified with correlative imaging (CT, MRI, or X-ray) of 
the same anatomical region shall not be the only trigger for a PD assessment at that time point.

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18F-Fluoro-deoxyglucose-PET/CT
18F-fluoro-deoxyglucose positron emission tomography(PET)/CT scans may be used as a 
method for identifying new extrahepatic lesions (but not intrahepatic lesions) for RECIST 1.1 
assessments according to the following algorithm: NLs will be recorded where there is positive 
18F-Fluoro-deoxyglucose uptake1 not present on baseline or prior 18F-fluoro-deoxyglucose-PET 
scan or in a location corresponding to a NL on a companion CT/MRI collected close in time to 
the 18F-fluoro-deoxyglucose-PET scan. The PET portion of the PET/CT introduces additional 
data that may bias an investigator if it is not routinely or serially performed. Therefore, if there 
is no baseline or prior 18F-fluoro-deoxyglucose-PET scan available for comparison, and no 
evidence of NLs on companion CT/MRI scans, then follow-up CT/MRI assessments should 
continue as per the regular imaging schedule to verify the unequivocal presence of NLs.
At 
present, 
low-dose 
or 
attenuation 
correction 
CT 
portions 
of 
a 
combined 
18F-fluoro-deoxyglucose-PET/CT scan are of limited use in anatomically based efficacy 
assessments, and it is therefore suggested that they should not substitute for dedicated diagnostic 
contrast-enhanced CT scans for tumour measurements by RECIST 1.1. In exceptional 
situations, if a site can document that the CT performed, as part of a PET/CT examination, is of 
identical diagnostic quality (with IV contrast) to a dedicated diagnostic CT scan, then the CT 
portion of the PET/CT can be used for RECIST 1.1 tumour assessments. Caution that this is not 
recommended because the PET portion of the CT introduces additional (PET) data that may 
bias an investigator if it is not routinely or serially performed.
Ultrasound 
Ultrasound examination will not be used for RECIST 1.1 assessment of tumours as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation, and may 
not provide an accurate assessment of the true tumour size. Tumours identified by ultrasound 
will need to be assessed by correlative CT or MRI anatomical scan.
Other tumour assessments
Clinical examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will not 
be used for RECIST 1.1 assessments. Tumours identified by clinical examination will need to 
be assessed by correlative CT or MRI anatomical scans.
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumour assessments as they are not validated 
in the context of tumour assessment.
                                               
1
A positive 18F-fluoro-deoxyglucose-PET scan lesion should be reported only when an uptake (eg, standard uptake 
value) greater than twice that of the surrounding tissue or liver is observed.

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Histology and cytology
Histology or tumour markers on tumour biopsy samples will not be used as part of the tumour
response assessment as per RECIST 1.1.
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, and pleural effusion) that appears or worsens during the study will not be 
used as part of the tumour response assessment as per RECIST 1.1.
Furthermore, an overall assessment of CR (all other disease disappears/reverts to normal) would 
be changed to PR if an effusion remains present radiologically.
Measurability of tumour lesions at baseline
RECIST 1.1 measurable lesions at baseline
A tumour lesion that can be accurately measured at baseline as ≥10 mm in the longest diameter 
for non-nodal lesions or ≥15 mm in short axis2 diameter for lymph node lesions with IV 
contrast-enhanced CT or MRI and that is suitable for accurate repeated measurements. Please 
see additional RECIST 1.1 guidance below on measurability of intrahepatic hepatocellular 
carcinoma lesions and porta hepatis lymph nodes.
Non-measurable lesions at baseline
!
Truly non-measurable lesions include the following:
∀
Bone lesions (see exception below for soft tissue component).
∀
Leptomeningeal disease.
∀
Ascites, pleural effusion, or pericardial effusion.
∀
Inflammatory breast disease.
∀
Lymphangitic involvement of skin or lung.
!
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph 
nodes with ≥10 mm to <15 mm short axis diameter at baseline).3
!
Previously irradiated lesions.4
!
Brain metastasis.
Special considerations regarding lesion measurability at baseline
!
Bone lesions:
                                               
2
The short axis is defined as the longest in-plane axis perpendicular to the long axis.
3
Lymph nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded or followed 
as NTLs.
4
Localised post-radiation changes that affect lesion size may occur. Therefore, lesions that have been previously 
irradiated are typically considered non-measurable and as NTL at baseline and followed up as part of the NTL 
assessment.

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∀
Bone scan, PET scan, or plain X-ray are not considered adequate imaging techniques 
to measure bone lesions; however, these techniques can be used to confirm the 
presence or disappearance of bone lesions.
∀
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability.
∀
Blastic lesions are considered non-measurable.
!
Cystic lesions thought to represent cystic metastases can be considered measurable lesions 
if they meet the criteria for measurability from a radiological point of view, but if non-
cystic lesions are present in the same participant, these should be selected over cystic 
lesions as TLs.
RECIST 1.1 TL selection at baseline
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including lymph 
nodes collectively considered as a single organ), representative of all lesions involved should 
be identified as TLs at baseline. TLs should be selected on the basis of their size (longest 
diameter for non-nodal lesions or short axis diameter for nodal lesions), but in addition should 
be those that lend themselves to reproducible repeated measurements. It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be selected.
Lymph nodes, in any location (local/regional and distant), are collectively considered as a single 
organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, adrenal glands), a 
segmented organ (eg, liver), or a multilobed organ (eg, lung) is each considered as a single 
organ.
The site and location of each TL should be documented, as well as the longest axis diameter for 
non-nodal lesions (or short axis diameter for lymph nodes). All measurements should be 
recorded in millimetres. At baseline, the sum of the diameters for all TLs will be calculated and 
reported as the baseline sum of diameters. At follow-up visits, the sum of diameters for all TLs 
will be calculated and reported as the follow-up sum of diameters.
Special cases for TL assessment at baseline
!
For TLs measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis 
diameter.
!
When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
vector of the longest diameter should be used to determine the perpendicular vector for the 
maximal short axis diameter of the coalesced mass. Non-nodal lesions that coalesce should 
similarly be assessed by the longest axis diameter.

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!
Tumour lesions selected for newly acquired screening biopsy should not be selected as TLs, 
unless imaging occurred at least approximately 2 weeks after biopsy, allowing time for 
healing.
!
If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan.
!
If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a lesion 
appears in the same location on a subsequent scan, it will be recorded as a NL.
RECIST 1.1 NTL selection at baseline
All other lesions, including non-measurable lesions and surplus measurable lesions, not 
recorded as TLs should be identified as NTLs at baseline. Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout follow-up.
Evaluation of tumour response and progression
RECIST 1.1 TL assessment at follow-up
This section defines the criteria used to determine objective tumour visit response for 
RECIST 1.1-defined TLs. The imaging modality, location, and scan date of each TL identified 
previously at baseline should be documented at follow-up visits with the long axis diameter for 
non-nodal lesions or short axis diameter for lymph node lesions. All measurements should be 
recorded in millimetres. The sum of the diameters for all TLs at each follow-up visit will be 
compared with the baseline sum of diameters (for response or SD) or to the smallest prior (nadir) 
sum of diameters (for progression) (Table 11).
Special cases for TL assessment at follow-up:
!
If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a lesion 
appears in the same location on a subsequent scan, it will be recorded as an NL.
!
If a TL splits into 2 or more parts, the sum of the diameters of those parts should be 
recorded.
!
If 2 or more TLs merge, then the sum of the diameters of the combined lesion should be 
recorded for 1 of the lesions and 0 mm recorded for the other lesion(s). If the merged TLs 
are non-nodal lesions, record the long axis diameter of the merged lesion. If pathologic 
lymph nodes coalesce and are no longer individually separable within a conglomerate mass, 
the vector of the longest diameter of the coalesced mass should be used to determine the 
perpendicular vector for the maximal short axis diameter.
!
If a TL is believed to be present and is faintly seen but too small to measure, a default value 
of 5 mm should be assigned. If an accurate measure can be given, this should be recorded, 
even if it is below 5 mm.

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!
If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion. 
!
When a TL has had any intervention (eg, definitive radiotherapy, embolisation, surgery, 
transarterial chemoembolisation, etc) during the study, the size of the TL should still be 
provided where possible and the intervention recorded in the RECIST 1.1 CRF for the 
current imaging visit and all subsequent visits. If a TL has been completely removed 
(surgery) or disappears, the longest diameter should be recorded as 0 mm.
Table 11
RECIST 1.1 Evaluation of Target Lesions
CR
Disappearance of all TLs since baseline. Any pathological lymph nodes 
selected as TLs must have a reduction in short axis diameter to <10 mm.
PR
At least a 30% decrease in the sum of the diameters of TL, taking as reference 
the baseline sum of diameters.
SD
Neither sufficient decrease in the sum of diameters to qualify for PR nor 
sufficient increase to qualify for PD.
PD
At least a 20% increase in the sum of diameters of TLs, taking as reference the 
smallest previous sum of diameters (nadir). This includes the baseline sum if
that is the smallest on study. In addition to the relative increase of 20%, the 
sum must demonstrate an absolute increase of at least 5 mm from nadir.
NE
Only relevant if any of the TLs at follow-up were not assessed or NE (eg, 
missing anatomy) or had a lesion intervention at this visit. Note: If the sum of 
diameters meets the PD criteria, PD overrides NE as a TL response.
Not applicable
Only relevant if no TLs present at baseline.
CR=complete response; NE=not evaluable; PD=progression of disease; PR=partial response; SD=stable disease; TL=target 
lesion.
RECIST 1.1 NTL assessment at follow-up
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline. Measurements are not required for these lesions, but their status should be followed at 
subsequent visits. At each visit, an overall assessment of the NTL response should be recorded 
by the investigator (Table 12).
To achieve “unequivocal progression” on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, the 
overall tumour burden has increased sufficiently to merit unequivocal progression by NTLs. A 
modest “increase” in the size of 1 or more NTLs is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PD of target disease will therefore be extremely 
rare.

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Table 12
RECIST 1.1 Evaluation of Non-Target Lesions
CR
Disappearance of all NTLs since baseline. All lymph nodes must be 
non-pathological in size (<10 mm short axis).
Non CR/non PD
Persistence of 1 or more NTLs.
PD
Unequivocal progression of existing NTLs. Unequivocal progression may be due 
to an important progression in 1 lesion only or in several lesions. In all cases, the 
progression MUST be clinically significant for the physician to consider 
changing (or stopping) therapy.
NE
Only relevant when 1 or some of the NTLs were not assessed and, in the 
investigator’s opinion, they are not able to provide an evaluable overall NTL 
assessment at this visit.
Note: For participants without TLs at baseline, this is relevant if any of the NTLs 
were not assessed at this visit and the progression criteria have not been met.
Not applicable
Only relevant if no NTLs present at baseline.
CR=complete response; NE=not evaluable; NTL=non-target lesion; PD=progression of disease; TL=target lesion.
RECIST 1.1 NL identification at follow-up
Details, including the imaging modality, the date of scan, and the location of any NLs will also 
be recorded in the CRF. The presence of 1 or more NLs is assessed as progression. The finding 
of a NL should be unequivocal, ie, not attributable to differences in scanning technique, change 
in imaging modality, or findings thought to represent something other than tumour. If a NL is 
equivocal, for example because of its small size, the treatment and tumour assessments should 
be continued until the previously (pre-existing) NL has been assessed as unequivocal at a 
follow-up visit, and then the progression date should be declared using the date of the initial 
scan when the NL first appeared.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate PD.
RECIST 1.1 evaluation of overall visit response at follow-up
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs uses the algorithm shown in Table .
Table 2
RECIST 1.1 Overall Visit Response
Target Lesions
Non-Target Lesions
New Lesions
Overall Visit Response
CR
CR
No
CR
CR
NA
No
CR
CR
Non CR/Non PD 
No
PR
CR
NE
No 
PR
PR
Non PD or NE or NA
No
PR

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Target Lesions
Non-Target Lesions
New Lesions
Overall Visit Response
SD 
Non PD or NE or NA
No
SD
NE
Non PD or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Non-CR/Non-PD for overall response if only NTL (no TLs) are present at baseline.
Note: An overall assessment of CR (all other disease disappears/reverts to normal) would be changed to PR if ascites remains 
present radiologically.
CR=complete response; NA=not applicable (only relevant if there were no TLs or NTLs at baseline), NE=not evaluable; 
NTL=non-target lesion; PD=progression of disease; PR=partial response; SD=stable disease; TL=target lesion.
The following overall visit responses are possible depending on the extent of tumour disease 
at baseline:
!
For participants with TLs (at baseline): CR, PR, SD, PD, or NE.
!
For participants with NTLs only (at baseline): CR, Non-CR/Non-PD, PD, or NE.
!
For participants with no disease at baseline: no evidence of disease (available as an option 
in the eCRF), PD, or NE.
References
1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur 
J Cancer 2009;45(2):228-47.

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Appendix E
Contraception Requirements
Contraception requirements for this study are as follows.
E 1
Female Participants
Women of Childbearing Potential (WoCBP) are defined as women between menarche and 
menopause who have not been permanently or surgically sterilized and are capable of 
procreation.
Women not of childbearing potential are defined as those who are permanently or surgically 
sterile (ie, bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or who 
are post-menopausal.
Women who have undergone tubal occlusion should be managed on trials as if they are of 
WoCBP (eg, undergo pregnancy testing etc., as required by the study protocol).
Women will be considered post-menopausal if they have been amenorrhoeic for 12 months
without an alternative medical cause. The following age-specific requirements apply:
!
Women <50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy and if they have luteinizing hormone and follicle-stimulating hormone levels in the 
post-menopausal range for the institution.
!
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy, or had radiation-induced menopause with last menses >1 year ago, or had 
chemotherapy-induced menopause with last menses >1 year ago.
Women of childbearing potential who are not totally sexually abstinent (ie, refraining from 
heterosexual intercourse during the entire period of risk associated with study interventions) 
and intend to be sexually active with a non-sterilised male partner must use at least 1 highly 
effective method of contraception (Table 3). They should have been stable on their chosen 
method of birth control for a minimum of 2 weeks before entering the study and continue to use
it throughout the total duration of the drug treatment and the drug washout period (42 days after 
the last dose of study intervention). 
Female participants should refrain from breastfeeding throughout this period.
E 2
Male Participants with a Female Partner of Childbearing 
Potential
Non-sterilised male participants (including males sterilised by a method other than bilateral 

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orchidectomy, eg, vasectomy) who intend to be sexually active with a female partner of 
childbearing potential must be using an acceptable method of contraception from the time of 
screening throughout the total duration of the treatment and the drug washout period (6 months 
after discontinuing chemotherapy or at least 4 months after discontinuing osimertinib) to 
prevent pregnancy in a partner. 
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods 
of contraception. Male participants should refrain from sperm donation or banking throughout 
this period.
Female partners (of childbearing potential) of male participants must also use a highly effective 
method of contraception throughout this period (Table 3).
E 3
Highly Effective Methods of Contraception
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly, are described in Table 3. 
Table 3
Highly Effective Methods of Contraception (<1% Failure Rate)
Non-Hormonal Methods
Hormonal Methods
•
Total sexual abstinence (evaluate in relation to 
the duration of the clinical study and the 
preferred and usual lifestyle choice of the 
participant)
•
Vasectomised sexual partner plus male condom 
(with participant assurance that partner received 
post-vasectomy confirmation of azoospermia)
•
Tubal occlusion plus male condom
•
Intrauterine device (provided coils are 
copper-banded) plus male condom
•
Injection: Medroxyprogesterone injection 
(eg, Depo-Provera®)a plus male condom
•
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®)a plus male condom
•
Implants: Etonogestrel-releasing implants 
(eg, Implanon® or Norplant®) plus male condom
•
Intravaginal devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®) plus male 
condom
•
Combined pill: Normal and low dose combined 
oral contraceptive pill plus male condom
•
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Ortho Evra®) plus male 
condom
•
Mini pill: Progesterone based oral contraceptive 
pill using desogestrel plus male condom.
Cerazette® is currently the only highly effective 
progesterone-based pill
a
Hormonal methods not prone to drug-drug interactions.
The following methods are considered not to be highly effective and are therefore not acceptable 
contraceptive methods in AstraZeneca clinical trials:

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
Triphasic combined oral contraceptives (COCs)

All progesterone only pills except, Cerazette

All barrier methods, if intended to be used alone

Non-copper containing Intra-Uterine Devices (IUDs)

Fertility awareness methods

Coitus interruptus

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Appendix F
Concomitant Medications
F 1
Guidance Regarding Potential Interactions with Concomitant 
Medications
The use of any natural/herbal products or other “folk remedies” should be discouraged, but use 
of these products, as well as use of all vitamins, nutritional supplements, and all other 
concomitant medications must be recorded in the eCRF.
DRUGS INDUCING OR INHIBITING CYTOCHROME P450 (CYP) 3A4/5
METABOLISM THAT ASTRAZENECA STRONGLY RECOMMENDS ARE NOT 
COMBINED WITH STUDY INTERVENTION
Osimertinib is metabolised by CYP3A4 and CYP3A5 enzymes. Therefore, inhibitors or 
inducers of CYP3A4/5 may increase or decrease exposure, respectively, to osimertinib.
A drug-drug interaction study of osimertinib evaluated in patients showed that there is potential 
for osimertinib being a victim when co-administered with strong inducers of CYP3A4 
(osimertinib concentrations are decreased when co-dosed with rifampicin).
The following potent inducers of CYP3A4 should not be used during this study for any 
participant receiving osimertinib.
Drugs inducing CYP3A4
Contraindicated drugs
Withdrawal period prior to Study 
treatment start
Carbamazepine, phenobarbital, phenytoin, 
rifampicin, rifabutin, rifapentin
St John’s Wort
3 weeks
Phenobarbitone
5 weeks
This list is not intended to be exhaustive, and a similar restriction will apply to other agents 
that are known to strongly modulate CYP3A4 activity.  Appropriate medical judgment is 
required.  Contact AstraZeneca with any queries you have on this issue.

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Table 4
Drugs known to be inhibitors of CYP3A4/5
Strong CYP3A4/5 inhibitors
(should not be combined)
Moderate CYP3A4/5 inhibitors
(permitted with caution)
boceprevir
clarithromycin
conivaptan
elvitegravir/ritonavir
fluconazole
grapefruit juicea,b
indinavir
itraconazole
ketoconazole
lopinavir/RIT
mibefradil
nefazodone
nelfinavir
posaconazole
ritonavir
saquinavir
amprenavir
aprepitant
atazanavir
casopitant
cimetidine
ciprofloxacin
crizotinib
cyclosporine
darunavir
diltiazem
dronedarone
erythromycin
grapefruit juiceb
imatinib
schisandra sphenanthera
tofisopam

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Table 4
Drugs known to be inhibitors of CYP3A4/5
Strong CYP3A4/5 inhibitors
(should not be combined)
Moderate CYP3A4/5 inhibitors
(permitted with caution)
telaprevir
telithromycin
tipranavir/ritonavir
troleandomycin
voriconazole
verapamil
a
Double-strength grapefruit juice
b
Participants should abstain from eating large amounts of grapefruit and Seville oranges (and other products 
containing these fruits eg, grapefruit juice or marmalade) during the study (eg, no more than a small glass of 
grapefruit juice [120 mL] or half a grapefruit or 1 to 2 teaspoons [15 g] of Seville orange marmalade daily)
This list is not intended to be exhaustive, and a similar restriction will apply to other agents that 
are known to strongly modulate CYP3A4/5 activity. Appropriate medical judgment is required. 
Please contact AstraZeneca with any queries you have on this issue.
If the investigator feels that concomitant administration of medications or herbal supplements 
that strongly modulate CYP3A4/5 is essential (eg, to treat AEs), osimertinib treatment should
be discontinued.
MEDICINES WHOSE EXPOSURES MAY BE AFFECTED BY OSIMERTINIB THAT 
ASTRAZENECA CONSIDERS MAY BE ALLOWED WITH CAUTION
Osimertinib may increase the concentration of sensitive BCRP and Pgp substrates 
(concentration of the sensitive BCRP substrate, rosuvastatin and sensitive Pgp substrate, 
fexofenadine, are increased).

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Table 5
Exposure, Pharmacological Action, and Toxicity May be Increased by 
Osimertinib
Drug with Warning of Possible Interaction
Advice
Rosuvastatin
Drugs are permitted but caution should be exercised and 
participants monitored closely for possible drug 
interactions. Please refer to the full Prescribing 
Information for all drugs prior to co-administration with 
study intervention.
Sulfasalazine
Doxorubicin
Daunorubicin
Topotecan
Dabigatran
Aliskiren
Digoxin
DRUGS THAT PROLONG QT INTERVAL
The drugs listed in this section are taken from information provided by the Arizona Centre for 
Education 
and 
Research 
on 
Therapeutics 
(ArizonaCert) 
website 
(https://www.crediblemeds.org/). The website categorises drugs based on the risk of inducing 
Torsades de Pointes (TdP).
During screening, the drugs that participants are currently using (prescription and 
non-prescription) should be checked opposite the ArizonaCert website. In addition, drugs 
intended for use during study intervention should be checked opposite the website.
Drugs with a known risk of Torsades de Pointes
The following drugs prolong the QT interval and are clearly associated with a known risk of 
TdP, even when taken as recommended.
Before study intervention
These drugs must have been discontinued prior to the start of administration of study 
intervention in accordance with guidance provided in Table 6.
During study intervention
It is recommended that these drugs are not co-administered with study intervention considered 
essential for participant management to co-administer these drugs with study intervention, close 
monitoring with ECGs and electrolytes is recommended.
The list of drugs may not be exhaustive and is subject to change as new information becomes 
available. As such, investigators are recommended to search the website to provide the most 
up to date information.

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Table 6
Drugs with a Known Risk of Torsades de Pointes
Drug Name
Withdrawal Period Prior to 
Study Intervention Startb
Anagrelide, ciprofloxacin, clarithromycin, cocaine, droperidol, erythromycin, 
levofloxacin, ondansetron, papaverine hydrochloride, procainamide, 
sulpiride, sultopride, terfenadine, terlipressin
2 days
Cilostazol, cisapride, disopyramide, dofetilide, domperidone, flecainide, 
gatifloxacin, grepafloxacin, ibutilide, moxifloxacin, oxaliplatin, propofol, 
quinidine, roxithromycin, sevoflurane, sotalol, sparfloxacin, thioridazine
7 days
Azithromycin bepridil, citalopram, chlorpromazine, dronedarone, 
escitalopram, fluconazole, halofantrine, haloperidol, levomepromazine, 
levosulpiride, mesoridazine
14 days
Donepezil, terodiline
3 weeks
Levomethadyl, methadone, pimozide
4 weeks
Arsenic trioxidea, ibogaine
6 weeks
Pentamidine
8 weeks
Astemizole, probucol, vandetanib
4 months
Amiodarone, chloroquine
1 year
a
Estimated value as pharmacokinetics of arsenic trioxide has not been studied.
a
Check for the latest updates on this list of drugs on the ArizonaCert website to ensure accuracy.
Other TdP risk Categories 
Participants receiving drugs that prolong QT interval or may increase the risk of TdP from other 
TdP risk categories can be enrolled, notwithstanding other exclusions and restrictions, if these 
drugs are considered essential for participant management, and the participant has been stable 
on therapy. Close monitoring with ECGs and electrolytes is recommended.
Participants with congenital long QT syndrome (CLQTS) are excluded from this study.
Guidance regardless of TdP risk category
During study intervention and for a period of 2 weeks after discontinuing study intervention, if 
it is considered essential for participant management to co-administer drugs known to prolong 
corrected QT interval, regardless of TdP risk category, close monitoring with ECGs and 
electrolytes is recommended.
F 2
Restricted, Prohibited, and Permitted Concomitant 
Medications/Therapies
Restricted, prohibited, and permitted concomitant medications/therapies are described in 
Table 7, Table 8, and Table 9. Refer also to the dose modification guidelines for management of 

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study intervention-related toxicities in Section 0.
Table 7
Restricted medications/therapies
Medication/class of drug/therapy
Usage (including limits for duration permitted and 
special situations in which it’s allowed)
Hormonal therapy
For non-cancer-related conditions (eg, hormone 
replacement therapy) only
Corticosteroids and/or bisphosphonates
For the treatment of bone metastases and for the 
treatment of specific adverse drug reactions (refer to 
Toxicity Management Guidelines document)
Foods or medications that are moderate inducers or 
inhibitors of CYP3A4/5.
See Appendix F 1
CYP3A4/5=Cytochrome P450 3A4/5.
Table 8
Prohibited medications/therapies
Prohibited medication/class of drug/therapy
Usage
Any anticancer therapy other than those under 
investigation in this study (including curative 
radiotherapy)
Must not be given concomitantly while the participant
is on study intervention
Herbal and natural remedies that may interfere with 
interpretation of study results
Must not be given concomitantly unless agreed by the 
Sponsor
Foods or medications that are strong inducers or 
inhibitors of CYP3A4/5 , which are deemed to 
impact the pharmacokinetics of study medications
Must not be given concomitantly unless agreed by the 
Sponsor (See Appendix F 1)
CYP3A4/5=Cytochrome P450 3A4/5.
Table 9
Supportive medications/therapies
Supportive medication/class of drug/therapy
Usage
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) deemed 
necessary to provide adequate adverse event
management, except for those medications 
identified as “prohibited,” as listed above 
To be administered as prescribed by the investigator 
except for those medications identified as 
“prohibited,” as listed in Table 8
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy, 
etc]) except for those medications identified as 
“prohibited,” as listed above
Should be used, when necessary, for all participants 
except for those medications identified as 
“prohibited,” as listed in Table 8
Corticosteroids and/or bisphosphonates for the 
treatment of bone metastases and for the treatment 
of specific adverse drug reactions (refer to Toxicity 
Management Guidelines document)
Permitted

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Supportive medication/class of drug/therapy
Usage
Inactivated viruses, such as those in the influenza 
vaccine
Permitted

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Appendix G
Calculated Creatinine Clearance
Original, Weight-Based Cockcroft and Gault Formula for Calculated Creatinine 
Clearance for Men
For serum creatinine concentration in mg/dL:
CrCl =
    (140 – agea) x (wtb) x 1.0
(mL/min)
72 x serum creatinine (mg/dL)
For serum creatinine concentration in μmol/L:
CrCl =
   (140 – agea) x (wtb) x 1.0
(mL/min)
0.81 x serum creatinine (mg/dL)
a Age in years.
b Weight (wt) in kilograms.
Source: Cockcroft and Gault 1976.
Original, Weight-Based Cockcroft and Gault Formula for Calculated Creatinine 
Clearance for Women
For serum creatinine concentration in mg/dL:
CrCl =
    (140 – agea) x (wtb) x 0.85
(mL/min)
72 x serum creatinine (mg/dL)
For serum creatinine concentration in μmol/L:
CrCl =
   (140 – agea) x (wtb) x 0.85
(mL/min)
0.81 x serum creatinine (mg/dL)
a Age in years.
b Weight (wt) in kilograms.
Source: Cockcroft and Gault 1976.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16:31–41

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Appendix H
Abbreviations
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
AE
Adverse Event
eCRF
electronic Case Report Form
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Event
DAE
Discontinuation of Investigational Product due to Adverse Event
DCO
Data cut off
ctDNA
Circulating tumour deoxyribonucleic acid 
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
EGFRm
Epidermal growth factor receptor mutations
FSI
First Subject In
GCP
Good Clinical Practice
ICH
International Conference on Harmonisation
IP
Investigational Product 
ITT
Intention To Treat
IV
Injection of vein
KM
Kaplan-Meier
LSI
Last Subject In
LSLV
Last Subject Last Visit
NGS
Next-generation sequencing technology
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
PFS
Progression-free survival
PI
Principal Investigator 
p.o.
Orally
RA
Research Agreement
RECIST
Response Evaluation Criteria in Solid Tumours
SAE
Serious adverse event 

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Abbreviation or 
special term
Explanation
TKI
Tyrosine kinase inhibitor
WoCBP
Women of childbearing potential

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11
REFERENCES
1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) - Non-Small Cell Lung 
Cancer.  Version 4.2020 – May 15, 2020.  Available at: 
https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.  Accessed May 15, 2020.
2. Yang J C H, Sequist L V, Geater S L, et al. Clinical activity of afatinib in patients with advanced 
non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of 
LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6[J]. The lancet oncology, 2015, 16(7): 830-838.
3. Cho J H, Lim S H, An H J, et al. Osimertinib for patients with non–small-cell lung cancer harboring 
uncommon EGFR mutations: a multicenter, open-label, phase II trial (KCSG-LU15-09)[J]. Journal of 
Clinical Oncology, 2020, 38(5): 488.
4. Seike M, Inoue A, Sugawara S, et al. 1382PD Phase III study of gefitinib (G) versus gefitinib+ 
carboplatin+ pemetrexed (GCP) as first-line treatment for patients (pts) with advanced non-small cell 
lung cancer (NSCLC) with EGFR mutations (NEJ009)[J]. Annals of Oncology, 2018, 29(suppl_8): 
viii493-viii547.
5. Nakamura A, Inoue A, Morita S, et al. Phase III study comparing gefitinib monotherapy (G) to 
combination therapy with gefitinib, carboplatin, and pemetrexed (GCP) for untreated patients (pts) 
with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009)[J]. J Clin Oncol. 
2018;36 (15_suppl):abstr 9005.
6. Mok T S, Wu Y L, Ahn M J, et al. Osimertinib or platinum–pemetrexed in EGFR T790M–positive 
lung cancer[J]. New England Journal of Medicine, 2017, 376(7): 629-640.
7. Soria J C, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non–
small-cell lung cancer[J]. New England journal of medicine, 2018, 378(2): 113-125.
8. Cheng T Y D, Cramb S M, Baade P D, et al. The international epidemiology of lung cancer: 
latest trends, disparities, and tumor characteristics[J]. Journal of Thoracic Oncology, 2016, 
11(10): 1653-1671.
9. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN 
estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA: a cancer 
journal for clinicians, 2018, 68(6): 394-424.
10. NCI SEER 2018 National Cancer Institute.  Surveillance, Epidemiology, and End Results
Program. 
 
Cancer 
Stat 
Facts: 
lung 
and 
bronchus 
cancer. 
 
Available 
at: 
https://seer.cancer.gov/statfacts/html/lungb.html.  Accessed November 8, 2018.
11. Belani C P, Marts S, Schiller J, et al. Women and lung cancer: epidemiology, tumor biology, 
and emerging trends in clinical research[J]. Lung Cancer, 2007, 55(1): 15-23.
12. Zheng R S, Sun K X, Zhang S W, et al. Report of cancer epidemiology in China, 2015[J]. 
Zhonghua zhong liu za zhi [Chinese journal of oncology], 2019, 41(1): 19-28.

Clinical Study Protocol - 1.0
AstraZeneca
Osimertinib(TAGRISSO®) - D5161C00017
CONFIDENTIAL AND PROPRIETARY
119 of 123
13. Cao M, Chen W. Epidemiology of lung cancer in China[J]. Thoracic cancer, 2019, 10(1): 
3-7.
14. Zang R, Shi J F, Lerut T E, et al. Ten-year trends of clinicopathologic features and surgical 
treatment of lung cancer in China[J]. The Annals of Thoracic Surgery, 2020, 109(2): 389-395.
15. Keedy V L, Temin S, Somerfield M R, et al. American Society of Clinical Oncology 
provisional clinical opinion: epidermal growth factor receptor (EGFR) mutation testing for 
patients with advanced non–small-cell lung cancer considering first-line EGFR tyrosine kinase 
inhibitor therapy[J]. Journal of clinical oncology, 2011, 29(15): 2121-2127.
16. Barlesi F, Blons H, Beau-Faller M, et al. Biomarkers (BM) France: results of routine EGFR, 
HER2, KRAS, BRAF, PI3KCA mutations detection and EML4-ALK gene fusion assessment 
on the first 10,000 non-small cell lung cancer (NSCLC) patients (pts)[J]. 2013.
17. Esteban E, Majem M, Aguillo M M, et al. Prevalence of EGFR mutations in newly 
diagnosed locally advanced or metastatic non-small cell lung cancer Spanish patients and its 
association with histological subtypes and clinical features: the Spanish REASON study[J]. 
Cancer Epidemiology, 2015, 39(3): 291-297.
18. Gahr S, Stoehr R, Geissinger E, et al. EGFR mutational status in a large series of Caucasian 
European NSCLC patients: data from daily practice[J]. British journal of cancer, 2013, 109(7): 
1821-1828.
19. Herbst RS, Heymach JV, Lippman SM[J]. Lung cancer. N Engl J Med, 2008, 359: 1367.
20. Han B, Tjulandin S, Hagiwara K, et al.  Determining the prevalence of EGFR mutations in 
Asian and Russian patients (pts) with advanced non-small-cell lung cancer (ANSCLC) of 
adenocarcinoma (ADC) and non-ADC histology: IGNITE study [J].  Ann Oncol. 2015;26 
(suppl 1):i29-44.
21. Shi Y, Au JSK, Thongprasert S, et al.  A prospective, molecular epidemiology study of 
EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma 
histology (PIONEER) [J].  J Thorac Oncol. 2014;9(2):154-62.
22. Tokumo M, Toyooka S, Kiura K, et al.  The relationship between epidermal growth factor 
receptor mutations and clinicopathologic features in non-small cell lung cancers [J].  Clin 
Cancer Res. 2005;11(3):1167-73.
23. Yoshida K, Yatabe Y, Park JY, et al.  Prospective validation for prediction of gefitinib 
sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell 
lung cancer [J].  J Thorac Oncol. 2007;2(1):22-8.
24. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, et al. Screening for epidermal growth 

Clinical Study Protocol - 1.0
AstraZeneca
Osimertinib(TAGRISSO®) - D5161C00017
CONFIDENTIAL AND PROPRIETARY
120 of 123
factor receptor mutations in lung cancer[J]. N Engl J Med. 2009;361: 958–967.
25. Shi Y, Li J, Zhang S, et al. Molecular epidemiology of EGFR mutations in Asian patients with 
advanced non-small-cell lung cancer of adenocarcinoma histology–mainland China subset analysis of 
the PIONEER study[J]. PloS one, 2015, 10(11): e0143515.
26. Sharma S V, Bell D W, Settleman J, et al. Epidermal growth factor receptor mutations in lung 
cancer[J]. Nature Reviews Cancer, 2007, 7(3): 169-181.
27. O’Kane G M, Bradbury P A, Feld R, et al. Uncommon EGFR mutations in advanced non-small cell 
lung cancer[J]. Lung Cancer, 2017, 109: 137-144.
28. Tu H Y, Ke E E, Yang J J, et al. A comprehensive review of uncommon EGFR mutations in patients 
with non-small cell lung cancer[J]. Lung Cancer, 2017, 114: 96-102.
29. Heuckmann JM, Rauh D, Thomas RK.  Epidermal growth factor receptor (EGFR) signaling and 
covalent EGFR inhibition in lung cancer[J].  J Clin Oncol. 2012;30(27):3417 20.
30. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al.  Gefitinib or 
chemotherapy for non-small-cell lung cancer with mutated EGFR [J].  N Engl J Med. 
2010;362(25):2380-8.
31. Rosell R, Carcereny E, Gervais R, et al.  Erlotinib versus standard chemotherapy as first-line 
treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer 
(EURTAC): a multicentre, open-label, randomised phase 3 trial [J].  Lancet Oncol. 2012;13(3):239-46.
32. Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, et al.  Afatinib versus cisplatin plus gemcitabine 
for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR 
mutations (LUX-Lung 6): an open-label, randomised phase 3 trial [J].  Lancet Oncol. 2014;15: 213–
22.
33. Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, et al.  Metastatic non-small cell 
lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up [J].  Annals 
Oncol. 2018;29(suppl_4):iv192-iv237.
34. Masters GA, Temin S, Azzoli CG, Giaccone G, Baker S Jr, Brahmer JR, et al.  Systemic therapy 
for stage IV non-small-cell lung cancer: American Society of Clinical Oncology Clinical Practice 
Guideline Update [J].  J Clin Oncol. 2015;33(30):3488-515.
35. Wen S, Dai L, Wang L, et al. Genomic Signature of Driver Genes Identified by Target Next‐
Generation Sequencing in Chinese Non‐Small Cell Lung Cancer[J]. Oncologist, 2019, 24(11): p. 
e1070-e1081.
36. Zhang T, Wan B, Zhao Y, et al. Treatment of uncommon EGFR mutations in non-small cell lung 
cancer: new evidence and treatment[J]. Translational lung cancer research, 2019, 8(3): 302-316.

Clinical Study Protocol - 1.0
AstraZeneca
Osimertinib(TAGRISSO®) - D5161C00017
CONFIDENTIAL AND PROPRIETARY
121 of 123
37. Kate S, Chougule A, Joshi A, et al. Outcome of uncommon EGFR mutation positive newly 
diagnosed advanced non-small cell lung cancer patients: a single center retrospective analysis[J]. Lung 
Cancer: Targets and Therapy, 2019, 10: 1‐10.
38. Chantharasamee J, Poungvarin N, Danchaivijitr P, Techawatanawanna S. Clinical outcome of 
treatment of metastatic non-small cell lung cancer in patients harboring uncommon EGFR mutation[J]. 
BMC Cancer. 2019;19(1):701.
39. Xu J, Jin B, Chu T, et al. EGFR tyrosine kinase inhibitor (TKI) in patients with advanced non-
small cell lung cancer (NSCLC) harboring uncommon EGFR mutations: A real-world study in 
China[J]. Lung Cancer. 2016;96:87-92.
40. Watanabe S, Minegishi Y, Yoshizawa H, et al. Effectiveness of gefitinib against non–small-cell 
lung cancer with the uncommon EGFR mutations G719X and L861Q[J]. Journal of thoracic oncology, 
2014, 9(2): 189-194.
41. Chiu CH, Yang CT, Shih JY, et al. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor 
Treatment Response in Advanced Lung Adenocarcinomas with G719X/L861Q/S768I Mutations[J]. J 
Thorac Oncol. 2015;10(5):793-799.
42. Liu H, Han G, Peng M, et al. Efficacy of EGFR tyrosine kinase inhibitors in non-small cell lung 
cancer patients harboring different types of EGFR mutations: A retrospective analysis[J]. Current 
Medical Science, 2017, 37(6): 864-872.
43. Zhang Y, Wang Z, Hao X, et al. Clinical characteristics and response to tyrosine kinase inhibitors
of patients with non-small cell lung cancer harboring uncommon epidermal growth factor receptor 
mutations[J]. Chin J Cancer Res. 2017;29(1):18-24.
44. Chen K, Yu X, Wang H, et al. Uncommon mutation types of epidermal growth factor receptor and 
response to EGFR tyrosine kinase inhibitors in Chinese non-small cell lung cancer patients[J]. Cancer 
Chemotherapy and Pharmacology, 2017, 80(6): 1179-1187.
45. Li H, Wang C, Wang Z, et al. Efficacy and long-term survival of advanced lung adenocarcinoma 
patients with uncommon EGFR mutations treated with 1st generation EGFR-TKIs compared with 
chemotherapy as first-line therapy[J]. Lung Cancer, 2019, 130: 42-49.
46. Shi J, Yang H, Jiang T, et al. Uncommon EGFR mutations in a cohort of Chinese NSCLC patients 
and outcomes of first-line EGFR-TKIs and platinum-based chemotherapy[J]. Chinese Journal of 
Cancer Research, 2017, 29(6): 543.
47. Yang, G., et al., EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer 
patients: molecular heterogeneity and treatment outcome from nationwide real-world study[J]. J Lung 
Cancer, 2020, 145: 186-194.
48. Chinese Society of Clinical Oncology (CSCO) Clinical Practice Guidelines in Oncology - Non-
Small Cell Lung Cancer. 2020. Publised May 26, 2020.

Clinical Study Protocol - 1.0
AstraZeneca
Osimertinib(TAGRISSO®) - D5161C00017
CONFIDENTIAL AND PROPRIETARY
122 of 123
49. Fang, W., et al., EGFR exon 20 insertion mutations and response to osimertinib in non-small-cell 
lung cancer [J]. BMC Cancer, 2019. 19(1): p. 595.
50. Piotrowska Z, Wang Y, Sequist L V, et al. ECOG-ACRIN 5162: A phase II study of osimertinib 160 
mg in NSCLC with EGFR exon 20 insertions[J]. Journal of Clinical Oncology 38, no. 15_suppl (May 
20, 2020) 9513-9513
51. Cheng Y, Murakami H, Yang P C, et al. Randomized phase II trial of gefitinib with and without 
pemetrexed as first-line therapy in patients with advanced nonsquamous non–small-cell lung cancer 
with activating epidermal growth factor receptor mutations[J]. Journal of Clinical Oncology, 2016, 
34(27): 3258-3266.
52. Han B, Jin B, Chu T, Niu Y, Dong Y, Xu J. Combination of chemotherapy and gefitinib as first-line 
treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: A 
randomized controlled trial[J]. Int J Cancer. 2017;141(6):1249-56.
53. Yang JCH, Cheng Y, Murakami H, et al. Gefitinib with or without pemetrexed in nonsquamous 
(NS) non-small cell lung cancer (NSCLC) with EGFR mutation (mut): Final overall survival (OS) 
results from a randomized phase II study[J]. Annals Oncol. 2018;29 (suppl_8):1381PD.
54. Yoshimura N, Kudoh S, Mitsuoka S, et al. Phase II study of a combination regimen of gefitinib and 
pemetrexed as first-line treatment in patients with advanced non-small cell lung cancer harboring a 
sensitive EGFR mutation[J]. Lung Cancer. 2015;90(1):65-70.
55. Noronha V, Patil VM, Joshi A, et al. Gefitinib Versus Gefitinib Plus Pemetrexed and Carboplatin 
Chemotherapy in EGFR-Mutated Lung Cancer[J]. J Clin Oncol. 2020;38(2):124-136.
56. Dudnik E, Lopategui J, Chevarie-Davis, Natale RB. Combined chemotherapy (CT) and erlotinib 
(E) as a first-line treatment of EGFR-mutated (EGFR M) NSCLC[J]. J Clin Oncol. 2014; 32 
(no.15_suppl):e19076.
57. Wu, M., et al., Combined gefitinib and pemetrexed overcome the acquired resistance to epidermal 
growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer[J]. Mol Med Rep, 2014. 
10(2): p. 931-8.
58. Scagliotti GV, Parikh P, von Pawel J, et al.  Phase III study comparing cisplatin plus gemcitabine 
with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell 
lung cancer [J].  J Clin Oncol. 2008;26(21):3543-51.
59. Paz-Ares L, de Marinis F, Dediu M, et al.  Maintenance therapy with pemetrexed plus best 
supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus 
cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, 
phase 3, randomised controlled trial [J].  Lancet Oncol. 2012;13(3): 247–55.
60. Sugawara S, Oizumi S, Minato K, et al.  Randomized phase II study of concurrent versus 
sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer 

Clinical Study Protocol - 1.0
AstraZeneca
Osimertinib(TAGRISSO®) - D5161C00017
CONFIDENTIAL AND PROPRIETARY
123 of 123
with sensitive EGFR mutations: NEJ005/TCOG0902 [J].  Annals of Oncol. 2015;26(5):888-94.
61. Visser S, Huisbrink J, van ‘t Veer N, van Toor J, van Boxem A, van Walree N et al. Renal 
impairment during pemetrexed maintenance in patients with advanced nonsmall cell lung cancer: a 
cohort study [J]. Eur Respir J. 2018;Oct 25;52(4). pii: 1800884.
62. Middleton G, Gridelli C, De Marinis F, et al. Evaluation of changes in renal function in 
PARAMOUNT: a phase III study of maintenance pemetrexed plus best supportive care versus placebo 
plus best supportive care after induction treatment with pemetrexed plus cisplatin for advanced 
nonsquamous non-small-cell lung [J]. Cancer Current Medical Research and Opinion. 2018; 34 
(5):865–71.
63. Giaccone G, Herbst RS, Manegold C, et al.  Gefitinib in combination with gemcitabine and 
cisplatin in advanced non-small-cell lung cancer: a phase III trial - INTACT 1 [J].  J Clin Oncol. 
2004;22(5):777-84.
64. Gatzemeier U, Pluzanska A, Szczesna A, et al.  Phase III study of erlotinib in combination with 
cisplatin and gemcitabine in advanced non-small cell lung cancer: The Tarceva Lung Cancer 
Investigation Trial [J].  J Clin Oncol. 2007;25(12):1545-52.
65. Herbst RS, Giaccone G, Schiller JH, et al.  Gefitinib in combination with paclitaxel and carboplatin 
in advanced non-small-cell lung cancer: a phase III trial - INTACT2 [J].  J Clin Oncol. 
2004;22(5);785-94. 
66. Herbst RS, Prager D, Hermann R, et al.  TRIBUTE: A Phase III trial of erlotinib hydrochloride 
(OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung 
cancer [J].  J Clin Oncol. 2005;23(25):5892-9.
67. Ardizzoni A, Boni L, Tiseo M, Fossella FV, et al.  Cisplatin- versus carboplatin-based 
chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data 
meta-analysis [J].  J Natl Cancer Inst. 2007;99(11):847-57.
68. Okada M, Tanaka K, Asahina H,  et al.  Safety analysis of an open label, randomized phase 2 study 
of osimertinib alone versus osimertinib plus carboplatin-pemetrexed for patients with non-small cell 
lung cancer (NSCLC) that progressed during prior epidermal growth factor receptor (EGFR) tyrosine 
kinase inhibitor (TKI) therapy and which harbors a T790 mutation of EGFR [J].  J Clin Oncol. 
2018;36(15_suppl):e21073.
69. Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al.  Recommendations for 
the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline 
Update[J].  J Clin Oncol. 2015;33(28):3199-3212.