A Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter, International Study of Osimertinib as Maintenance Therapy in Patients With Locally Advanced, Unresectable EGFR Mutation-positive Non-Small Cell Lung Cancer (Stage III) Whose Disease Has Not Progressed Following Definitive Platinum-based Chemoradiation Therapy (LAURA).
Phase: PHASE3
Conditions: Non Small Cell Lung Cancer (Stage III)
Sponsor: AstraZeneca

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Clinical Study Protocol 
Drug Substance
Osimertinib 
Study Code
D5160C00048
Version
5.0
Date
03 November 2023
A Phase III, randomized, double-blind, placebo-controlled, multicenter, 
international study of osimertinib as maintenance therapy in patients with 
locally advanced, unresectable EGFR mutation-positive Non-Small Cell 
Lung Cancer (Stage III) whose disease has not progressed following 
definitive platinum-based chemoradiation therapy (LAURA)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Local sponsor in Japan: AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan.
Regulatory Agency Identifying Number(s):
US IND 117879; 
EudraCT number: 2018-001061-16
EU CT Number: 2022-500860-36-00

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VERSION HISTORY
Version 1, 23 March 2018
Initial Creation 
Version 2, 28 February 2020
Changes to the protocol are summarized below:
The primary change in this protocol is:
!
To add that before the PFS analysis, patients may receive open-label osimertinib 
after BICR-confirmed disease progression. After the PFS analysis, patients may 
receive open-label osimertinib after investigator-assessed disease progression.
In addition, changes have been made to update the protocol with the current data from the 
osimertinib development programme.
The primary, secondary and exploratory objectives of this protocol remain unchanged.
Major changes to the protocol are summarized below:
Section 1.1 (Schedule of Activities), Section 1.2 (Synopsis), Section 1.3 (Schema), 
Section 4.1 (Overall Design), Section 7.2 (Treatment with open-label osimertinib), 
Section 7.5 (Patient management post-primary PFS analysis): Added that patients may 
receive open-label osimertinib after BICR-confirmed disease progression. Patients must not 
receive any other anti-cancer therapies between discontinuation of study treatment and start 
of open-label osimertinib.
Section 1.1 (Schedule of Activities) and Section 8.3.2 (Time period and frequency for 
collecting AE and SAE information): Increased duration of AESI monitoring during 
progression and survival follow-up.
Section 1.2 (Synopsis), Section 2.3 (Study rationale): Data from the data-cut off 2 of the 
FLAURA study were added.
Section 2.5.4 (Overall benefit/risk): The frequency of ILD and ILD-like ADRs was added, 
including the frequency of fatal events. 
Section 5.1 (Inclusion criteria): It was added that patients with a stage III tumor of 
squamous histology who have a pre-existing local positive test result (Ex19del or L858R) 
are eligible for Part I screening. Also clarified the tumor tissue specimen required for entry 
into Part I screening.

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Section 5.2 (Exclusion criteria): Text was added to clarify that patients are eligible in Part 
I of the study if none of the Part II screening exclusion criteria 1, 2, 7, 9-11, and 15-20 
apply. The exclusion criterion relating to risk of QTc prolongation was also updated, with 
further definition of electrolyte abnormalities and medical history. In addition, minor 
changes were made to exclusion criteria 6, 8, 10, and 13.
Section 5.3.2 (Blood donation): Patients may not donate blood from date of randomization 
until 28 days after the last dose of study treatment.
Section 6.1.1 (Investigational products): Supply of open-label osimertinib was added.
Section 6.6 (Dose modification), Section 8.4.4.1 (QTc prolongation): Procedures for 
handling dose interruptions for patients with QTc prolongation were updated to match 
current recommendations. Guidance for correction of electrolyte levels before first dose was 
also added.
Section 8.4.4.4 (Erythema multiforme and Stevens-Johnson syndrome): Management of 
patients with signs and symptoms of erythema multiforme or Stevens-Johnson syndrome 
were added, following updates to the osimertinib prescribing information.
Section 9.4.1.1 (Primary analysis of PFS), Section 9.4.2.2 (Analysis of overall survival), 
Section 9.4.2.3 (Analysis of objective response rate), Section 9.4.2.4 (Analysis of 
Duration of Response): Definitions of these endpoints were added.
Section 9.4.2.10 (Analysis of post-progression outcomes): The definition of time to first 
and time to second subsequent therapies or death were changed to match the statistical 
analysis plan.
Section 9.6 (China Cohort): It was added that analysis of the China cohort will take place 
after analysis of the Global cohort.
CSP Version 3.0, 03 February 2021 
Changes to the protocol are summarized below:
The primary changes in this protocol are:
!
To enable the use of the FoundationOne® CDx test for local EGFR mutation status 
testing 
!
To clarify the PRO data collection schedule 
!
To provide further clarification on the timing of when patients may receive open-label 
osimertinib, and the supply of open-label osimertinib after the final OS analysis.
!
To provide further clarification on various inclusion and exclusion criteria concerning 
patient disease characteristics, concurrent chemoradiation (CCRT), electrolyte 
correction, eligibility for participants with a resolved or chronic hepatitis B virus 
(HBV) infection, and other study participation

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!
To provide further clarification on the timing of adverse events (AE), serious adverse 
events (SAE), and adverse events of special interest (AESI) collection.
The primary, secondary and exploratory objectives of this protocol remain unchanged. The 
above and other additional changes are described in detail below. Minor editorial changes 
have also been made, however these are not included in the summary below.
Section 1.1 (Schedule of assessments [Table 1]):
!
Adverse event and concomitant medication data collection added at Screening Part I to 
clarify AE/SAEs are to be collected from signature of the first ICF.
!
Table and Footnote (e): Clarified that either archival or newly acquired tumor tissue 
samples can be provided for prospective and retrospective central EGFR mutation 
analysis. This change was also reflected throughout the CSP. 
!
Footnote (f): The FoundationOne® CDx test was included as a FDA-approved 
tissue-based CDx for EGFR mutation status. Language amended to clarify that tissue is 
to be provided for retrospective testing only for patients that did not undergo Part 1 
screening. 
!
Footnote (l): Clarified that the collection of the plasma sample for PK can be omitted 
if the patient did not have exposure to IP for at least 7 days prior to the visit.
!
Footnote (n): Clarification of the timings given for collection of PROs at treatment 
discontinuation following BICR-confirmed disease progression are relative to the date 
of the treatment discontinuation visit; and for patients who discontinue prior to 
BICR-progression the timings of collection of PROs are relative to the disease 
progression visit.
Section 1.2 (Synopsis): Updated in line with changes made throughout the CSP.
Section 4.1 (Overall design): 
!
Correction made to the number of patients needing to be screened, changed to 
1333 patients.
!
Clarified that recruitment will continue in mainland China until at least 40 patients 
have been randomized. 
!
Text added to clarify that relevant local EGFR mutation-positive test results are those 
obtained using a tissue-based FDA-approved CDx for TAGRISSO (i.e., cobas® EGFR 
Mutation Test v2 or FoundationOne® CDx test). 
!
Text added to describe when study blind will be broken, and also when cessation of 
AstraZeneca supplied open-label osimertinib will occur.
!
Clarified that either archival or newly acquired tumor tissue samples can be provided 
for prospective and retrospective central EGFR mutation analysis. 
Section 5.1.1 (Part I Screening, Inclusion Criteria): Text added to clarify that relevant 
local EGFR test results are those obtained using a tissue-based FDA-approved CDx for 
TAGRISSO (i.e., cobas® EGFR Mutation Test v2 or FoundationOne® CDx test), 
performed in a CLIA-certified (USA sites) or an accredited local laboratory (sites outside of 
the USA) and conducted according to the manufacturer’s instructions for use.

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Section 5.1.2 (Part II Screening, Inclusion criteria): Text added to clarify that relevant 
local EGFR test results are those obtained using a tissue-based FDA-approved CDx for 
TAGRISSO (i.e., cobas® EGFR Mutation Test v2 or FoundationOne® CDx test), 
performed in a CLIA-certified (USA sites) or an accredited local laboratory (sites outside of 
the USA) and conducted according to the manufacturer’s instructions for use.
Section 5.1.2 (Part II Screening, Inclusion criterion 5): The following clarification text 
was added:  *Patients with a stage III tumor of squamous histology who have a pre-existing 
local positive test result (Ex19del or L858R), irrespective of EGFR test used or lab 
accreditation, and confirmed by central testing during Part I screening, are eligible for Part 
II screening.
Section 5.1.2 (Part II Screening, Inclusion criterion 6): Text added to clarify that 
relevant local EGFR test results are those obtained using a tissue-based FDA-approved CDx 
for TAGRISSO (i.e., cobas® EGFR Mutation Test v2 or FoundationOne® CDx test).
Section 5.1.2 (Part II Screening, Inclusion criterion 8): Clarified final chemotherapy 
administration must be completed prior to, or concurrently with, the final dose of radiation. 
Reference to platinum and pemetrexed doublet therapy removed and changed to a final 
cycle of chemotherapy is permitted up to 7 days after the last dose of radiation, if at least 
2 cycles have already been given concurrently.
Section 5.2.2 (Part II Screening, Exclusion Criterion 5): Text added to specify correction 
of electrolyte abnormalities to within normal ranges can be performed during the screening 
period.
Section 5.2.2 (Part II Screening, Exclusion Criterion 8): Updated eligibility for 
participants with a resolved or chronic HBV infection.
Section 5.2.2 (Part II Screening, Exclusion criterion 14): Text amended to clarify that 
patients are excluded if a participant in another clinical study with an IP administered in the 
previous 4 weeks prior to randomization.
Section 5.3.1 (Pregnancy) and Appendix J: Text amended to specify a ‘highly effective’ 
contraceptive measure must be used in female patients of child-bearing potential.
Section 5.3.3 (Chronic hepatitis B): New section added outlining recommendations for the 
management of patients with chronic HBV infection.
Section 6.6 (Dose modification, Table 5): Text amended to clarify that dose modifications 
are only permitted for adverse reactions. In addition, the timing of recovery and permanent 
study treatment withdrawal for patients with QTc prolongations were clarified as relative to 
study drug interruption, and additional clarification text regarding restart dose was added. 
Section 6.7 (Treatment after the end of the study): Text amended to describe when 
cessation of AstraZeneca supplied open-label osimertinib will occur, and further options for 
drug supply.

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Section 7.1.1.2 (Survival follow-up): Text moved from Section 7.1.1.2.2 (Post primary 
PFS analysis) to this section, since survival follow-up of patients is applicable prior to and 
post primary PFS analysis.
Section 7.1.1.2.1 (Prior to primary PFS analysis): Text added to clarify that follow-up for 
completion of ePROs are relative to the date of the treatment discontinuation visit. In 
addition, text was added to clarify that both SAEs and AESIs are collected only if 
considered related to prior study treatment, or open-label osimertinib.
Section 7.1.1.2.2 (Post primary PFS analysis): Text added to clarify that follow-up for 
completion of ePROs are relative to the date of the treatment discontinuation visit.
Section 7.2 (Treatment with open-label osimertinib): Text amended to clarify when 
treatment assignment may be unblinded and when the patient may receive open-label 
osimertinib. In addition, text added to advise the investigator should monitor the patient per 
local clinical guidance during open-label treatment with osimertinib.
Section 7.6 (Patient management post-final OS analysis): AESIs added to the list of 
information collected during treatment and for 28 days after last dose. In addition, AESI 
added to be reported following discontinuation of study treatment (plus 28-day follow-up) 
when considered causally related to osimertinib. Text added to describe when cessation of 
AstraZeneca supplied open-label osimertinib will occur.
Section 8.1.1 (RECIST v1.1) and Section 8.1.2 (Screening tumor sample for EGFR 
mutation analysis), including all subsections: Sections 8.1.1 and 8.1.2 were re-ordered for 
logical flow, in order to appear in the sequence in which the assessments are to be 
performed during the study. 
Section 8.1.1.1.1 (Patients without a positive local tissue-based EGFR mutation test 
result): Previously Section 8.2.1.1.1. Title simplified. Instructions relating to the provision 
of tumor tissue revised (from a minimum of 8 sections to preferably 12 [except in China]), 
and reference to the Laboratory Manual for further details added. Clarified that either 
archival or newly acquired tumor tissue samples can be provided for central EGFR mutation 
analysis.
Section 8.1.1.1.2 (Patients with a positive local tissue-based EGFR mutation test 
result): Previously Section 8.2.1.1.2. Title simplified. Local cobas® EGFR Mutation Test 
v2 changed to local EGFR test, in line with early changes. Clarified that either archival or 
newly acquired tumor tissue samples can be provided for central EGFR mutation analysis.
Section 8.1.1.2 (Plasma samples for EGFR mutation testing): Previously Section 8.2.1.2.
China specific requirement for blood volume added.
Section 8.1.3 (Clinical outcome assessments): Text added to clarify the timing of PRO 
collection for patients who discontinue study treatment prior to BICR-confirmed 
progression.

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Section 8.2.1 (Clinical safety laboratory assessments, Table 6): Footnote (c) added to 
clarify either dipstick and local lab testing are acceptable methods of urinalysis and results 
to be reported as qualitative outcomes.
Section 8.2.4 (Vital signs): Added option of taking measures in a sitting position if supine 
not feasible.
Section 8.3.2 (Time period and frequency for collecting AE and SAE information): 
Text amended to clarify AE/SAEs to be collected from signature of the first ICF. Table 8 
amended to clarify when and which SAEs and AESIs need to be collected during each 
follow-up stage of the study. Footnote (a) added to note additional safety assessments 
maybe performed in line with local clinical practice post final OS analysis but not collected 
as part of the study data capture.
Section 8.3.7 (Adverse events based on examinations and tests): Additional reason of 
‘considered clinically relevant as judged by the investigator’ added to the list of reasons to 
report a laboratory value or vital signs as an AE.
Section 8.4.4.1 (General dose adjustments for adverse events): Text amended to clarify 
that dose interruptions are only permitted for adverse reactions (related to 
osimertinib/matching placebo). In addition, the timing of recovery and permanent study 
treatment withdrawal, for patients with toxicities, were clarified as relative to study drug 
interruption.
Section 8.4.4.3 (QTc prolongation): The timing of recovery and permanent study 
treatment withdrawal, for patients with toxicities, were clarified as relative to study drug 
interruption.
Section 8.5 (Pharmacokinetics): Text added to describe when collection of the plasma 
sample for PK can be omitted.
Section 8.5.2 (Storage and destruction of pharmacokinetic samples): Timing of 
destruction of all PK samples and residual samples added as maximally 12 months post 
final CSR.
Section 8.8.3 (Storage, re-use and destruction of biomarker samples): Text added to 
describe the requirement in China for mutation testing residual plasma and tissue samples to 
be destroyed or repatriated maximally 5 years after study indication approval for marketing 
in China.
Section 9.2 (Sample size determination): Clarified that recruitment will continue in 
mainland China until at least 40 patients have been randomized.
Section 9.3.3 (Pharmacokinetic Analysis Set): Definition of the PK Analysis Set revised 
for consistency with the SAP.

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Section 9.4.1.1.1 (Primary analysis of PFS): Details of strata collapse strategy removed 
and a cross-reference to the SAP added for further details.
Section 9.4.1.1.3 (Subgroup analyses): Revised details of results to be presented for 
subgroup analyses in line with the SAP. 
Section 9.4.1.2.2 (Analysis of overall survival): Text added to clarify the sufficient 
number of events is ≥20 deaths across both treatment groups with at least 5 events per arm.
Section 9.4.1.2.4 (Analysis of Duration of Response): Removed reference to Expected 
Duration of Response analysis, in line with the SAP. 
Section 9.4.1.3.6 (Comparison of baseline tumor EGFR mutation status): Text added to 
describe the analysis method to be used to compare baseline tumor EGFR mutation status 
between local and central tests.
Section 9.6 (China Cohort): Clarified that recruitment will continue in mainland China 
until at least 40 patients have been randomized. Reference to a separate Asia population 
analysis removed. 
Appendix C (Handling of Human Biological Samples): Text added to describe the 
requirement in China for mutation testing residual tissue and plasma samples to be 
destroyed or repatriated maximally 5 years after study indication approval for marketing in 
China, and timing of destruction of all PK samples and residual samples collected in China 
added as maximally 12 months post final CSR.
CSP Version 4.0, 25 February 2022 
Changes to the protocol are summarized below:
The primary changes in this protocol are:
!
To clarify the number of patients planned to be recruited in China.
!
To remove the requirement for the collection of PROs after the primary PFS analysis.
!
To clarify the nature and timing of AE data collection in relation to the Screening Part I 
and Screening Part II study periods.
The primary, secondary and exploratory objectives of this protocol remain unchanged. The 
above and other additional changes are described in detail below. Minor editorial changes 
have also been made; however, these are not included in the summary below.
Section 1.1 (Schedule of assessments [Table 1]): Footnote (n) was revised to state that 
PROs will no longer be collected for any patient after the primary PFS analysis. New 
footnote (aa) added to clarify that only AEs and SAEs related to study procedures will be 
collected during Screening Part I.
Section 1.2 (Synopsis): Updated in line with changes made throughout the CSP.

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Section 4.1 (Overall design): Updated in line with changes made throughout the CSP. 
Section 7.1.1.2.2 (Post primary PFS analysis) and Section 8.1.3 (Clinical outcome 
assessments): The requirement for the collection of PRO data after the primary analysis has 
been removed.
Section 7.5 (Patient management post primary PFS analysis and up to final OS 
analysis): Text clarified to state study assessments will continue per the SoA following the 
primary PFS analysis for all patients still on study treatment.
Section 8.1.3 (Clinical outcome assessments): Text revised to note that PRO data will no 
longer be collected for any patient after the primary PFS analysis. Text clarifying the timing 
of PRO collection for patients who discontinue study treatment prior to BICR-confirmed 
progression was removed.
Section 8.3.2 (Time period and frequency for collecting AE and SAE information): The 
types of AEs to be collected in the Part I Screening period has been clarified (all SAEs and 
AEs related to study procedures only) and details added to Table 8. Further details on AE 
collection from the time of signing the Part II Screening ICF until the 28-day follow-up visit 
has been added to the text.
Section 9.2 (Sample size determination) and Section 9.6 (China cohort): Text revised to 
state that 200 patients will be “randomized” (change from “recruited”) and approximately 
30 to 40 patients are planned to be recruited in China. The requirements for these patients to 
be recruited from mainland China was also removed.
Section 9.3.1 (Full Analysis Set), Section 9.3.2 (Safety Analysis Set), and Section 9.6 
(China Cohort): Text revised to remove statement that any patients recruited in China, 
after global recruitment has ended, will not be included in the FAS and SAF. The FAS will 
include all randomized patients, and the SAF will include all randomized patients who 
received at least one dose of study treatment. Analysis of PFS and OS in the China cohort 
will be conducted at the same time as for the overall population.
Section 9.4.1.1.3 (Subgroup analyses): Patients enrolled at a Chinese site and declaring 
themselves of Chinese ethnicity vs patients enrolled at non-Chinese site or declaring 
themselves of non-Chinese ethnicity was added as a subgroup for analyses. 
Section 9.4.1.2.11 (Analysis of EORTC QLQ-C30 and QLQ-LC13): Clarification added 
that PRO analyses will only take place at the time of the primary PFS analysis.

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CSP Version 5.0, 03 November 2023
Changes to the protocol are summarized below:
The primary changes in this protocol are:
!
To update the MTP to increase the chance of formally testing OS by changing the 
hierarchy to PFS, OS, and then CNS PFS ensuring OS is tested prior to CNS PFS.
The primary, secondary, and exploratory objectives of this protocol remain unchanged. The 
above and other additional changes are described in detail below. Minor editorial changes 
have also been made; however, these are not included in the summary below.
Throughout: Updates made to MTP; applies to Synopsis, Section 9.1, Section 9.2, 
Section 9.4.1.2.1, and Section 9.4.2.2. The MTP has been updated to change the hierarchy to 
PFS, OS, and then CNS PFS, so that OS is tested prior to CNS PFS. With the changing 
importance of an OS benefit for EGFRm NSCLC, this increases the chance of formally 
testing OS.
Throughout: Updates made to align with the latest PSSR (v28); applies to Section 6.5.1, 
Section 6.6, Section 8.4.2.2, Section 8.4.4.6, and Appendix I. Section 8.4.4.7 added.
Throughout: Updates made to include mandatory text from the recently released Late 
Development Oncology CSP Template (based on the AstraZeneca CSP TransCelerate 
Template TMP-0010225) and to harmonize the content to meet the EU CTR requirements; 
applies to Section 4.4, Section 6.7, Section 7.6, Section 8.4.5, Appendix A, and
Appendix B.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.

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TABLE OF CONTENTS
PAGE
VERSION HISTORY..........................................................................................................2
TABLE OF CONTENTS................................................................................................... 11
1
PROTOCOL SUMMARY ................................................................................. 17
1.1
Schedule of Activities (SoA) up to Primary PFS Analysis.................................. 17
1.2
Synopsis ............................................................................................................ 23
1.3
Schema .............................................................................................................. 29
2
INTRODUCTION ............................................................................................. 31
2.1
Stage III Non-Small Cell Lung Cancer............................................................... 31
2.2
Locally advanced unresectable EGFR mutation positive NSCLC ....................... 34
2.2.1
Incidence and management ................................................................................ 34
2.2.2
Efficacy outcomes following chemoradiation in patients with locally 
advanced unresectable EGFR mutation-positive NSCLC ................................... 34
2.2.2.1
Prospective Studies ............................................................................................ 34
2.2.2.2
Retrospective Studies......................................................................................... 35
2.2.2.3
Summary of data on demography/disease characteristics and efficacy 
outcomes for patients with locally advanced EGFR mutation positive 
NSCLC.............................................................................................................. 37
2.3
Study rationale................................................................................................... 37
2.4
Background........................................................................................................ 39
2.5
Benefit/risk assessment ...................................................................................... 41
2.5.1
Potential benefits................................................................................................ 41
2.5.2
Overall risks....................................................................................................... 41
2.5.3
ILD/Radiation pneumonitis................................................................................ 41
2.5.3.1
Effects on Cardiac Contractility ......................................................................... 43
2.5.3.2
Maintenance Studies of EGFR TKI therapies in patients with EGFR 
unselected Stage III NSCLC .............................................................................. 44
2.5.4
Overall benefit/risk ............................................................................................ 44
3
OBJECTIVES AND ENDPOINTS.................................................................... 45
4
STUDY DESIGN............................................................................................... 47
4.1
Overall design.................................................................................................... 47
4.2
Scientific rationale for study design ................................................................... 51
4.2.1
Rationale for 2:1 randomization schedule........................................................... 51
4.2.2
Rationale for choice of comparator..................................................................... 51
4.2.3
Rationale for selection of chemoradiation regimens............................................ 51
4.2.4
Rationale for proposed treatment duration.......................................................... 52
4.2.5
Rationale for primary endpoint of PFS ............................................................... 53
4.2.6
Rationale for the secondary efficacy endpoint of time to CNS progression.........54

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4.3
Justification for dose.......................................................................................... 55
4.4
End of study definition....................................................................................... 55
5
STUDY POPULATION .................................................................................... 56
5.1
Inclusion Criteria ............................................................................................... 56
5.1.1
Part I Screening.................................................................................................. 56
5.1.2
Part II Screening ................................................................................................ 57
5.2
Exclusion Criteria .............................................................................................. 60
5.2.1
Part I Screening.................................................................................................. 60
5.2.2
Part II Screening ................................................................................................ 60
5.3
Lifestyle restrictions........................................................................................... 63
5.3.1
Pregnancy .......................................................................................................... 63
5.3.2
Blood donation................................................................................................... 64
5.3.3
Chronic HBV infection ...................................................................................... 64
5.4
Meals and dietary restrictions............................................................................. 64
5.5
Screen failures ................................................................................................... 64
5.6
Procedures for handling incorrectly enrolled or randomized patients.................. 64
6
STUDY TREATMENTS................................................................................... 65
6.1
Treatments administered .................................................................................... 65
6.1.1
Investigational products ..................................................................................... 65
6.2
Preparation/handling/storage/accountability....................................................... 67
6.2.1
Preparation and Handling................................................................................... 67
6.2.2
Storage............................................................................................................... 67
6.2.3
Accountability.................................................................................................... 67
6.3
Measures to minimize bias: randomization and blinding..................................... 67
6.3.1
Methods For Randomization .............................................................................. 67
6.3.2
Methods For Blinding ........................................................................................ 68
6.3.3
Blind Break........................................................................................................ 68
6.4
Treatment compliance........................................................................................ 68
6.5
Concomitant therapy.......................................................................................... 69
6.5.1
Restricted and prohibited concomitant medications............................................ 69
6.5.1.1
Drugs known to prolong QTc interval ................................................................ 70
6.5.2
Other concomitant treatment .............................................................................. 70
6.6
Dose modification.............................................................................................. 71
6.7
Treatment after the end of the study ................................................................... 71
7
DISCONTINUATION OF TREATMENT AND PATIENT
WITHDRAWAL ............................................................................................... 72
7.1
Discontinuation of study treatment..................................................................... 72
7.1.1
Procedures for discontinuation of study treatment .............................................. 73

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7.1.1.1
Progression follow-up ........................................................................................ 73
7.1.1.2
Survival follow-up ............................................................................................. 74
7.2
Treatment with open-label osimertinib ............................................................... 76
7.3
Lost to follow-up ............................................................................................... 77
7.4
Withdrawal from the study................................................................................. 77
7.5
Patient management post primary PFS analysis and up to final OS analysis .......78
7.6
Patient management post-final OS analysis ........................................................ 78
8
STUDY ASSESSMENTS AND PROCEDURES............................................... 79
8.1
Efficacy assessments.......................................................................................... 79
8.1.1
Screening tumor sample for EGFR mutation analysis......................................... 79
8.1.1.1
Biopsied tissue samples for EGFR mutation testing............................................ 79
8.1.1.2
Plasma samples for EGFR mutation testing........................................................ 81
8.1.2
RECIST v1.1 ..................................................................................................... 81
8.1.2.1
Central reading of scans ..................................................................................... 82
8.1.2.2
Assessment of second progression...................................................................... 83
8.1.3
Clinical outcome assessments ............................................................................ 83
8.1.3.1
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire – Core 30 items (EORTC QLQ-C30) ................................... 84
8.1.3.2
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire – Lung Cancer 13 items (EORTC QLQ-LC13)..................... 84
8.1.3.3
Patients Global Impression of Severity (PGIS)................................................... 84
8.1.3.4
Patient Reported Outcomes version of the Common Terminology Criteria 
for Adverse Event (PRO-CTCAE) ..................................................................... 84
8.1.3.5
EuroQoL 5-Dimension 5-Levels (EQ-5D-5L) .................................................... 85
8.1.3.6
Administration of electronic Patient Reported Outcomes.................................... 85
8.1.4
Health Resource Use Module............................................................................. 86
8.2
Safety assessments............................................................................................. 87
8.2.1
Clinical safety laboratory assessments................................................................ 87
8.2.2
Volume of blood................................................................................................ 88
8.2.3
Physical examinations........................................................................................ 89
8.2.4
Vital signs.......................................................................................................... 89
8.2.5
Electrocardiograms ............................................................................................ 89
8.2.6
Echocardiogram/MUGA scan ............................................................................ 90
8.2.7
WHO performance status................................................................................... 91
8.3
Collection of adverse events............................................................................... 91
8.3.1
Method of detecting AEs and SAEs ................................................................... 92
8.3.2
Time period and frequency for collecting AE and SAE information ................... 92
8.3.3
Follow-up of AEs and SAEs .............................................................................. 93
8.3.4
Adverse event data collection............................................................................. 93
8.3.5
Causality collection............................................................................................ 94
8.3.6
Adverse events based on signs and symptoms.................................................... 94
8.3.7
Adverse events based on examinations and tests ................................................ 94

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8.3.8
Hy’s law ............................................................................................................ 95
8.3.9
Disease-under study (DUS)................................................................................ 95
8.3.10
Disease progression............................................................................................ 95
8.3.11
New cancers....................................................................................................... 95
8.3.12
Handling of deaths ............................................................................................. 95
8.4
Safety reporting and medical management ......................................................... 96
8.4.1
Reporting of serious adverse events ................................................................... 96
8.4.2
Pregnancy .......................................................................................................... 97
8.4.2.1
Maternal exposure.............................................................................................. 97
8.4.2.2
Paternal exposure............................................................................................... 97
8.4.3
Overdose............................................................................................................ 98
8.4.4
Management of IP-related toxicities................................................................... 98
8.4.4.1
General dose adjustments for adverse events...................................................... 98
8.4.4.2
Pneumonitis ....................................................................................................... 99
8.4.4.3
QTc prolongation............................................................................................. 103
8.4.4.4
Keratitis ........................................................................................................... 103
8.4.4.5
Changes in cardiac contractility........................................................................ 103
8.4.4.6
Erythema multiforme, and Stevens-Johnson syndrome, and Toxic 
epidermal necrolysis ........................................................................................ 103
8.4.4.7
Aplastic anaemia.............................................................................................. 104
8.4.5
Medication error, drug abuse, and drug misuse................................................. 104
8.4.5.1
Timelines......................................................................................................... 104
8.4.5.2
Medication error .............................................................................................. 104
8.4.5.3
Drug abuse....................................................................................................... 104
8.4.5.4
Drug misuse..................................................................................................... 104
8.5
Pharmacokinetics ............................................................................................. 105
8.5.1
Determination of drug concentration................................................................ 105
8.5.2
Storage and destruction of pharmacokinetic samples........................................ 106
8.6
Pharmacodynamics .......................................................................................... 106
8.7
Genetics........................................................................................................... 106
8.7.1
Optional exploratory genetic sample ................................................................ 106
8.7.2
Storage and destruction of genetic samples ...................................................... 106
8.8
Biomarkers & Exploratory Research................................................................ 107
8.8.1
Exploratory biomarkers.................................................................................... 107
8.8.2
Additional research .......................................................................................... 108
8.8.3
Storage, re-use and destruction of biomarker samples ...................................... 108
9
STATISTICAL CONSIDERATIONS.............................................................. 108
9.1
Statistical hypotheses ....................................................................................... 108
9.2
Sample size determination................................................................................ 109
9.3
Populations for analyses................................................................................... 110
9.3.1
Full Analysis Set.............................................................................................. 110
9.3.2
Safety Analysis Set .......................................................................................... 110

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9.3.3
Pharmacokinetic Analysis Set .......................................................................... 110
9.3.4
Evaluable for Response Analysis Set................................................................ 110
9.4
Statistical analyses ........................................................................................... 111
9.4.1
Efficacy analyses ............................................................................................. 111
9.4.1.1
Analysis of the primary variable....................................................................... 111
9.4.1.2
Analysis of secondary variables ....................................................................... 113
9.4.1.3
Exploratory analysis......................................................................................... 120
9.4.2
Methods for multiplicity control....................................................................... 120
9.5
Interim analyses............................................................................................... 121
9.5.1
Independent data monitoring committee........................................................... 122
9.6
China Cohort.................................................................................................... 122
10
REFERENCES ................................................................................................ 124
11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS....................................................................................... 138
LIST OF TABLES
Table 1
Study Assessments................................................................................17
Table 2
Study objectives....................................................................................24
Table 3
Study objectives....................................................................................45
Table 4
Study treatments....................................................................................65
Table 5
Study treatment dose adjustment information for adverse reactions.......71
Table 6
Laboratory safety variables ...................................................................88
Table 7
Approximate blood sample volumes (mL) d ..........................................88
Table 8
Time period and collection of AEs and SAEs........................................92
Table 9
Dose reduction levels ............................................................................99
Table 10
‘Pneumonitis’a Dosing modification and Toxicity Management 
Guideline ............................................................................................ 101
Table 11
Visit responses for symptoms and HRQoL.......................................... 119
Table 12
Summary of methods of assessment .................................................... 166
Table 13
Evaluation of target lesions .................................................................171
Table 14
Evaluation of non-target lesions .......................................................... 172
Table 15
Overall visit response.......................................................................... 173
Table 16
Drugs inducing CYP3A4..................................................................... 192

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Table 17
Exposure, pharmacological action and toxicity may be increased 
by Osimertinib .................................................................................... 192
Table 18
Drugs with a known risk of TdP.......................................................... 193
LIST OF FIGURES
Figure 1
Study design .........................................................................................30
LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations........................ 139
Appendix B
Adverse event definitions and additional safety information................ 147
Appendix C
Handling of Human Biological Samples.............................................. 153
Appendix D
Genetics.............................................................................................. 156
Appendix E
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law ....................................................................... 160
Appendix F
Guidelines for evaluation of objective tumor response using 
RECIST 1.1 criteria (Response Evaluation Criteria in Solid 
Tumors) .............................................................................................. 165
Appendix G
Patient Reported Outcome................................................................... 176
Appendix H
Abbreviations...................................................................................... 186
Appendix I
Guidance regarding Potential Interactions With Concomitant 
Medications ........................................................................................ 192
Appendix J
Definition of Women of Childbearing Potential and Acceptable 
Contraceptive Methods ....................................................................... 195

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1
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA) up to Primary PFS Analysis
Table 1
Study Assessments
Screening
Treatment Period
Follow-up Period
Details in CSP 
section
Visit (V) Name
Screening
Part I
Screening
Part II/V1
Random-
ization/ 
V2
V3
V4
V5
V6 V7-9 a V10-
11 a
V12+ 
a
Treatment 
Discont-
inuation
28-day
Follow-up b
Progression 
Follow-up c
Survival 
Follow-up
Week
NA
NA
1
2
4
8
12
16-24 32-40
48+
NA
NA
NA
NA
Day
NA
-28 to 0
1
15
29
57
85
113-
169
225-
281
337+
NA
NA
NA
NA
Window (days)
NA
NA
NA
±2
±2
±3
±3
±3
±7
± 7
+ 7
+ 7
± 7
± 7
Written informed 
consent for Part I 
Screening
X
Section 5.1
Written informed 
consent for Part II 
Screening d 
X
Section 5.1 and 
5.2
Diagnostic clinical procedures 
Tumor sample 
(archival or newly 
acquired) for 
prospective central 
EGFR mutation 
analysis e
X
Section 5.1 and 
Section 8.1.1
Tumor sample 
(archival or newly 
acquired) for 
retrospective 
central EGFR 
mutation analysis
X f
Section 5.1 and 
Section 8.1.1

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Table 1
Study Assessments
Screening
Treatment Period
Follow-up Period
Details in CSP 
section
Visit (V) Name
Screening
Part I
Screening
Part II/V1
Random-
ization/ 
V2
V3
V4
V5
V6 V7-9 a V10-
11 a
V12+ 
a
Treatment 
Discont-
inuation
28-day
Follow-up b
Progression 
Follow-up c
Survival 
Follow-up
Week
NA
NA
1
2
4
8
12
16-24 32-40
48+
NA
NA
NA
NA
Day
NA
-28 to 0
1
15
29
57
85
113-
169
225-
281
337+
NA
NA
NA
NA
Window (days)
NA
NA
NA
±2
±2
±3
±3
±3
±7
± 7
+ 7
+ 7
± 7
± 7
Plasma sample for 
retrospective 
central EGFR 
mutation testing
X
Section 8.1.1
Routine clinical procedure
Demography & 
baseline 
characteristics u
X
X
Section 5.1
Medical/surgical 
history
X
X
Section 5.1
Inclusion/exclusion
X
X
X
Section 5.1 and 
5.2
Physical 
examination 
including weight g
X
X
(pre-dose)
X
X
X
X
X
X
X 
X
Section 8.2.3
Height
X
Section 8.2.3
WHO performance 
status
X
X
(pre-dose)
X
X
X
X
X
X
X 
X
X
  
Section 8.2.7
Vital signs g
X
X
(pre-dose)
X
X
X
X
X
X
X 
X
Section 8.2.4
Digital ECG h
X
X
(pre-dose)
X
X
X
X
X
X
X
X
Xh
Section 8.2.5
Echocardiogram/
MUGA (for LVEF)
X
every 12 weeks relative to randomization 
(+7 days) including week 36 (+7 days) i
Xi
Section 8.2.6
Concomitant 
medication
X
X
At every visit and may be conducted by phone at 28-day follow-up 
Section 6.5
Anti-cancer and 
surgical treatment
X
X
X
Section 7.1.1.1
and 7.1.1.2

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Table 1
Study Assessments
Screening
Treatment Period
Follow-up Period
Details in CSP 
section
Visit (V) Name
Screening
Part I
Screening
Part II/V1
Random-
ization/ 
V2
V3
V4
V5
V6 V7-9 a V10-
11 a
V12+ 
a
Treatment 
Discont-
inuation
28-day
Follow-up b
Progression 
Follow-up c
Survival 
Follow-up
Week
NA
NA
1
2
4
8
12
16-24 32-40
48+
NA
NA
NA
NA
Day
NA
-28 to 0
1
15
29
57
85
113-
169
225-
281
337+
NA
NA
NA
NA
Window (days)
NA
NA
NA
±2
±2
±3
±3
±3
±7
± 7
+ 7
+ 7
± 7
± 7
Routine safety measurements
Adverse events
Xaa
X
At every visit and may be conducted by phone at 28-day follow-up
Xc, x
Xx
Section 8.3
Pregnancy test j
X
Section 8.2.2
Safety laboratory 
assessments 
(clinical chemistry, 
hematology and 
urinalysis)g
X
X
(pre-dose)
X
X
X
X
X
X
X 
X
Section 8.2.1
Biomarker analyses
Tumor sample upon 
disease progression 
(optional)t
at 
progression
at progression
Section 8.8
Plasma sample for 
ctDNA and blood 
borne biomarkers t
X
X
(pre-dose)
X
X
X
X
X
X
X 
X
Xk
Section 8.8
Pharmacokinetic measurements
Pre-dose blood 
sample
(including 
metabolites)l
X
X
X 
(Day 
169/ 
Week 
24 
only)
Section 8.5
Other assessments 
EORTC QLQ-
LC13m, n
X
(pre-dose)
Weekly up to week 8, thereafter every 4 
weeks (±3 days) relative to randomization 
X
X
X
Section 8.1.3.2
EORTC QLQ-
C30m, n
X
(pre-dose)
Week 4, week 8 and thereafter every 8 weeks 
(±3 days) relative to randomization
X
X
X
Section 8.1.3.1
PGISm, n
X 
(pre-dose)
Every 8 weeks (±3 days) relative to 
randomization 
X
X
X
Section 8.1.3.3

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Table 1
Study Assessments
Screening
Treatment Period
Follow-up Period
Details in CSP 
section
Visit (V) Name
Screening
Part I
Screening
Part II/V1
Random-
ization/ 
V2
V3
V4
V5
V6 V7-9 a V10-
11 a
V12+ 
a
Treatment 
Discont-
inuation
28-day
Follow-up b
Progression 
Follow-up c
Survival 
Follow-up
Week
NA
NA
1
2
4
8
12
16-24 32-40
48+
NA
NA
NA
NA
Day
NA
-28 to 0
1
15
29
57
85
113-
169
225-
281
337+
NA
NA
NA
NA
Window (days)
NA
NA
NA
±2
±2
±3
±3
±3
±7
± 7
+ 7
+ 7
± 7
± 7
PRO-CTCAEm, n
X 
(pre-dose)
Weekly up to week 8, thereafter every 4 
weeks (±3 days) relative to randomization 
X
X
X
Section 8.1.3.4
EQ-5D-5Lm, n
X
(pre-dose)
Week 4, week 8 and thereafter every 8 weeks 
(±3 days) relative to randomization 
X
X
X
Section 8.1.3.5
Health Resource 
Use Module 
X
(pre-dose)
X
X
X
X
X
X
X
X
Xw
Xy
Section 8.1.4
Efficacy measurements
Tumor assessments 
- Body CT/MRI 
and brain MRI
(RECIST v1.1)o
Xo
(Incl. 
planning 
scan)
Every 8 weeks (± 1 week) for the first 48 weeks and then change to every 12 weeks 
(relative to randomization) until BICR-confirmed PDz
Section 8.1.2
and Appendix F
Pharmacogenetic sampling (optional)
Genetic consent and 
blood sample 
(optional)p
X
Section 8.7
Study treatment administration
Randomization
Xv
Section 6.3
Study treatment  
dispensed (daily 
dosing)
Xs
X
X
X
X
X
X 
Section 6.1
Survival follow up 
Subsequent 
response / 
progression data q
X 
Section 7.1.1.2
Survival status r
Xx
Section 7.1.1.2
AESI = adverse event of special interest; BICR = blinded independent central review; CDx = companion diagnostic; CSP = Clinical Study Protocol; CT = computed tomography; ctDNA = circulating 
tumor deoxyribonucleic acid;; ECG = electrocardiogram; ECHO = echocardiogram; EGFR = epidermal growth factor receptor; EORTC QLQ-C30; European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire – Core 30 items; EORTC QLQ-LC13 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Lung 

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Cancer 13 items; ePRO = electronic patient reported outcome;  EQ-5D-5L = EuroQoL 5-Dimension 5-Levels; HRU= Health Resource Use; FDA = Food and Drug Administration; 
IP = investigational product; IVRS/IWRS = interactive voice response system/interactive web response system; LVEF = Left Ventricular Ejection Fraction; MRI = magnetic resonance imaging; 
MUGA = Multigated Acquisition Scan; NA = not applicable; OS = overall survival; PFS = progression free survival; PGIS=Patients Global Impression of Severity; PRO = patient reported outcome; 
PRO-CTCAE = Patient Reported Outcome version of the Common Terminology Criteria for Adverse Event approximately 17 items; PD = Progressive Disease; PK = pharmacokinetics; 
RECIST v 1.1 = Response Evaluation Criteria in Solid Tumors version 1.1; SAE = serious adverse event;  V = Visit; WHO = World Health Organization.
a.
Patients to attend visits every 8 weeks from Visit 9/Week 24 until Visit 12/Week 48, then every 12 weeks afterwards until BICR-confirmed disease progression.
b.
As a minimum, telephone contact should be made with the patient 28 days (+ 7 days) following the discontinuation of study drug.
c.
Patients who discontinue study drug for reasons other than BICR-confirmed disease progression will continue RECIST 1.1 tumor assessments every 8 weeks (relative to 
the date of randomization) or every 12 weeks after week 48 until BICR-confirmed disease progression. At the same time points WHO performance status, plasma 
samples for ctDNA and blood borne markers and information on HRU and anti-cancer and surgical treatments will be collected. EORTC QLQ-LC13, EORTC QLQ-
C30, PGIS, PRO-CTCAE, EQ-5D-5L questionnaires will continue to be carried out at the same frequency as the treatment period until BICR-confirmed disease 
progression. Both SAEs and AESIs considered related to study treatment and/or study procedures will be collected throughout progression follow-up. After the primary 
PFS analysis, patients who are in progression follow-up will move on to survival follow-up and have progression assessed in accordance with local clinical practice. 
Formal RECIST v 1.1 measurements, ePROs, HRU, WHO performance status, ctDNA and blood-borne biomarkers will no longer be collected. 
d.
Consent may be taken prior to 28-day window if required. Part II screening period of 28 days will then start with first study-related assessment.
e.
Tissue block (archival or newly acquired) must not be older than 12 months or slides must not be older than 60 days. 
f.
Tissue (archival or newly acquired) to be provided (where available) only for retrospective testing patients that did not undergo Part I screening (i.e., in circumstances 
where an EGFR positive-result was already available, derived from a tissue-based FDA approved CDx for TAGRISSO [i.e., cobas® EGFR Mutation Test v2 or 
FoundationOne® CDx test]). Tissue block must not be older than 12 months or slides must not be older than 60 days. A retrospective central EGFR mutation status test 
result is not needed to proceed with patient randomization.
g.
The assessments are to be completed pre-dose on visit day. If screening assessments have been performed within 7 days prior to starting study treatment, they do not 
have to be repeated at Visit 2 if the patient's condition has not changed.
h.
All ECG data (with the exception of screening ECG if the central ECG machine is not available) will be collected digitally for central analysis at scheduled visits and in 
the event of any cardiac adverse event. A 28-day follow-up ECG will be required if an on treatment assessment showed clinically significant abnormalities at treatment 
discontinuation to confirm reversibility of the abnormality.   
i.
MUGA or ECHO will be performed at screening, every 12 weeks relative to the date of randomization, at study treatment discontinuation and as clinically required. If a 
patient has had a MUGA or echocardiogram performed within 4 weeks prior to treatment discontinuation, the discontinuation visit ECHO/MUGA scan is not required 
unless clinically indicated. Patient will return for ECHO/MUGA assessment at week 36 additionally to align the assessment frequency every 12 weeks.
j.
Pregnancy test (blood or urine tests are acceptable based on the site’s standard clinical practice) will be conducted in women of child-bearing potential only
k.
If a patient discontinues study treatment prior to BICR-confirmed progression, samples should continue to be collected every 8 weeks until week 48 and every 12 weeks 
after week 48 (relative to the date of randomization) until BICR-confirmed progression. 
l.
Plasma PK sampling (2 mL each) will be performed at pre-dose on day 29 (visit 4/ week 4), day 85 (visit 6/week 12) and day 169 (visit 9/week 24). Pre-dose PK samples 
should be collected within 1 hr before the dose on the day of collection. The collection of the plasma sample for PK can be omitted if the patient did not have exposure to 
IP for at least 7 days prior to the visit.
m.
ePRO (Electronic devices; LogPads) must be assigned to patients only on the day of randomization; baseline ePROs must be completed by patients prior to dosing, when 
they are still in the clinic on the day of randomization. PRO-CTCAE will be administered only in the languages where a linguistically validated version exists. LogPads 
used for ePRO collection should be returned to site at the nearest visit as soon as the last assessment is completed by patient. 
n.
PROs to be collected at treatment discontinuation visit following BICR-confirmed disease progression and at week 8 (±3 days), week 16 (±3 days), and week 32 
(±3 days) relative to the date of the treatment discontinuation visit. For patients who discontinue study treatment prior to BICR-confirmed progression, PROs should be 
collected at the study treatment discontinuation visit and continue to be collected at the same frequency as the treatment period during progression follow-up until BICR-

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confirmed disease progression, then at disease progression and at week 8 (±3 days), week 16 (±3 days), and week 32 (±3 days) relative to the disease progression visit. 
PROs will not be collected for any patient after the primary PFS analysis. 
o.
The baseline assessments should be performed during the 28 day screening period and preferably as close as possible to and prior to the date of randomization. 
Subsequent assessments are to be performed every 8 weeks (±1 week) relative to randomization for the first 48 weeks and then every 12 weeks (±1 week) until objective 
radiological disease progression as per RECIST v1.1 as confirmed by BICR, even if a patient discontinues treatment prior to progression or receives other anti-cancer 
treatment. Tumor assessment will be performed using contrast enhanced CT or MRI of the chest and abdomen (including liver and adrenal glands). Any other sites where 
disease is suspected or known at baseline must also be imaged. In addition contrast-enhanced MRI of the brain will be performed at all imaging timepoints. Duplicate 
images from all scans will be collected for independent review. Expedited analysis by BICR will be triggered upon investigator-assessed progression. Results of the 
BICR of scans for those patients with disease progression as assessed by the investigator will be reported back promptly to sites. Please refer to section 8.1.1 for more 
details. During Part II screening, radiotherapy planning scans from the definitive radiation treatment delivered prior to randomization are to be submitted to 
AstraZeneca’s chosen imaging vendor. 
p.
If for any reason the sample is not drawn prior to dosing, it may be taken at any visit until the last study visit. Ensure genetic consent has be provided prior to sample 
collection. Blood samples for genetic analyses will not be collected in China as per local regulations.
q.
Following BICR-confirmed progression, time to second progression on a subsequent treatment (PFS2) 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. Investigator 
assessment of subsequent response/progression to be collected every 12 weeks up to the data cut off for the primary PFS analysis.
r.
Patient will be contacted for survival follow-up every 12 weeks. Patients should be contacted in the week after data cut-off for each study analysis (primary progression 
free survival [PFS] and OS) to establish survival status. 
s.
Study drug will only be dispensed to patient at randomization day (visit 2) after all study procedures and assessments have been performed as described in above table 
and all eligibility criteria are met.
t.
Blood and tumor samples for exploratory biomarker analyses are not applicable for China as per local regulations.
u.
Demographic data and other characteristics will be recorded and will include date of birth or age, gender, race and ethnicity during Part I screening or during Part II 
screening for patients who directly enter Part II. Smoking history will be collected at Part II for all patients. 
v.
Randomization will be made in IVRS/IWRS system as soon as all the eligibility criteria are met as confirmed by the investigator. Every effort should be made to 
minimize the time between randomization and starting study treatment. It is recommended that patients commence study treatment as soon as possible after 
randomization and whenever possible within one day. (i.e., on the same day after randomization in the IVRS/IWRS). 
w.
Patients who discontinue study treatment for a reason other than BICR-confirmed progression should have HRU module collected at that time of study treatment 
discontinuation and every 8 weeks up to week 48 and then every 12 weeks afterwards (relative to the date of randomization) until BICR-confirmed progression. 
Following BICR-confirmed progression, HRU module will be collected every 12 weeks during survival follow-up for all patients. Assessments for Healthcare resource 
will no longer be collected after the primary PFS analysis. 
x.
SAEs and AESIs (only if considered related to study treatment) will be collected throughout progression follow-up. SAEs and AESIs (only if considered related to open-
label osimertinib) will be collected throughout survival follow-up.
y.
Assessments for Healthcare resource will no longer be collected after the primary PFS analysis.
z.
Treatment assignment may be unblinded for each patient who has BICR-confirmed PD. Patients receiving placebo may receive open-label osimertinib. Patients assigned 
to osimertinib may receive open-label osimertinib post progression if, in the opinion of their treating physician, they are continuing to derive clinical benefit (see Section 
7.2).
aa.
Only AEs and SAEs due to study procedures are to be collected during Screening Part I.
  

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1.2
Synopsis 
Principal investigators 
 
Emory University School of Medicine, 1365 Clifton Rd, N.E., Atlanta, GA 30322
 Shanghai Chest Hospital, 241 Hauaihai West Road, Shanghai, 
China
Protocol Title: A Phase III, randomized, double-blind, placebo-controlled, multicenter, 
international study of osimertinib as maintenance therapy in patients with locally 
advanced, unresectable EGFR mutation-positive Non-Small Cell Lung Cancer (Stage III) 
whose disease has not progressed following definitive platinum-based chemoradiation 
therapy (LAURA)
Rationale: 
Non-small cell lung cancer (NSCLC) represents approximately 80% to 85% of all lung 
cancers, and approximately 30% of patients present with Stage III disease. The standard 
treatment for patients with unresectable Stage III NSCLC is platinum-based doublet 
chemotherapy and radiotherapy (CRT) administered either concurrently (CCRT) for 
patients with a good performance status (PS) or sequentially (SCRT) for less fit patients, 
both with curative intent. A meta-analysis of concurrent versus (vs) sequential CRT in 
patients with epidermal growth factor receptor (EGFR) unselected Stage III NSCLC 
showed a small improvement in 5 year overall survival (OS) of 15.1% vs 10.6% for CCRT 
vs SCRT, respectively. In more recent trials with improved staging and delivery of 
chemoradiation, a 5 year OS rate of ~20%-30% has been observed in patients receiving 
CCRT. 
There is limited data on outcomes for patients with EGFR mutation positive NSCLC 
receiving chemoradiation. The standard of care (SoC) for patients with unresectable EGFR 
mutation-positive NSCLC is the same as that for EGFR wildtype (EGFRwt) disease, i.e., 
chemoradiation. Whilst there is evidence that local control of disease following 
chemoradiation may be superior in EGFR mutation-positive patients, distant control is 
inferior and in particular, brain metastases occur more commonly (Ochiai et al 2016). As 
such, there is a strong rationale for use of maintenance therapy in this molecularly selected 
group of patients. 
Osimertinib has demonstrated statistically significant superior progression-free survival 
(PFS) compared with an investigator choice of gefitinib or erlotinib in patients with 
first-line locally advanced or metastatic EGFR mutation positive NSCLC (median 18.9 
months vs. 10.2 months; hazard ratio (HR) for disease progression or death, 0.46; 95% 
confidence interval [CI], 0.37 to 0.57; P<0.001). (FLAURA Soria et al 2017). Benefit was 
observed both in patients with and without brain metastases at baseline. At a later data 
cut-off, OS was statistically significantly longer for patients in the osimertinib arm 
compared with the SoC arm (median 38.6 months vs. 31.8 months; HR 0.7999; 
PPD
PPD

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95% CI 0.6409, 0.9963; p=0.0462) (Ramalingam et al 2020). These data in the first-line 
advanced setting provide support for evaluation of osimertinib in the even earlier disease 
setting of locally advanced unresectable NSCLC given the similar biology, i.e, EGFR-
tyrosine kinase inhibitor (TKI) treatment-naïve NSCLC. The central nervous system 
(CNS) data observed with osimertinib in the FLAURA study is consistent with CNS 
efficacy data seen in patients with later lines of disease who have EGFR T790M positive 
NSCLC and indicate that osimertinib has the potential to delay or prevent the development 
of CNS metastases in patients with locally advanced unresectable NSCLC following 
chemoradiation.
Limited data from small prospective studies of EGFR TKI therapies in conjunction with 
chemoradiation or with radiation alone in patients with locally advanced unresectable 
EGFR mutation positive NSCLC and data from adjuvant trials of EGFR TKI therapies in 
EGFR mutation positive patients provide additional support for evaluation of osimertinib 
in this setting.
Thus administration of osimertinib following chemoradiation has the potential to 
prevent/delay disease progression, including in the CNS, prolong OS and potentially to 
increase the proportion of patients achieving ‘cure’ or long-term survival in comparison 
with chemoradiation alone.
Table 2
Study objectives
Primary objective:
Endpoint/Variable:
To assess the efficacy of osimertinib 
treatment compared with placebo as 
measured by progression free survival (PFS)
!
PFS using BICR assessment according to 
RECIST v1.1
Sensitivity analysis of PFS using Investigator assessment
according to RECIST v1.1
Secondary objective:
Endpoint/Variable:
To assess the efficacy of osimertinib 
treatment compared with placebo by 
assessment of PFS in patients with:
!
EGFR Ex19del or L858R mutation
!
EGFRm+ Ex19del or L858R detectable 
in plasma-derived ctDNA
!
PFS using BICR assessment according to 
RECIST v1.1
Sensitivity analysis of PFS using Investigator assessment 
according to RECIST v1.1
To assess the efficacy of osimertinib versus 
placebo on CNS PFS 
!
Time to CNS PFS (time to the earliest of CNS 
progression or death) using BICR assessments 
according to RECIST v1.1
!
Cumulative incidence rate of CNS PFS by BICR at 12 
and 24 months
To further assess the efficacy of osimertinib 
compared with placebo 
!
OS
!
ORR 
!
DoR 
!
DCR and tumor shrinkage 
!
TTDM 
All assessed by BICR according to RECIST v1.1
!
TTD

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Table 2
Study objectives
To further assess the efficacy of osimertinib 
compared to placebo post progression
!
PFS2
!
TFST
!
TSST
To assess disease-related symptoms and 
health-related QoL in patients treated with 
osimertinib compared with placebo
!
Change from baseline in EORTC QLQ-C30
!
Change from baseline in EORTC QLQ-LC13
To assess the safety and tolerability profile 
of osimertinib compared with placebo
!
AEs (graded by CTCAE v5);
!
Clinical chemistry, hematology and urinalysis;
!
Vital signs (pulse and blood pressure), physical 
examination, weight;
!
ECG parameters;
!
LVEF;
!
WHO Performance Status.
To assess the PK of osimertinib
!
Trough plasma concentrations of osimertinib, and its 
metabolite AZ5104 
If conducted, PK Parameters (CLss/F, Css, min and Css, max, 
AUCss) may be derived using population PK analysis and 
reported separately to the CSR. Data from this study may 
form part of a pooled analysis with data from other studies
Exploratory Objectives 
Endpoint/Variable:
To assess potential treatment-related adverse 
effects in patients treated with osimertinib 
compared with placebo using PRO-CTCAE
The PRO-CTCAE questionnaire will be used to identify 
change in treatment-related symptoms
To assess the patients’ overall impression of 
the severity of their cancer symptoms using 
PGIS
PGIS: Proportion of patients assessing current symptom 
severity
To compare osimertinib treatment with 
placebo treatment on health state utility
The EQ-5D-5L health state utility index will be used to 
derive health state utility based on patient reported data.
To compare health resource use associated
with osimertinib treatment versus placebo
HRU Module
To investigate the relationship between 
osimertinib (and metabolite) PK and 
selected endpoints (which may include 
efficacy, safety and/or PRO), where deemed 
appropriate
Correlation of PK with other primary, secondary or 
exploratory endpoints in patients treated with 
osimertinib.* 
To compare the baseline tumor EGFR 
mutation status in screened patients with 
evaluable results from baseline plasma 
samples
Data may be used to support diagnostic 
development
Comparison of EGFR mutation status between tumor 
DNA) and plasma-derived ctDNA.
To compare the local EGFR mutation test 
result used for patient selection with the 
retrospective central cobas® EGFR 
Mutation Test v2 results from baseline 
tumor samples.
Comparison of EGFR mutation status between the local 
EGFR mutation test results and central cobas® EGFR 
Mutation Test v2 results from tumor samples with 
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Table 2
Study objectives
To collect and store DNA for future 
exploratory research into genes/genetic 
variation that may influence PK or response 
to osimertinib (i.e., absorption, distribution, 
metabolism, excretion, safety and efficacy) 
and/or susceptibility to/development of 
cancers
Correlation of polymorphisms with variation in PK, 
pharmacodynamics, safety or response observed in 
patients treated with osimertinib or comparator.*
To assess the relationship between PK and 
blood-borne biomarkers.
Correlation of blood based biomarkers, including 
alterations in ctDNA, with variation in PK*.
To collect and store tumor samples to 
evaluate the association between exploratory 
biomarkers and key efficacy endpoints
Key markers to include, but not limited to mutations, 
amplifications, or expression changes in EGFR mutations, 
HER2 and MET.*
To collect and store plasma for isolation of 
ctDNA and to evaluate the association 
between exploratory biomarkers and key 
efficacy endpoints
Longitudinal analysis of ctDNA for mutations, 
amplifications or expression changes in EGFR, HER2, 
MET and other genes.*
To collect and store plasma to assess the 
relationship between blood borne 
biomarkers and key efficacy endpoints
Biomarkers will include but will not be limited to growth 
factors, or cytokines.*
To identify innate resistance mechanisms to 
study treatment.
Assessment of innate resistance mechanisms including but 
not limited to identify mutations, amplifications, or 
expression changes in EGFR, HER2 and MET in baseline 
ctDNA and/or tissue biopsies.* 
To identify acquired resistance mechanisms 
to study treatment.
Assessment of resistance mechanisms including but not 
limited to identify mutations, amplifications, or expression 
changes in EGFR, HER2 and MET in ctDNA and/or tissue 
biopsies taken at time of disease progression.*
To conduct exploratory research on tissue 
and plasma samples into factors that may 
influence susceptibility to/development of 
NSCLC/cancer and/or response to 
osimertinib (where response is defined 
broadly to include efficacy, tolerability or 
safety). Tissue and plasma samples may be 
used to support diagnostic development
Samples may be analyzed retrospectively for novel 
biomarker discovery research and/or diagnostic 
development.* 
*Samples may be analysed retrospectively. The results of this research will be reported either in the CSR itself or as 
an addendum, or separately in a scientific report or publication. The results of this research may be pooled with data 
from other studies with the study drug to generate hypotheses to be tested in future research.
AE=adverse event; AUCss=area under plasma concentration-time curve during any dosing interval at steady state 
[amount·time/volume]; BICR=blinded independent central review; CLss/F=apparent total body clearance at steady 
state; CNS=central nervous system; CSR=clinical study report; Css, max=maximum plasma concentration at steady 
state; Css, min=minimum plasma concentration at steady state; CTCAE=Common Terminology Criteria for Adverse 
Events; ctDNA=circulating tumor DNA; DCR=disease control rate; DNA=deoxyribonucleic acid; DoR=duration of 
response; ECG=electrocardiogram; EGFR=epidermal growth factor receptor; EGFRm+ = EGFR mutation positive; 
EORTC QLQ-C30=European Organization for Research and Treatment of Cancer Quality of Life Questionnaire –
Core 30 items; EORTC QLQ-LC13=European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire – Lung Cancer 13 items; EQ-5D-5L = EuroQoL 5-Dimension 5-Levels; Ex19del=Exon 9 deletion; 
HER2=human epidermal growth factor receptor 2; MET=tyrosine-protein kinase Met;; NSCLC=non-small cell lung 
cancer; ORR=objective response rate; OS=overall survival; PFS2=time to second progression on a subsequent 
treatment; PFS=progression-free survival; PGIS=Patients Global Impression of Severity; PK=pharmacokinetic(s); 
PRO=patient reported outcomes; PRO-CTCAE=Patient-Reported Outcomes version of the Common Terminology 

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Table 2
Study objectives
Criteria for Adverse Events; QoL=quality of life; RECIST=Response Evaluation Criteria in Solid Tumors; 
TFST=Time to first subsequent therapy; TSST=Time to second subsequent therapy; TTD= Time to treatment 
discontinuation; TTDM=time to death or distant metastases; WHO=World Health Organization.
Overall design
This is a Phase III, randomized, double-blind, placebo-controlled, multicenter international 
study assessing the efficacy and safety of osimertinib, as maintenance therapy in patients 
with locally advanced, unresectable EGFR mutation positive NSCLC (Stage III), whose 
disease has not progressed following definitive platinum-based chemoradiation therapy. 
Study period
Estimated date of first patient enrolled is June 2018
Estimated date of last patient completed (OS cut off) is May 2025 
Number of Patients
Approximately 200 patients will be randomized in a 2:1 ratio (osimertinib to placebo). Of 
those, it is planned that approximately 30 to 40 patients will be recruited in China.
Patients randomized will have achieved a complete response (CR), partial response (PR), 
or have stable disease (SD) following definitive, platinum-based, chemoradiation.
Randomization will be stratified by: sequence of chemoradiation (concurrent vs 
sequential), disease stage prior to chemoradiation (IIIA vs IIIB/IIIC) and will also include 
China cohort (enrolled at a Chinese site and patient declaring themselves of Chinese
ethnicity vs enrolled at Non-Chinese site or patient declaring themselves of non-Chinese 
ethnicity) as a stratification factor to allow separate randomization for the purposes of 
reporting in China.
In order to reflect global clinical practice, recruitment will be monitored on an ongoing 
basis and will be managed to ensure that the majority (≥60%) of patients entering the study 
have received prior CCRT. Study entry is permitted based on the detection of an Exon 19 
deletion (Ex19del) and/or L858R mutation via central, tissue-based EGFR testing using 
the cobas® EGFR Mutation Test v2, or from a pre-existing local EGFR test result obtained 
using a tissue-based Food and Drug Administration (FDA)-approved Companion 
Diagnostic (CDx) for TAGRISSO (i.e., cobas® EGFR Mutation Test v2 or 
FoundationOne® CDx test) from a Clinical Laboratory Improvement Amendments 
(CLIA)-certified (United States of America [USA] sites) or an accredited local laboratory 
(sites outside of the USA).
Treatments and Treatment Duration
Patients will be randomized in a 2:1 ratio to one of two treatment arms as follows:
!
Osimertinib 80mg oral (po) once daily (QD) until objective radiological disease 

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progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 which is 
confirmed by blinded independent central review (BICR) or until another treatment 
discontinuation criterion is met.
!
Matching placebo 80 mg po QD until objective radiological disease progression per 
(RECIST) v1.1 which is confirmed by BICR or until another treatment discontinuation 
criterion is met.
Treatment assignment may be unblinded for each patient with BICR-confirmed 
progression per RECIST v1.1. Patients assigned to osimertinib may continue to receive 
osimertinib if, in the opinion of their treating physician, they are continuing to derive 
clinical benefit. Patients receiving placebo may receive open-label osimertinib, in 
accordance with local clinical practice and the judgement of their treating physician. 
Patients must not receive any other anti-cancer therapies between discontinuation of study 
treatment and the start of treatment with open-label osimertinib. For all patients, 
post-progression treatment with osimertinib may continue as long as the treating physician 
considers the patient to be deriving clinical benefit. 
After the final OS analysis, AstraZeneca will continue to supply open-label osimertinib 
until the patient stops deriving clinical benefit (as judged by the investigator), or until 
osimertinib is commercially available for use in the first-line setting in the patients’ 
respective country/territory.
Patients who discontinue study treatment for any reason prior to BICR-confirmed disease 
progression enter progression follow up and should continue to have tumor assessments 
according to the schedule of assessments until disease progression confirmed by BICR.
Patients who discontinue study treatment due to BICR-confirmed disease progression per 
RECIST v1.1 will enter survival follow up.
Data Monitoring Committee:
An Independent Data Monitoring Committee (IDMC) will be convened, and will meet to 
review unblinded safety data, initially approximately 6 months after the study has started, 
as long as a minimum of 20 patients have been randomized and treated for >1 month. 
Three subsequent meetings will take place every 6 months and then meetings will be held 
yearly thereafter until primary analysis completion. Further meetings for review of safety 
data from all patients may be convened at the discretion of the IDMC. Following each 
meeting the IDMC will evaluate whether the trial should continue without change, be 
modified or stopped due to potential harm to patients. 
Full details of the IDMC procedures and processes can be found in the IDMC Charter.
Statistical methods 
Approximately 200 patients will be randomized, globally, in a 2:1 ratio (osimertinib: 
placebo) to this study. These patients will be stratified by disease stage that chemoradiation 

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was received for (IIIA vs IIIB/IIIC), chemoradiation schedule (CCRT vs SCRT) and China 
cohort (enrolled at a Chinese site and patient declaring themselves of Chinese ethnicity vs 
enrolled at Non-Chinese site or patient declaring themselves of non-Chinese ethnicity). 
The primary endpoint of the study is PFS by BICR in the Full Analysis Set (FAS) 
population. The primary analysis of PFS will occur when approximately 120 progression 
events have been observed from the globally randomized patients. If the true PFS hazard 
ratio for the comparison of osimertinib vs placebo is 0.53, 120 progression events will 
provide 90% power to demonstrate a statistically significant difference in PFS at a 5% 2-
sided significance level (translating to an approximate improvement in median PFS from 8 
to 15 months assuming exponential data distribution and proportional hazards). The 
smallest treatment difference that would be statistically significant is a PFS HR of 0.68 
(translating to an approximate 4m improvement). 
The analysis of PFS in the China cohort will be conducted at the same time as the analysis
of PFS for the overall population. 
The final analysis of OS will be conducted at approximately 60% maturity when 
approximately 120 death events (across both arms) have occurred. Since two OS analyses 
are planned, the Lan DeMets approach that approximates the O’Brien and Fleming 
spending function will be used to maintain an overall 2-sided 5% type I error across the 
testing of two planned analyses of OS.
The final analysis of OS in the China cohort will be conducted at the same time as the final 
analysis of OS for the overall population.
PFS will be analyzed using a log rank test stratified by chemoradiation schedule 
(concurrent vs sequential), disease stage prior to chemoradiation (IIIA vs IIIB/IIIC) and 
China cohort (enrolled at a Chinese site and patient declaring themselves of Chinese 
ethnicity vs enrolled at Non-Chinese site or patient declaring themselves of non-Chinese 
ethnicity). The primary analysis will be based on BICR assessment of disease progression 
by RECIST v1.1. A sensitivity analysis of PFS will be performed based on data assessed 
by investigator assessment for all patients.
The two secondary endpoints of OS and CNS PFS in the overall population will be tested 
sequentially after the primary PFS analysis in a hierarchical procedure at the time of the 
PFS analysis. OS will be tested sequentially after PFS in a hierarchical procedure at an 
interim (time of PFS analysis) and final (approximately 60% maturity) timepoint.  
1.3
Schema 
The general study design is summarized in Figure 1.

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Figure 1
Study design 
Abbreviations: BICR=Blinded Independent Central Review; CR=complete response; 
CRT=chemoradiotherapy; EGFRm=EGFR mutation positive; Ex19Del=Exon 19 deletion; PFS2=time 
of second progression on a subsequent treatment; PR=partial response; OS=overall survival; QD=once 
daily; RECIST=Response Evaluation Criteria in Solid Tumors; SD=stable disease; SCRT=sequential 
chemoradiotherapy; TFST=time to first subsequent therapy; TSST=time to subsequent second therapy.
a
Patients with a positive local EGFR test result via a tissue-based FDA approved CDx for TAGRISSO (i.e., cobas®
EGFR Mutation Test v2 or FoundationOne® CDx test) do not need to undergo Part I screening.
b
Assessment of PFS2 will not be collected after the primary PFS analysis

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2
INTRODUCTION
2.1
Stage III Non-Small Cell Lung Cancer
Primary lung cancer is the most common form of cancer (12.9% of all new cancers 
worldwide) after non-melanocytic skin cancer and it remains the leading cause of cancer-
related death overall (19.4% of all deaths from cancer) (GLOBOCAN 2012). NSCLC 
represents approximately 80% to 85% of all lung cancers.
Locally advanced NSCLC is defined as Stage III NSCLC according to the most recent (8th) 
Edition of the International Association for the Study of Lung Cancer (IASLC)/Union for 
International Cancer Control tumor/node/metastasis (TNM) staging classification 
(Goldstraw et al 2016). Stage III NSCLC represents a heterogeneous group of patients. At 
one end of the spectrum, patients with T3 and N1 disease are generally considered 
resectable. However, patients with T4 disease, i.e., that invades vital central structures 
(diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, 
esophagus, vertebral body, and carina) and/or patients with ipsilateral mediastinal nodal 
involvement (N2), ipsilateral distant nodal disease or contralateral nodal involvement (N3) 
are generally consider unresectable. The various combinations of T stage and nodal status 
determine whether disease is classified as Stage IIIA, IIIB or IIIC, which are associated 
with progressively poorer outcomes (Goldstraw et al 2016).
Given the heterogeneity in extent and distribution of disease in Stage III NSCLC, 
international guidelines recommend that an individualized decision on patient management 
must be made within a multidisciplinary team including pulmonologists, thoracic/medical 
oncologists, radiation oncologists, thoracic surgeons, radiologists and pathologists 
(National Comprehensive Cancer Network (NCCN) NSCLC 2018, Eberhardt et al 2015
[ESMO (European Society for Medical Oncology) Consensus Conference]) and treatment 
should be carried out in high-volume centers.
Based on a US National Cancer Database of 813,032 patients diagnosed with NSCLC 
between 1998 and 2006 and with available staging information, the proportion of patients 
diagnosed with Stage III disease was approximately 27% (Morgensztern et al 2010).
Whilst these patients have unresectable disease, they may still have disease that can be 
cured with definitive chemoradiation. CCRT is considered the SoC for younger patients 
with good performance status and minimal comorbidities. Based on a NSCLC 
Collaborative Group meta-analysis comparing CCRT with SCRT, CCRT was associated 
with a significant benefit on OS (HR, 0.84; 95% CI, 0.74 to 0.95; P =.004), with an 
absolute benefit of 4.5% at 5 years (15.1% vs 10.6%) (Aupérin et al 2010). However, 
CCRT was associated with increased Grade 3 to 4 acute esophageal toxicity (18% vs 4%). 
As such, SCRT is reserved for patients who are less fit.
In one study, only approximately 40% of patients were considered eligible for CCRT (De 
Ruysscher et al 2009). Advanced age, and cardiac and pulmonary comorbidities were the 
principal reasons for non-eligibility. Similarly, in a United Kingdom (UK) national survey

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including 49 centers that evaluated the current practice of CCRT in patients with locally 
advanced unresectable disease, most of the respondents estimated that less than 30% of 
patients were suitable for CCRT (Helbrow et al 2012). Based on market research in the 
United States (US), Western Europe and Japan, of the patients that received 
chemoradiation treatment, the proportion varied from region to region however overall 
approximately two thirds of patients received CCRT and one third received SCRT (Kantar 
Health 2017).
Trials included in the NSCLC Collaborative Group meta-analysis were conducted in the 
late 1980’s, 1990s and early 2000s, and did not include staging work-up consistent with 
current standards. In particular, most were not staged with positron emission tomography 
(PET) scans and brain magnetic resonance imaging (MRI) and it is known that 
approximately 10% to 30% of patients with non-metastatic NSCLC as determined by 
conventional imaging may be found to have distant metastases with more modern 
diagnostic tools (MacManus et al 2001, Pfister et al 2004). Moreover, most trials in the 
NSCLC Group meta-analysis used a two-dimensional radiotherapy technique and the total 
dose of radiotherapy was below modern day standards in two of the six trials. The median 
OS associated with CCRT in the larger trials in the meta-analysis was 16 to 17 months 
(Furuse et al 1999, Curran et al 2003, Curran et al 2011, Fournel et al 2005, Belderbos et al 
2007).
As a consequence of improvements in (i) tumor staging (leading to stage migration); (ii) 
planning and delivery of radiotherapy, eg, intensity-modulated radiotherapy (IMRT); and 
(iii) management of toxicities associated with chemoradiation, efficacy outcomes 
associated with CCRT have improved. In more recent studies the median OS ranges from 
20.6 to 28.7 months (Bradley et al 2015, Senan et al 2016, Liang et al 2017, Ahn et al 
2015, Mitchell et al 2015) and in one study 5 year OS of 32% was observed (Bradley et al 
2017)
In addition to the use of CCRT, studies of induction chemotherapy prior to CCRT or 
consolidation chemotherapy after CCRT have been conducted. A Phase III study of 
induction chemotherapy failed to show a survival benefit (Vokes et al 2007). Similarly 
three phase III randomized studies of consolidation therapy showed no OS benefit, (Hanna 
et al 2008, Ahn et al 2015; Flentje et al 2016) and this was confirmed in a meta-analysis 
that included five studies with a total of 958 patients (Odds Ratio [OR]=1.24; 95% CI: 
0.89-1.72; P=0.21). They did find a significant increase in the risk of toxicity, including 
infection, pneumonitis and treatment-related death. (Chang et al 2016). In addition, a 
pooled analysis of 41 trials (34 Phase II Trials and 7 Phase III trials) including 45 arms 
(CCT+: 25; CCT−: 20) failed to provide evidence that consolidation chemotherapy after 
CRT yields significant survival benefit for locally advanced NSCLC (Tsujino et al 2013). 
In contrast, a meta-analysis of 5 studies with a total of 1036 patients found that 
consolidation chemotherapy after CCRT followed by consolidation chemotherapy 
improved OS (pooled HR 0.85; 95% CI 0.73-0.99; P = 0.03). (Wang et al 2017). Based on 
these data overall there is no consistent evidence that supports use of induction 

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chemotherapy or consolidation chemotherapy in conjunction with CCRT.
Studies in EGFR unselected patients indicate that patients with adenocarcinoma of the 
lung are less likely to progress at the primary site than patients with squamous cell 
carcinoma or large cell carcinoma following chemoradiation (Cox et al 1999). In contrast, 
patients with adenocarcinoma are more likely than patients with squamous cell carcinoma 
to develop metastases to the brain (Cox et al 1999, Hendriks et al 2016) and other distant 
sites (Cox et al 1999). The incidence of brain metastases as first site of relapse is 11-16% 
in patients with adenocarcinoma or non-squamous carcinoma (Cox et al 1999, Senan et al 
2016), compared with 8% in patients with squamous cell carcinoma (Cox et al 1999). In 
one study approximately 27% of patients with Stage III adenocarcinoma developed 
symptomatic brain metastases following chemoradiation compared with approximately 7% 
of patients with stage III squamous cell cancer (Hendriks et al 2016). However, these 
differences in recurrence patterns have not led to different management strategies for these 
different entities.
Recently durvalumab, a selective, high-affinity, human IgG1 monoclonal antibody that 
blocks programmed death ligand 1 (PD-L1) binding to programmed death 1 (PD-1) and 
CD80, was approved for use in patients with unresectable, Stage III NSCLC whose disease 
has not progressed following concurrent platinum-based chemotherapy and radiation 
therapy. Approval was based on data from a Phase III randomized placebo-controlled study 
in which durvalumab was associated with a significant prolongation of PFS compared with 
placebo given as a maintenance therapy in patients without disease progression after two 
or more cycles of definitive concurrent platinum-based chemoradiation (median PFS from 
randomization 16.8 months (95% CI, 13.0 to 18.1) with durvalumab vs 5.6 months (95% 
CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 
95% CI, 0.42 to 0.65; P<0.001) (Antonia et al 2017). As a result of these data National 
Comprehensive Cancer Network (NCCN) guidelines 2018 recommend durvalumab as a 
consolidation (maintenance) therapy in patients whose disease has not progressed 
following definitive CCRT (National Comprehensive Cancer Network (NCCN) NSCLC 
2018).
In this study, EGFR mutations were observed in 6.0% of the patients (6.1% in the 
durvalumab group, and 5.9% in the placebo group. The observed treatment effect was in 
favor of durvalumab in the EGFR positive patients (PFS HR: 0.76; 95% CI: 0.35, 1.64). 
However, these results should be interpreted with caution due to the small number of 
patients who were EGFR positive (29 in the durvalumab group and 14 in the placebo 
group) and the small number of events (17 in the durvalumab group and 11 in the placebo 
group).
There are no other approved maintenance therapies following chemoradiation in patients 
with stage III NSCLC.

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2.2
Locally advanced unresectable EGFR mutation positive NSCLC
2.2.1
Incidence and management
The proportion of patients with adenocarcinoma that is EGFR mutation-positive appears 
broadly similar across stages and is approximately 50% to 60% in Asian patients and 15% 
to 20% in patients from the West (Shi et al 2014, Wu et al 2014, Dogan et al 2012). 
However, in predominantly single center retrospective studies that assessed the relative 
outcome of efficacy of chemoradiation in patients with EGFR wildtype (EGFRwt) and 
EGFR mutation-positive tumors, the incidence of EGFR mutation-positivity in patients 
with adenocarcinoma appeared lower than expected in Asian patients (20% to 30%) 
(Tanaka et al 2015, Yagishita et al 2015, Akamatsu et al 2014, Hayashi et al 2012) but was 
as expected in Western patients (Mak et al 2011, Komaki et al 2015).
The SoC for patients with locally advanced unresectable EGFR mutation positive NSCLC 
is the same as that for EGFRwt NSCLC i.e., chemoradiation of curative intent. 
International guidelines indicate that there is currently no role for EGFR-TKIs in the 
management of locally advanced EGFR mutation-positive NSCLC, a consequence of 
which is that EGFR mutation testing is not universally considered to be standard practice. 
(Eberhardt et al 2015 [ESMO Consensus Conference], Saijo et al 2010 [Lung Cancer 
Working Group Report], Tan et al 2016 [IASLC Consensus Statement]. However, 
enrolment into randomized trials to address the potential for benefit in this population is 
encouraged (Tan et al 2016 [IALSC Consensus Statement]. As such, Study D5160C00048 
has been designed to assess the potential benefit of osimertinib in this patient group.
2.2.2
Efficacy outcomes following chemoradiation in patients with locally 
advanced unresectable EGFR mutation-positive NSCLC
The literature on outcomes of chemoradiation in patients with locally advanced EGFR 
mutation positive NSCLC is limited and is largely based on single center retrospective 
analyses, together with some small prospective studies.
2.2.2.1
Prospective Studies
Whilst there are numerous published Phase III studies of chemoradiation in patients with 
unresectable EGFR-unselected NSCLC (Ahn et al 2015, Bradley et al 2015, Mitchell et al 
2015, Senan et al 2016, Liang et al 2017, Curran et al 2011,Bradley et al 2017, Butts et al 
2014), there are no Phase III studies that have assessed the efficacy outcomes of 
chemoradiation in patients with EGFR mutation-positive disease.
Xing and colleagues reported preliminary data at American Society of Clinical Oncology 
(ASCO) 2017 from a multicenter, randomized, open-label, Phase II trial that compared 
etoposide/cisplatin with concurrent radiotherapy vs erlotinib with concurrent radiotherapy 
followed by maintenance erlotinib for up to 2 years. The primary endpoint was PFS. Forty-
one patients were enrolled into the erlotinib (n=20) and etoposide/cisplatin (n=21) arms. 
Compared with etoposide/cisplatin, the median PFS in the erlotinib arm was significantly 
improved (27.86 vs 6.41 months;HR: 0.053, 95% CI: 0.006 to 0.463; P<0.001) (Xing et al 

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2017). OS data from this study are not available at this time.
In a very small, prospective, randomized, Phase II trial in patients with Stage III EGFR 
mutation-positive NSCLC, induction erlotinib, chemoradiation concurrent with erlotinib 
followed by 6 cycles of consolidation erlotinib (Arm A; n=7) was compared with induction 
erlotinib and subsequent chemoradiation (Arm B; n=5). Median PFS and OS were 
numerically longer in Arm A than Arm B. In Arm A and Arm B, median PFS was 11.6 
months (95% CI 0.1 to 23.2) vs 8.1 months (95% CI 2.7 to 13.6) , respectively, and median 
OS was 39.3 months (95% CI, 0.7 to 83.3) vs 31.2 months (95% CI, 0.1 to 90.2) 
(p=0.442), respectively (Lee et al 2017)
Another small prospective single arm study (n=8) assessed afatinib induction, followed by 
chemoradiation and surgery if feasible, then adjuvant afatinib for up to two years (Warren 
et al 2016). At a median follow-up of 24 months, 7/8 of patients were recurrence-free.
2.2.2.2
Retrospective Studies
Data on the relative efficacy of chemoradiation in patients with unresectable EGFR 
mutation-positive NSCLC compared with EGFRwt NSCLC are available from a number 
of retrospective studies, predominantly from single institutions (Tanaka et al 2015, 
Yagishita et al 2015, Li et al 2011, Lim et al 2017, Ahn et al 2013, Mak et al 2011, Komaki 
et al 2015, Hayashi et al 2012, Akamatsu et al 2014, Ishihara et al 2017) or multi-
institutions (Ready et al 2010). 
Across the studies, patient numbers are generally small and there is marked heterogeneity 
with respect to disease characteristics at baseline, prior chemoradiation regimen employed 
and whether additional treatment strategies are permitted, eg, surgery (Mak et al 2011, Ahn 
et al 2013, Warren et al 2016) or EGFR-TKIs (Ready et al 2010, Lee et al 2017, Komaki et 
al 2015, Warren et al 2016). As such, these data should be interpreted with caution.
Across studies of chemoradiation without surgery or EGFR-TKIs, the median PFS ranges 
from 6.3 to 13.1 months in patients with EGFR mutation-positive NSCLC (Xing et al 
2017,Tanaka et al 2015, Yagishita et al 2015, Akamatsu et al 2014, Hayashi et al 2012, 
Ishihara et al 2017 and 9.5 to 18.6 months in patients with EGFRwt NSCLC (Tanaka et al 
2015, Yagishita et al 2015, Akamatsu et al 2014, Hayashi et al 2012, Ishihara et al 2017). 
In two of these studies, the PFS was statistically significantly lower in the EGFR 
mutation-positive group (Tanaka et al 2015; Ishihara et al 2017); no significant differences 
were observed in the remaining studies. Overall based on these data the median PFS in the 
EGFR mutation-positive groups was either similar or lower than that observed in the 
EGFRwt groups.
A more detailed analysis of data indicates that EGFR mutation status impacts upon the 
patterns of disease recurrence after chemoradiation for locally advanced NSCLC and 
highlights that patients with EGFR mutation-positive tumors are more likely to have 
superior local control but inferior distant control, including brain metastases, compared 
with patients with EGFRwt tumors (predominantly adenocarcinoma). Specifically Ochiai 

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and colleagues performed a literature review and pooled analysis of data from three 
studies, including 76 patients with EGFR mutation-positive tumors and 270 patients with 
EGFRwt tumors (Ochiai et al 2016; Tanaka et al 2015, Yagishita et al 2015, Akamatsu et al 
2014).
Patients with EGFR mutation-positive tumors were more likely to be female (OR 4.94, 
P<0.001) and never-smokers (OR 11.10, P<0.001) and were less likely to have advanced 
T-stage (OR 0.14, P<0.001) compared with patients with EGFRwt tumors. No significant 
difference was observed between the EGFR mutation-positive group and EGFRwt group 
for objective response rate (ORR; OR 1.46, 95% CI, 0.79-2.70, P=0.228) or disease 
recurrence (OR 1.37, 95% CI, 0.68 to 2.75, P=0.379). However compared with patients 
with EGFRwt tumors, there was a lower incidence of local/locoregional progression (OR 
0.35, 95% CI, 0.18 to 0.71, P=0.003) and a higher incidence of distant progression (OR 
2.97, 95% CI, 1.59 to 5.54, P<0.001) in patients with EGFR mutation-positive tumors. 
Moreover, brain metastasis was the most frequent site of disease relapse in the EGFR 
mutation-positive group in two studies (Tanaka et al 2015, Akamatsu et al 2014) and 
across the studies the incidence was significantly higher in the EGFR mutation-positive 
group, 26.3% vs 11.1%, (OR 2.75, 95% CI, 1.43 to 5.31, P=0.003) (Ochiai et al 2016).
Additional studies of chemoradiation (+/- additional treatment strategies) have revealed 
similar findings with a statistically significant higher risk of distant progression (Ahn et al 
2013, Ishihara et al 2017) or statistically significant lower risk of local progression (Lim et 
al 2017, Mak et al 2011) in the EGFR mutation-positive group compared with the EGFRwt 
group.
Additional studies of chemoradiation (+/- additional treatment strategies) have revealed a 
statistically significant lower incidence of advanced T-stage (Lim et al 2017) or a trend 
towards lower incidence of advanced T-stage in patients with EGFR mutation-positive 
tumors compared to EGFRwt (Ahn et al 2013; Mak et al 2011).
Across studies of chemoradiation without surgery or EGFR-TKI, the median OS ranges 
from 37.1 to 67.5 months in patients with EGFR mutation-positive NSCLC and 21.1 to 
42.9 months in patients with EGFRwt NSCLC (Tanaka et al 2015, Yagishita et al 2015, 
Akamatsu et al 2014, Hayashi et al 2012, Tanaka et al 2015). Median OS was higher in the 
EGFR mutation-positive groups compared with EGFRwt groups, but there were no 
statistically significant differences between the groups in these studies.
In other studies that have allowed additional treatment strategies, the median OS in the 
EGFR mutation-positive groups has been either significantly longer (Lee et al 2017), 
numerically longer (Mak et al 2011; Komaki et al 2015) or numerically lower than in the 
EGFRwt groups (Ready et al 2010)
In three studies, post-progression survival was statistically significantly longer in patients 
with EGFR mutation-positive NSCLC compared with EGFRwt NSCLC (Yagishita et al 
2015, Lee et al 2017, Ishihara et al 2017).

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2.2.2.3
Summary of data on demography/disease characteristics and efficacy 
outcomes for patients with locally advanced EGFR mutation positive 
NSCLC   
Patients with EGFR mutation-positive tumors are more likely to be female, never-smokers 
and are less likely to have advanced T-stage tumors compared with patients with EGFRwt 
tumors. There are limited data on the outcomes of CCRT in patients with unresectable 
EGFR mutation-positive cancer. In comparison with patients with unresectable EGFRwt 
NSCLC (predominantly adenocarcinoma), for patients with EGFR mutation-positive 
NSCLC:
(i) The median PFS is similar or lower.
(ii) Within this, locoregional control is superior and distant control inferior – the brain is a 
common site of relapse.
(iii) Median OS is generally longer, likely due in part to administration of EGFR-TKIs at 
the time of disease progression.
2.3
Study rationale
Whilst definitive chemoradiation is given as a treatment of curative intent for patients with 
Stage III disease, the majority of patients will subsequently have disease progression and 
hence these patients have a high unmet medical need. The increased risk of distant 
metastases including brain metastases, observed in patients with EGFR mutation NSCLC 
following chemoradiation supports the rationale for administration of an effective systemic 
therapy with an oral EGFR TKI therapy. Of the available EGFR TKI therapies clinical data 
indicate that osimertinib has the greatest potential to provide benefit in this setting.  
In addition to demonstrating efficacy in patients with T790M positive disease treated in the 
≥second-line setting (Mok et al 2017a, Goss et al 2016, Yang et al 2016, Yang et al 2017) 
osimertinib has demonstrated benefit in patients with previously untreated, locally 
advanced or metastatic EGFR mutation-positive NSCLC (FLAURA- Soria et al 2017). In 
a randomized Phase III study comparing osimertinib with a standard EGFR-TKI (gefitinib 
or erlotinib) with a primary endpoint of PFS, PFS was significantly longer with 
osimertinib than with standard EGFR-TKIs (median 18.9 months vs. 10.2 months; HR for 
disease progression or death, 0.46; 95% CI, 0.37 to 0.57; P<0.001). Data on OS were 
immature at the PFS analysis (25% maturity). At a later data cut-off (OS maturity 57.7%), 
OS was statistically significantly longer for patients in the osimertinib arm compared with 
the SoC arm (median 38.6 months vs. 31.8 months; HR 0.7999; 95% CI 0.6409, 0.9963; 
p=0.0462) (Ramalingam et al 2020).
The PFS benefit for osimertinib compared with standard EGFR-TKIs (gefitinib or 
erlotinib) was observed both in patients with (n=116) and without CNS metastases at study 
entry (n=440) (HR 0.47 [95% CI 0.30, 0. 74 p=0.0009] and 0.46 [95% CI 0.36, 0.59]; 
p<0001 for patients with and without CNS metastases respectively) (Ramalingam et al 
2017).

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In an analysis of patients with at least 1 CNS lesion (measurable or non-measurable) at 
baseline as determined by CNS BICR, (23% of all randomized patients), there was a 
nominally statistically significant and clinically meaningful improvement in CNS PFS for 
patients on osimertinib compared to patients on SoC (HR=0.48, 95% CI 0.26, 0.86; 
P=0.014) (Reungetwattana et al 2018). As the CNS PFS analysis was third in the 
hierarchical statistical testing strategy, this improvement was formally statistically 
significant following the statistically significant improvement in OS (Ramalingam et al 
2020). Irrespective of CNS metastasis status at study entry, based on Investigator 
assessment, there were fewer patients with new CNS lesions in the osimertinib arm 
compared to the SoC arm (11/279 [3.9%] vs. 34/277 [12.3%], respectively) [Data on File]. 
In the subgroup of patients with a CNS metastasis status of “No” at baseline, there was a 
lower number of patients with newly identified CNS lesions as reason for progression in 
the osimertinib arm compared to the SoC arm (7/226 [3.1%] vs. 15/214 [7.0%], 
respectively) [Data on File.]
Further evidence of the activity of osimertinib in the CNS has been demonstrated in 
patients with T790M positive disease. In the pooled Phase II studies of 128 patients with 
CNS metastases on baseline brain scans, 50 patients had lesions that were evaluable for 
response. Confirmed CNS ORR and disease control rate (DCR) were 54% (27/50; 95% CI 
39, 68), and 92% (46/50; 95% CI 81, 98), respectively (Goss et al 2017). In addition in 
AURA3  osimertinib showed a significantly longer CNS PFS (cFAS; 11.7 vs 5.6 months;
HR 0.32; 95% CI 0.15, 0.69; p = 0.004) and higher CNS ORR (cEFR; 70% vs 31%; (OR, 
5.13; 95% CI 1.44, 20.64; p = 0.015)) compared with chemotherapy in patients with CNS 
metastases at baseline (Mok et al 2017b).
EGFR TKIs have demonstrated efficacy in reducing the risk of disease recurrence in 
patients with EGFRm NSCLC in adjuvant trials which represents an analogous setting to 
the D5160C00048 study i.e., maintenance treatment following therapy of curative intent in 
patients with non-metastatic EGFR mutation positive NSCLC. Further details are provided 
in Section 4.2.4.
The data outlined in Section 2.2.2 demonstrating the propensity for patients with EGFR 
mutation positive tumors to relapse with distant metastases, including brain metastases, 
provide a strong rationale for administration of an effective systemic therapy in this 
population of patients. Positive efficacy data with osimertinib in comparison with EGFR 
TKI SoC in patients with first line advanced NSCLC in the FLAURA trial provide strong 
support for the evaluation of osimertinib in the even earlier disease setting of locally 
advanced unresectable NSCLC given the similar biology, i.e., in patients with EGFR-TKI 
treatment-naïve NSCLC. Moreover limited data from small prospective studies of EGFR 
TKI therapies in conjunction with chemoradiation or with radiation alone in patients with 
locally advanced unresectable EGFR mutation positive NSCLC and from adjuvant trials in 
patients with EGFR m+ NSCLC provide additional support for evaluation of osimertinib 
in this setting.
Thus administration of osimertinib following chemoradiation has the potential to 

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prevent/delay disease progression, including in the CNS, and potentially to increase the 
proportion of patients achieving ‘cure’ or long-term survival in comparison with 
chemoradiation alone.
2.4
Background
Osimertinib (TAGRISSO™) is an oral, potent, selective, CNS active, irreversible EGFR-
TKI, effective against both EGFR-TKI-sensitizing mutations (EGFR mutation) as well as 
T790M mutation positive ([T790M mutation positive] TKI resistance conferring mutation) 
forms of EGFR.
As of 12 November 2017, osimertinib is marketed in 63 countries worldwide for the 
treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive 
NSCLC) whose disease has progressed on or after EGFR TKI therapy.
As of 12 November 2017, it is estimated that (i)10820 patients and 118 healthy volunteers 
have been enrolled into the clinical development and early access programs and real world 
treatment study, of which 10,414 subjects have received osimertinib and (ii) the 
post-marketing exposure is estimated to be ~13,500 patient-years cumulatively.
Osimertinib was evaluated in a Phase I (AURA1) trial over a range of 20 mg QD to 
160 mg QD. No dose limiting toxicities were observed and objective responses were seen 
at all doses. On the basis of the totality of the safety, pharmacokinetic and preliminary 
efficacy data, 80 mg QD was selected as the recommended Phase II dose (Janne et al 
2015).
Two Phase II studies (AURA ex and AURA 2 were conducted in patients with T790M 
positive disease (second line or greater) following prior use of an EGFR TKI therapy. In 
the pooled 411 pre-treated EGFR T790M mutation positive patients, the ORR BICR in the 
evaluable for response population was 66% (95% CI: 61, 71) (Yang et al 2016). ORRs by 
BICR above 50% were observed in all pre-defined subgroups analyzed, including line of 
therapy, race, age and region. In patients with a confirmed response by BICR, the median 
duration of response (DoR) was 12.5 months (95% CI: 11.1, not evaluable). The median 
PFS by BICR was 11.0 months 95% CI (9.6, 12.4). Median OS was 26.8 months (24.2, not 
calculable) (Mitsudomi et al 2017).
Osimertinib was evaluated in a Phase III, open-label, randomized study (2:1 ratio 
[osimertinib: platinum-based doublet chemotherapy]) to assess the efficacy and safety of 
osimertinib (80 mg, PO, QD) vs platinum-based doublet chemotherapy (pemetrexed plus 
carboplatin or pemetrexed plus cisplatin followed by optional pemetrexed maintenance) as 
second-line therapy in patients with advanced EGFR T790M mutation positive NSCLC 
who had progressed following treatment with 1 line of treatment with an approved EGFR-
TKI. The primary endpoint was PFS as assessed by the investigator.
In total, 419 patients were randomized: 279 in the osimertinib arm and 140 in the 
chemotherapy arm. There was a statistically significant and clinically meaningful 

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improvement in PFS for patients on osimertinib vs. patients on chemotherapy based on 
investigator assessment (HR: 0.30 [95% CI: 0.23, 0.41]; p-value: <0.001). The median 
PFS was 10.1 months (95% CI: 8.3, 12.3) in the osimertinib arm vs. 4.4 months (95% CI: 
4.2, 5.6) in the chemotherapy arm (Mok et al 2017a). In addition osimertinib was 
associated with statistically significant improvements in secondary endpoints of ORR, 
DoR, DCR and tumor shrinkage compared with chemotherapy.
In addition osimertinib was evaluated in previously untreated, EGFR mutation-positive 
NSCLC in the FLAURA study as described in Section 2.3.
In clinical trials osimertinib has been generally well –tolerated. Based on a review of 
1142 patients with EGFR mutation positive NSCLC who received osimertinib at a dose of 
80 mg daily in two randomized Phase III studies (FLAURA, first-line; AURA3, 
second-line only), two single arm Phase II studies (AURA ex; AURA2, second-line or 
greater) and one Phase I study (AURA1, first-line or greater) most adverse reactions were 
Grade 1 or 2 in severity. The most commonly reported adverse drug reactions (ADRs) 
were diarrhea (49%) and rash (47%). Grade 3 and Grade 4 adverse reactions with 
osimertinib were 9.7% and 0.9%, respectively. 
In patients treated with osimertinib 80 mg QD, dose reductions due to adverse reactions 
occurred in 2.1 % of the patients. Discontinuation due to adverse reactions was 4.3%.
Osimertinib has not been associated with gastrointestinal perforations or hemorrhagic 
diarrhea and no events leading to dehydration or renal failure have been reported. No 
severe bullous, blistering or exfoliative skin conditions were observed.  
Interstitial Lung Disease (ILD) or ILD-like adverse reactions (e.g. 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. In the FLAURA study comparing osimertinib with a SoC EGFR TKI 
(gefitinib or erlotinib) in patients with previously untreated locally advanced or metastatic 
EGFR mutation positive NSCLC, ILD was reported in a low but numerically higher 
proportion of patients in the osimertinib arm than in the SoC arm (osimertinib: 3.9%; SoC: 
2.2%). Serious adverse events (SAEs) were reported in 2.2% of patients in the osimertinib 
arm and 1.4% of patients in the SoC arm; and were Common Terminology Criteria for 
Adverse Events (CTCAE) grade 3 in 3 (1.1%) patients on osimertinib and 2 (0.7%) 
patients on SoC; no patients had CTCAE Grade 4 events in the osimertinib arm vs 2 
patients (0.7%) in the SoC arm. No grade 5 events were observed in either treatment 
group.
Of the 1142 patients in FLAURA and AURA studies treated with osimertinib 80 mg, 0.9% 
of patients were found to have a corrected QT (QTc) greater than 500 msec, and 3.6% of 
patients had an increase from baseline QTc greater than 60 msec. No QTc-related 

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arrhythmia events were reported in the FLAURA or AURA studies.
A pharmacokinetic (PK) analysis with osimertinib predicted a concentration-dependent 
increase in QTc interval prolongation. (14.2 msec with an upper bound (90% CI) of 15.8 
msec).
Keratitis was reported in 0.7% of the 1142 patients treated with osimertinib in the 
FLAURA and AURA studies.
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% (35/908) 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.
Additional information including pre-clinical and clinical data on osimertinib may be 
found in the Investigator’s Brochure.
2.5
Benefit/risk assessment
2.5.1
Potential benefits
Section 2.3 provides the data that support the rationale that for evaluation of osimertinib in 
study D5160C00048, in particular data demonstrating superior PFS and CNS PFS for 
osimertinib in comparison with EGFR TKI SoC in patients with previously untreated, 
EGFR mutation-positive NSCLC (FLAURA [Soria et al 2017]). Administration of 
osimertinib following chemoradiation has the potential to prevent/delay disease 
progression, including in the CNS, and potentially to increase the proportion of patients 
achieving ‘cure’ or long-term survival in comparison with chemoradiation alone.
2.5.2
Overall risks
This is the first study to evaluate the use of osimertinib in patients with unresectable 
Stage III NSCLC within 6 weeks of completion of chemoradiation in patients whose 
disease has not progressed and as such the safety of administering osimertinib in this 
setting is unknown.
Section 2.4 provides information on the safety profile of osimertinib based on the program 
of AstraZeneca Phase I-III studies of patients with EGFR TKI -Naïve first line EGFR 
mutation-positive disease and patients with ≥second line T790M mutation positive 
NSCLC. Osimertinib has been generally well–tolerated in these trials.
Safety topics potentially of relevance to the use of osimertinib given post-chemoradiation 
include ILD/Radiation pneumonitis and changes in cardiac contractility.
2.5.3
ILD/Radiation pneumonitis
In addition to the risk of drug-induced ILD, radiation treatment is also associated with 
pneumonitis. In recently published trials of patients with locally advanced unresectable 

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EGFR unselected NSCLC the incidence of ≥Grade 3 pneumonitis ranged from 
approximately 1% to 8.3% (Flentje et al 2016, Ahn et al 2015, Senan et al 2016, Bradley et 
al 2015, Liang et al 2017, Antonia et al 2017). With the exception of one trial where the 
rate of fatal pneumonitis was 4.2% to 5.2% (Liang et al 2017), the incidence of fatal 
pneumonitis in these trials was <2%.
The Phase III study comparing the anti–programmed death ligand 1 (PD-L1) antibody 
durvalumab with placebo as consolidation therapy (maintenance therapy) in patients with 
Stage III NSCLC whose disease had not progressed after CCRT, has a similar design to 
this study of osimertinib (Antonia et al 2017). In this study the incidence of all grade 
pneumonitis or radiation pneumonitis in the placebo arm was 24.8%, with Grade 3 or 4 
events occurring in 3.0 % of patients. Grade 5 adverse events (AEs) of pneumonitis and 
radiation pneumonitis occurred in 1.3% and 0.4% respectively of patients in the placebo 
arm. 
First or second generation EGFR TKIs, gefitinib and erlotinib have been given solely as 
maintenance treatment in patients following chemoradiation in two placebo-controlled 
studies (Kelly et al 2008, Rigas et al 2009) and two single arm studies (Casal Rubio et al 
2014, Warren et al 2016). In a study comparing gefitinib and placebo following 
chemoradiation and maintenance docetaxel in patients with EGFR unselected NSCLC the 
incidence of Grade 3/4 pneumonitis in patients receiving gefitinib was 2.8% compared 
with no patients on placebo. (Kelly et al 2008). No fatal events were observed. No excess 
of ≥ Grade 3 pneumonitis was reported in studies by Rigas et al 2009, Casal Rubio et al 
2014 and Warren et al 2016.
Other trials have assessed the use of first generation EGFR TKIs given concurrently with 
radiotherapy or CRT followed by maintenance EGFR TKI. These include two small 
randomized trials (Martinez et al 2016, Xing et al 2017) and eight single arm studies 
(Center et al 2010, Ready et al 2010, Wang et al 2011, Stinchcombe et al 2008, Niho et al 
2012, Socinski et al 2012, Zhuang et al 2014, Okamoto et al 2011). No consistent excess of 
≥Grade 3 radiation pneumonitis or ILD compared with control groups or historical 
controls was observed.
There is a theoretical risk however that the incidence and/or severity of pneumonitis 
observed in D5160C00048 (LAURA) in patients receiving osimertinib could be higher 
than has been observed in trials of osimertinib in patients who have not recently undergone 
radiation treatment or in trials of chemoradiation (in the absence of osimertinib).
Enrollment criteria and guidelines for management of toxicities will be included in the 
protocol to reduce the risk of severe pneumonitis (drug-induced and/or radiation induced).
Whilst recognizing that radiographic changes coinciding with radiation portals would 
favor the diagnosis of radiation pneumonitis, differentiating a potential drug-induced 
pneumonitis from radiation pneumonitis can be challenging. As such a single guidance on 
dosing modification and toxicity management for ‘pneumonitis’ is provided in 

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Section 8.4.4.2 which covers the medical concepts of pneumonitis/ILD and radiation 
pneumonitis.
Whilst patients with ≥Grade 3 pneumonitis require permanent discontinuation from study 
treatment, the guidance permits re-challenge with study treatment in patients who develop 
Grade 2 pneumonitis following resolution of symptoms. This recommendation is 
supported by a review of the AstraZeneca global safety database as of September 2017 
which identified 46 patients with osimertinib-related ILD who either continued osimertinib 
(n=11) or temporarily stopped and subsequently received re-challenge with osimertinib 
(n=35) (Data on File). Most were considered SAEs (37/46). The majority of cases were 
from a Japanese post-marketing surveillance study D5160C00025 (n=31/46). Some cases 
have been reported in the literature (Mamesaya et al 2017a Mamesaya et al 2017b, 
Miyauchi et al 2017, Nagasaka and Gadgeel 2017).
Of the 35 cases where osimertinib was temporarily stopped the majority were treated with 
steroids (29/35). In 16/35 case reports osimertinib was reintroduced alongside steroid 
treatment. Osimertinib was reintroduced at a dose of 80 mg QD in 17/35 case reports; in 
12/35 case reports the dosage was reduced from 80 mg QD to 40 mg QD. In the remaining 
cases where information was known, patients received 80mg every other day (EOD) or 
continuation of 40 mg QD. Recurrence of ILD was reported in 5 patients (14%), none of 
which were fatal. Of these 3/17=18% had ILD recurrence at a dose of 80 mg QD and 
2/14 =14% had ILD recurrence following a dose reduction to <80 mg QD. In 21 cases no 
recurrence of ILD was reported and in 9 patients information was not available.
Of the 11 case reports of ILD where osimertinib was continued six were treated with 
steroids.1/11 treatment was continued at the same dosage, in 1 case report the dosage was 
changed to 80 mg EOD, and in 2 case reports the dosage was changed to 40 mg EOD. A 
total of 8/11 reported an outcome of recovered or recovering, and 3/11 were ongoing at the 
time of the report.
2.5.3.1
Effects on Cardiac Contractility
Whilst based on the available clinical trial data, AstraZeneca considers that a causal 
relationship between effects on changes in cardiac contractility and osimertinib has not 
been established, for patients with cardiac risk factors and those with conditions that can 
affect LVEF, cardiac monitoring, including an assessment of LVEF at baseline and during 
treatment, should be considered. In patients who develop relevant cardiac signs/symptoms 
during treatment, cardiac monitoring including LVEF assessment should be considered.
Radiotherapy –associated heart toxicity has long been recognized in patients with breast 
cancer or Hodgkin lymphoma, with increases in cardiovascular events and deaths typically 
noted 10 or more years after treatment (Wang et al 2017). Recent data indicates that for 
patients with unresectable Stage III NSCLC receiving chemoradiation, heart dose is a 
predictor of the risk of radiation-associated cardiac toxicity (Wang et al 2017) and of OS 
(Speirs et al 2017). It has been suggested that radiotherapy-associated cardiac toxicity after 
treatment of Stage III NSCLC may occur earlier than historically understood (Wang et al 

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2017). As such it is recommended that heart dose is minimized. 
The D5160C00048 protocol provides recommendations for maximum radiation exposure 
of the heart. In addition, consistent with other trials of osimertinib, cardiac function will be 
monitored with baseline assessment of LVEF and every 12 weeks thereafter via 
echocardiogram (ECHO)/ multigated acquisition scan (MUGA) scans. Additional scans 
will also be performed as clinically indicated.
2.5.3.2
Maintenance Studies of EGFR TKI therapies in patients with EGFR 
unselected Stage III NSCLC
In a study of gefitinib vs placebo as maintenance treatment following CCRT and docetaxel 
consolidation in patients with EGFR unselected inoperable Stage III NSCLC, a statistically 
significant deficit in survival was observed for gefitinib (SWOG S0023-Kelly et al 2008). 
The reasons for this observation are unclear. Data on EGFR mutation status in the study is 
unavailable, however given that this study was conducted in the US it is likely that only a 
minority of patients would have had EGFR mutation positive tumors. Moreover erlotinib 
was not associated with a deficit in survival compared with placebo as maintenance 
treatment following CCRT in patients with EGFR unselected Stage III NSCLC in a trial 
conducted in the US (Rigas et al 2009). Given that Study D5160C00048 will be conducted 
exclusively in patients with EGFR mutation positive NSCLC, the adverse effect of 
gefitinib on survival in the SWOG0023 is not considered to be of clinical concern. 
2.5.4
Overall benefit/risk 
Although there can be no certainty of clinical benefit to patients, the positive efficacy data
for osimertinib from the Phase III trial in patients with first line advanced NSCLC, 
supported by studies of EGFR TKI therapies in the adjuvant setting and the Phase II study 
of erlotinib in conjunction with chemoradiation (RECEL) provide support for evaluation of 
osimertinib in patients with locally advanced unresectable EGFRm NSCLC. 
Osimertinib is generally well tolerated. The majority of adverse reactions are of Grade 1 or 
2 severity, and the most frequent reactions are typical EGFR-TKI side effects including 
rash and diarrhea. ILD or ILD-like ADRs (e.g. pneumonitis) are commonly reported (3.9% 
of patients in Phase I-III studies), and occasionally fatal (0.4%) for patients receiving 
osimertinib. Enrolment criteria, safety monitoring and toxicity management guidance, 
including specific guidance for pneumonitis, have been included in the protocol to prevent 
and manage severe toxicity.
It is therefore, reasonable and appropriate to evaluate the oral administration of 
maintenance treatment with osimertinib in comparison to placebo both following 
chemoradiation in patients with locally advanced unresectable EGFR mutation positive 
NSCLC (Stage III) according to the proposed study.

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3
OBJECTIVES AND ENDPOINTS
Table 3
Study objectives
Primary objective:
Endpoint/Variable:
To assess the efficacy of osimertinib treatment 
compared with placebo as measured by progression 
free survival (PFS)
!
PFS using BICR assessment according to 
RECIST v1.1
Sensitivity analysis of PFS using Investigator 
assessment according to RECIST v1.1
Secondary objective:
Endpoint/Variable:
To assess the efficacy of osimertinib treatment 
compared with placebo by assessment of PFS in 
patients with:
!
EGFR Ex19del or L858R mutation
!
EGFR Ex19del or L858R mutation detectable 
in plasma-derived ctDNA
!
PFS using BICR assessment according to 
RECIST v1.1
Sensitivity analysis of PFS using Investigator 
assessment according to RECIST v1.1
To assess the efficacy of osimertinib versus 
placebo on CNS PFS 
!
Time to CNS PFS (time to the earliest of CNS 
progression or death) using BICR assessments 
according to RECIST v1.1
!
Cumulative incidence rate of CNS PFS by 
BICR at 12 and 24 months
To further assess the efficacy of osimertinib 
compared with placebo 
!
OS
!
ORR
!
DoR
!
DCR and tumor shrinkage
!
TTDM 
All assessed by BICR according to RECIST v1.1
!
TTD
To further assess the efficacy of osimertinib 
compared to placebo post progression
!
PFS2
!
TFST
!
TSST
To assess disease-related symptoms and health-
related QoL in patients treated with osimertinib 
compared with placebo
!
Change from baseline in EORTC QLQ-C30
!
Change from baseline in EORTC QLQ-LC13
To assess the safety and tolerability profile of 
osimertinib compared with placebo
!
AEs (graded by CTCAE v5)
!
Clinical chemistry, hematology, and urinalysis
!
Vital signs (pulse and blood pressure), physical 
examination, weight
!
ECG parameters
!
LVEF
!
WHO Performance Status
To assess the PK of osimertinib
!
Trough plasma concentrations of osimertinib, 
and its metabolite AZ5104 
If conducted, PK Parameters (CLss/F, Css, min and Css, max, 
AUCss) may be derived using population PK analysis and 
reported separately to the CSR. Data from this study may 
form part of a pooled analysis with data from other 
studies

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Table 3
Study objectives
Exploratory Objectives 
Endpoint/Variable:
To assess potential treatment-related adverse 
effects in patients treated with osimertinib 
compared with placebo using PRO-CTCAE
The PRO-CTCAE questionnaire will be used to 
identify change in treatment-related symptoms
To assess the patients’ overall impression of the 
severity of their cancer symptoms using PGIS
PGIS: Proportion of patients assessing current 
symptom severity
To compare osimertinib treatment with placebo 
treatment on health state utility
The EQ-5D-5L health state utility index will be 
used to derive health state utility based on patient 
reported data.
To compare health resource use associated
with osimertinib treatment versus placebo
HRU Module
To investigate the relationship between osimertinib 
(and metabolite) PK and selected endpoints (which 
may include efficacy, safety and/or PRO), where 
deemed appropriate
Correlation of PK with other primary, secondary or 
exploratory endpoints in patients treated with 
osimertinib.* 
To compare the baseline tumor EGFR mutation 
status in screened patients with evaluable results 
from baseline plasma samples
Data may be used to support diagnostic 
development
Comparison of EGFR mutation status between 
tumor DNA and plasma-derived ctDNA.
To compare the local EGFR mutation test result 
used for patient selection with the retrospective 
central cobas® EGFR Mutation Test v2 results 
from baseline tumor samples.
Comparison of EGFR mutation status between the 
local EGFR mutation test results and central 
cobas® EGFR Mutation Test v2 results from tumor 
samples with evaluable results.
To collect and store DNA for future exploratory 
research into genes/genetic variation that may 
influence PK or response to osimertinib (i.e., 
absorption, distribution, metabolism, excretion, 
safety and efficacy) and/or susceptibility 
to/development of cancers
Correlation of polymorphisms with variation in PK, 
pharmacodynamics, safety or response observed in 
patients treated with osimertinib or comparator.*
To assess the relationship between PK and blood-
borne biomarkers.
Correlation of blood based biomarkers, including 
alterations in ctDNA, with variation in PK*.
To collect and store tumor samples to evaluate the 
association between exploratory biomarkers and 
key efficacy endpoints
Key markers to include, but not limited to 
mutations, amplifications, or expression changes in 
EGFR mutations, HER2 and MET.*
To collect and store plasma for isolation of ctDNA 
and to evaluate the association between exploratory 
biomarkers and key efficacy endpoints
Longitudinal analysis of ctDNA for mutations, 
amplifications or expression changes in EGFR, 
HER2, MET and other genes.*
To collect and store plasma to assess the 
relationship between blood borne biomarkers and 
key efficacy endpoints
Biomarkers will include but will not be limited to 
growth factors, or cytokines.*
To identify innate resistance mechanisms to study 
treatment.
Assessment of innate resistance mechanisms 
including but not limited to identify mutations, 
amplifications, or expression changes in EGFR, 
HER2 and MET in baseline ctDNA and/or tissue 
biopsies.* 

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Table 3
Study objectives
To identify acquired resistance mechanisms to 
study treatment.
Assessment of resistance mechanisms including but 
not limited to identify mutations, amplifications, or 
expression changes in EGFR, HER2 and MET in 
ctDNA and/or tissue biopsies taken at time of 
disease progression.*
To conduct exploratory research on tissue and 
plasma samples into factors that may influence 
susceptibility to/development of NSCLC/cancer 
and/or response to osimertinib (where response is 
defined broadly to include efficacy, tolerability or 
safety). Tissue and plasma samples may be used to 
support diagnostic development
Samples may be analyzed retrospectively for novel 
biomarker discovery research and/or diagnostic 
development.* 
*Samples may be analysed retrospectively. The results of this research will be reported either in the CSR itself or as 
an addendum, or separately in a scientific report or publication. The results of this research may be pooled with data 
from other studies with the study drug to generate hypotheses to be tested in future research.
AE=adverse event; AUCss=area under plasma concentration-time curve during any dosing interval at steady state 
[amount·time/volume]; BICR=blinded independent central review; CLss/F=apparent total body clearance at steady 
state; CNS=central nervous system; CSR=clinical study report; Css, max=maximum plasma concentration at steady 
state; Css, min=minimum plasma concentration at steady state; CTCAE=Common Terminology Criteria for Adverse 
Events; ctDNA=circulating tumor DNA; DCR=disease control rate; DNA=deoxyribonucleic acid; DoR=duration of 
response; ECG=electrocardiogram; EGFR=epidermal growth factor receptor; EGFRm+ = EGFR mutation positive, 
EORTC QLQ-C30=European Organization for Research and Treatment of Cancer Quality of Life Questionnaire –
Core 30 items; EORTC QLQ-LC13=European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire – Lung Cancer 13 items; EQ-5D-5L = EuroQoL 5-Dimension 5-Levels; Ex19del=Exon 19 deletion; 
HER2=human epidermal growth factor receptor 2; MET=tyrosine-protein kinase Met; MUGA=multigated 
acquisition; NSCLC=non-small cell lung cancer; ORR=objective response rate; OS=overall survival; PFS2=time to 
second progression on a subsequent treatment; PFS=progression-free survival; PGIS=Patients Global Impression of 
Severity; PK=pharmacokinetic(s); PRO=patient reported outcomes; PRO-CTCAE=Patient-Reported Outcomes 
version of the Common Terminology Criteria for Adverse Events; QoL=quality of life; RECIST=Response 
Evaluation Criteria in Solid Tumors; TFST=Time to first subsequent therapy; TSST=Time to second subsequent 
therapy; TTD= Time to treatment discontinuation; TTDM=time to death or distant metastases; WHO=World Health 
Organization.
4
STUDY DESIGN
4.1
Overall design 
This is a Phase III double-blind, randomized, placebo-controlled, multicenter international 
study assessing the efficacy and safety of osimertinib as a maintenance therapy in patients 
with locally advanced unresectable (Stage III), NSCLC centrally confirmed EGFR 
mutations (Ex19del and L858R) whose disease has not progressed following definitive 
platinum based-chemoradiation therapy. 
Accounting for patients who do not have EGFR Ex19del or L858R mutation detected, 
sample attrition and 85% screen fail rate for other reasons, in order to randomize 
approximately 200 patients, it is estimated that 1333 patients will be screened at 
approximately 130 sites in Asia, Europe, North America and South America. It is assumed 
that approximately 80% of patients will be recruited from Asia and approximately 20% 
from non-Asian countries. 
Approximately 200 patients will be randomized. Of those, it is planned that approximately 

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30 to 40 patients will be recruited in China. This is being done to ensure adequate Chinese 
patient participation to satisfy China Regulatory Authority requirements. The China cohort 
will support standalone safety and efficacy analyses of patients from China.
Study entry is permitted based on the detection of an Ex19del and/or L858R mutation via 
central, tissue-based EGFR testing using the cobas® EGFR Mutation Test v2, or from a 
pre-existing local EGFR test result obtained using a tissue-based FDA-approved CDx for 
TAGRISSO (i.e., cobas® EGFR Mutation Test v2 or FoundationOne® CDx test), 
performed in a CLIA-certified (USA sites) or an accredited local laboratory (sites outside 
of the USA).
Patients without a pre-existing local EGFR test result will be required to undergo a two-
stage screening process. In Part I screening, patients will be asked to consent to provide a 
recent tumor tissue sample for central prospective EGFR mutation testing using the cobas®
EGFR Mutation Test v2. Consent can be given for prospective testing of the tumor sample 
before, during, or after chemoradiation. Part II screening will be conducted following 
completion of chemoradiation and will be carried out in patients who have passed Part I 
screening i.e. have tumors that contain the Ex19del or L858R mutations. In addition, 
patients with an EGFR mutation-positive test result (Ex19del and/or L858R) based on a 
local EGFR test using a tissue-based FDA-approved CDx for TAGRISSO (i.e., cobas®
EGFR Mutation Test v2 or FoundationOne® CDx test), can enter Part II screening directly 
after completion of chemoradiation. For these patients investigators will be asked to 
provide a formalin-fixed and paraffin embedded (FFPE) tumor tissue sample, where 
available, for retrospective central analysis of EGFR mutation status in Part II screening 
for comparison with the local test. However, patient enrolment will be based upon the local 
test. 
Following completion of chemoradiation, all patients will be required to have a baseline 
CT scan (preferred) or MRI scan (chest and abdomen including liver and adrenal glands) 
and contrast-enhanced MRI of the brain ≤28 days prior to randomization. Patients whose 
disease has not progressed are eligible for the study. Patients must have sufficiently 
recovered from chemoradiation prior to randomization with no unresolved toxicity of 
CTCAE>Grade 2. Patients who meet all of the inclusion criteria and none of the exclusion 
criteria for this study will be randomized 2:1 to receive either osimertinib or placebo. 
Randomization must occur ≤6 weeks following completion of chemoradiation. Patients 
will be stratified by prior chemoradiation strategy (CCRT vs SCRT), tumor stage prior to 
chemoradiation (IIIA vs IIIB/IIIC) and China cohort (enrolled at a Chinese site and patient 
declaring themselves of Chinese ethnicity vs. enrolled at Non-Chinese site or patient 
declaring themselves of non-Chinese ethnicity) to allow separate randomization for China.
In order to reflect global clinical practice, recruitment will be monitored on an ongoing 
basis and will be managed to ensure that the majority (approximately ≥60%) of patients 
entering the study have received prior CCRT. 
Following randomization, treatment should continue until objective radiological disease 

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progression occurs as defined by RECIST v1.1 and as confirmed by BICR or until another 
discontinuation criterion is met. 
Tumor assessments will be performed using (i) CT scan (preferred) or MRI, each
preferably with contrast, of the chest and abdomen (including liver and adrenal glands) and 
additional anatomy imaging, as indicated by signs and symptoms of the patient; and (ii) 
contrast-enhanced T1w MRI of the brain.  
CT /MRI of chest/abdomen and MRI of the brain will be performed at all tumor imaging 
visits. The baseline assessment is part of the screening procedure. Objective tumor 
assessments will be made every 8 weeks (relative to the date of randomization) until 
48 weeks, then every 12 weeks thereafter, until objective radiological disease progression 
occurs as defined by RECIST v1.1 and as confirmed by BICR. Additional scans should be 
performed if clinically indicated, i.e., if disease progression is suspected. If an unscheduled 
assessment is performed, and the patient’s disease has not progressed per BICR, every 
attempt should be made to perform the subsequent assessments at their scheduled visits. 
Patients who discontinue trial therapy for any reason prior to BICR-confirmed disease 
progression should continue to have tumor assessments according to the schedule of 
activities (SoA; irrespective of the reason for stopping study drug and/or subsequent 
therapy). All imaging assessments (including unscheduled visit scans) will be sent to the 
AstraZeneca appointed central reader on an ongoing basis. Expedited Analysis by BICR 
will be triggered upon investigator-assessed progression. Results of the BICR of scans for 
patients with investigator-assessed disease progression will be reported back promptly to 
sites. Since the primary analysis of the study is based on BICR, it is important that study 
treatment and scheduled imaging assessments continue until progression by BICR is 
confirmed. If a subject has been deemed to have objective disease progression according to 
the investigator tumor assessment by RECIST v1.1, but it is not confirmed by BICR, study 
treatment should be continued and the patient should maintain tumor assessments 
according to the SoA. Investigators should notify the Clinical Research Organization 
(CRO) again when progression is assessed at a subsequent timepoint. Progression includes 
disease recurrence for subjects with no evidence of disease at baseline.
Patients will undergo safety assessments at baseline, Week 2, Week 4 and every 4 weeks 
until Visit 9/Week 24, every 8 weeks until Visit 12/Week 48, then every 12 weeks 
afterwards until treatment discontinuation.
Safety assessments will include clinical chemistry, hematology, urinalysis, 
electrocardiogram (ECG) and LVEF measurement with ECHO/MUGA scans. Tumor and 
blood sampling for biomarker analysis will be performed. PK sampling will also be 
performed. Patient reported outcomes (PROs) and health resource use (HRU) for 
monitoring patient’s health condition and HRU respectively will be collected during the 
course of the study. Following discontinuation of study drug, a treatment discontinuation 
visit will be performed. AEs/SAEs/AEs of special interest (AESIs) will be collected for 28 
days following discontinuation and followed-up until resolution. Thereafter, at any time, if 
an investigator learns of any SAEs (including death) or AESI possibly related to study 

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treatment or open-label osimertinib, AstraZeneca should be notified. See Section 8.3 for 
further information on AE reporting.
Treatment assignment may be unblinded for each patient with BICR-confirmed 
progression per RECIST v1.1. Patients assigned to osimertinib may continue to receive 
open-label osimertinib if, in the opinion of their treating physician, they are continuing to 
derive clinical benefit. Patients assigned to placebo may receive open-label osimertinib, in 
accordance with local clinical practice and the judgement of their treating physician. 
Patients must not receive any other anti-cancer therapies between the discontinuation of 
study treatment and the start of treatment with open-label osimertinib. Treatment with 
open-label osimertinib should continue until radiological or clinical progression or 
unacceptable toxicity as determined by the investigator, at which point open-label 
osimertinib will be discontinued.
Patients with BICR-confirmed progression per RECIST v1.1 will enter survival 
follow-up. See Section 7.1.1.2 for details of data collection requirements during survival 
follow-up both prior to and post the primary PFS analysis. Any SAEs and any AESIs 
considered related to study treatment or open-label osimertinib should be reported during 
survival follow-up (See Section 8.3.2).
If a patient has discontinued study treatment for a reason other than BICR confirmed 
objective radiological disease progression per RECIST v1.1, the patient will enter 
progression follow-up and will continue to have regular scheduled tumor assessments 
until BICR-confirmed progression per RECIST v1.1, together with additional assessments 
as defined in Section 7.1.1.1. Any SAEs considered related to study treatment or study 
procedures should be reported during progression follow-up (See Section 8.3.2).
Patients will be followed as per the study protocol until data cut-off for the primary 
analysis when approximately 120 BICR-confirmed PFS events have occurred. This is 
estimated to occur approximately 48 months following first patient randomized, based on a 
40 month recruitment period. Results from the primary analysis will be reported in the 
Clinical Study Report (CSR). The study blind will be broken (at the Sponsor level) at the 
time of the primary PFS analysis. Sites and subjects will remain blinded until study 
completion i.e., after final OS analysis. 
Following the primary PFS analysis patients who are continuing to receive study treatment 
will have study assessments as per the schedule of assessments.
Following the primary PFS analysis patients who are continuing to receive study treatment 
will have their tumor assessment in accordance with local clinical practice. Formal 
RECIST measurements will not be collected. Study treatment should continue until disease 
progression as determined by the investigator, or until a treatment discontinuation criterion 
is met, at which point study treatment will be discontinued. BICR confirmation of 
progression is not required (see Section 7.5). 

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For all patients receiving open-label osimertinib, treatment with open-label osimertinib 
should continue until radiological or clinical progression or unacceptable toxicity as 
determined by the investigator, at which point open-label osimertinib will be discontinued.
The final analysis of OS will be conducted at approximately 60% maturity when 
approximately 120 death events (across both arms) have occurred. After the final OS 
analysis, the study blind will be broken and AstraZeneca will continue to supply 
open-label osimertinib until the patient stops deriving clinical benefit (as judged by the 
investigator), or until osimertinib is commercially available for use in the first-line setting 
in the patients’ respective country/territory.
4.2
Scientific rationale for study design 
4.2.1
Rationale for 2:1 randomization schedule
The use of a 2:1 randomization has been selected to increase the chance that patients 
randomized into this study will receive osimertinib treatment, given the potential benefit of 
osimertinib in this setting.
4.2.2
Rationale for choice of comparator
As described in Section 2, based on the results of a placebo-controlled Phase III trial, the 
PD-L1 inhibitor durvalumab is approved for use (in the US) in patients with unresectable, 
Stage III NSCLC whose disease has not progressed following concurrent platinum-based 
chemotherapy and radiation therapy and is recommended in the 2018 NCCN guidelines as 
a consolidation (maintenance therapy) for use in this patient population (Antonia et al 
2017). In this study the HR for PFS in the EGFR mutant subgroup was 0.76, in favor of 
durvalumab, with a wide CI that crossed 1.0. The numbers of patients with EGFR 
mutation-positive tumors was small with few events; thus interpretation of the data from 
this subgroup should be made with caution. As such it is considered acceptable to compare 
osimertinib with placebo in the current study. 
4.2.3
Rationale for selection of chemoradiation regimens
As described in Section 2, the SoC for patients with locally advanced unresectable Stage 
III NSCLC is CCRT, which has been shown to be superior to SCRT. However the 
magnitude of benefit is considered small (De Ruysscher et al 2016) and CCRT is 
associated with more toxicity. As a consequence of this only 30-40% of patients are 
eligible to receive CCRT.
Given that the unmet medical need is high regardless of whether CCRT or SCRT is given 
and considering that the degree of benefit for osimertinib compared with placebo is 
anticipated to be large and is likely to be similar, enrolment of both populations is 
permitted. Prior use of CCRT vs SCRT will however be included as a stratification factor.
The 2015 ESMO treatment guideline on the treatment of locally advanced (Stage III) 
NSCLC defines CCRT as simultaneous (same-day) administration of an active 
chemotherapy in parallel to ongoing thoracic radiotherapy fractions. SCRT is defined as 

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giving upfront combination chemotherapy for several cycles followed by a block of 
fractionated radiotherapy only (for 5–7 weeks). In the meta-analysis comparing 
‘concomitant vs sequential radiochemotherapy’ concomitant chemotherapy was defined as 
chemotherapy administered during radiotherapy and sequential chemotherapy was defined 
as chemotherapy given before and/or after radiotherapy (Aupérin et al 2010). Two to three 
cycles of platinum-based chemotherapy were administered in the SCRT regimens (where 
chemotherapy was only given prior to radiation) in the studies that contributed to this 
meta-analysis (Furuse et al 1999, Curran et al 2003, Ulutin et al 2000, Fournel et al 2005, 
Belderbos et al 2007) with 2 cycles of platinum-based chemotherapy administered in the 
two largest studies (RTOG9410[Curran et al 2003] and WJLCG [Furuse et al 1999]). 
Recognizing the considerable variation in clinical practice with respect to choice of 
chemotherapy, radiation dose and timing of chemotherapy in relation to delivery of 
radiation,  inclusion criteria (Section 5.1) provide specific details of regimens that 
constitute CCRT and SCRT. Randomization will be carried out ≤6 weeks following 
completion of chemoradiation and the final chemotherapy cycle must end prior to, or 
concurrently with, the final dose of radiation (See Section 5.1 for clarification). Given the 
absence of consistent evidence to support the use of consolidation chemotherapy following 
CCRT (see Section 2) and the intent to introduce trial therapy as early as possible to 
maximize the potential for clinical benefit, consolidation chemotherapy is not permitted in 
the study.
4.2.4
Rationale for proposed treatment duration
Whilst in trials of chemoradiation in patients with EGFR unselected Stage III NSCLC the 
majority of progression events may be expected to have occurred by approximately three 
years, there is insufficient published data specifically in patients with EGFR mutation 
positive Stage III NSCLC to determine the optimal duration of treatment in the trial. 
Data from adjuvant trials of EGFR TKI therapies in patients with EGFR mutation positive 
disease support dosing to progression in this study. Specifically in a randomized open label 
Phase III study (ADJUVANT/CTONG1104-NCT01405079) 222 patients with completely 
resected, Stage II–IIIA (N1–N2), EGFR mutant NSCLC were randomly assigned to either 
four cycles of adjuvant vinorelbine plus cisplatin or 24 months of gefitinib in a 1:1 ratio 
(Zhong et al 2018). Approximately two-thirds of the patients had Stage IIIA disease.
Disease-free survival (the primary endpoint) was significantly longer for patients assigned 
gefitinib than for those assigned cisplatin-based chemotherapy (median 28·7 months, 95% 
CI 24·9–32.5 vs 18.0 months, 13.6–22.3; HR 0.60, 95% CI 0.42– 0.87; p=0.0054). 
However, after 24 months, the Kaplan-Meier (KM) curves for disease-free survival began 
to converge, meeting by 36 months, with no apparent tail of non-recurrent patients in 
either treatment group by 48 months. At the time of the analysis, OS data are not yet 
mature; 34% of events had occurred at data cut-off; 41 patients assigned to gefitinib and 35 
assigned to vinorelbine plus cisplatin had died.
Similar KM curves for disease-free survival were reported for the subgroup of 161 patients 

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with EGFR-mutant disease identified retrospectively in the RADIANT trial, in which 
patients with Stage IB–IIIA disease were randomly assigned to erlotinib or placebo for 24 
months after adjuvant chemotherapy (Kelly et al 2015). Disease-free survival was longer 
with erlotinib than with placebo (median 46·4 months vs 28·5 months; HR 0.61, 95% CI 
0.38–0.98;), however this result was not statistically significant because of hierarchical 
testing. The disease-free survival curves began to converge from around 36 months, 
meeting by about 48 months. The OS data are immature with 35 deaths (22%) reported in 
the EGFR mutation subgroup (HR,1.09; 95% CI,0.545 to 2.161; P=.815).
In addition, in a single arm trial of 100 patients with Stage IA–IIIA EGFR-mutant disease 
receiving 2 years of erlotinib after adjuvant chemotherapy, disease-free survival at 24 
months was 89%, however the survival curve declined thereafter, towards a tail of 60%
non-recurrent (presumably cured) disease at 4 years (Pennell et al 2014)
Collectively these data suggest that EGFR TKIs may prolong disease free survival through 
effective suppression of tumor growth during treatment but may not eliminate microscopic 
disease and hence may not be curative (Zhong et al 2018; Ng and Camidge 2018).
Whilst these data are from a different population to the proposed study population, both 
populations represent maintenance treatment following therapy of curative intent in 
patients with non-metastatic EGFR mutation positive NSCLC. As such these data are 
considered to be of relevance in determining the recommended duration of trial therapy. 
Treatment will continue until RECIST v1.1 defined disease progression and confirmed by 
BICR, or until another discontinuation criterion is met. 
There have been no new specific adverse reactions or more severe known adverse 
reactions that have been observed with long term osimertinib therapy that would preclude 
dosing until progression in this study.
4.2.5
Rationale for primary endpoint of PFS
The primary endpoint of this study is PFS. PFS represents a direct effect of osimertinib’s 
efficacy as it is not confounded by the efficacy of subsequent therapies used after disease 
relapse. It is accepted as a surrogate endpoint for clinical benefit in studies of patients with 
both advanced cancer (PFS and OS) and in patients with earlier stages of cancer (adjuvant 
disease-free survival). 
Moreover, based on a re-analysis of meta-analyses of individual patients’ data from 29 
trials involving 5211 patients, PFS has been shown to be a valid surrogate for OS in 
assessment of chemotherapy and radiotherapy in patients with locally advanced disease 
(Mauguen et al 2013).
Given the long post-progression survival anticipated in this setting and the confounding 
effects of subsequent lines of therapy that may include osimertinib, it would be difficult to 
detect an OS benefit in this setting. Nevertheless, OS is one of the study’s secondary 
endpoints and will serve to complement the PFS results.

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A PFS HR of 0.53 will be targeted which translates to an improvement of 7 months on an 
estimated median PFS of 8 months (see Section 9.2) which constitutes a clinically 
meaningful benefit in this patient population. Assessment of disease status after 
chemoradiation is known to be complex, as the majority of patients will be expected to 
have treatment-related radiographic changes (Bledsoe et al 2017). As such, in order to 
ensure the most robust assessment of the primary endpoint, PFS will be assessed by BICR. 
The study will also include assessment of post–progression outcomes, including time to 
second progression on a subsequent treatment (PFS2) and time to subsequent treatments, 
in order to allow a robust characterization of the efficacy of osimertinib.
4.2.6
Rationale for the secondary efficacy endpoint of time to CNS progression
As described in Section 2.2.2.2 brain metastases occur more frequently in patients with 
locally advanced EGFR mutation-positive NSCLC following chemoradiation compared 
with EGFRwt disease following chemoradiation (OR 2.75, 95% CI, 1.43 to 5.31, P=0.003) 
(Ochiai et al 2016).
Brain metastases are associated with poor median survival, ranging from 3 to 8 months 
(Mak et al 2015, Berger et al 2013). Whole brain radiotherapy (WBRT) is the standard 
treatment for patients with brain metastases in particular for multiple intracranial lesions. 
Whole brain radiotherapy results in improvement, or in most cases stabilization, in 
neurological symptoms, but is frequently associated with significant comorbidities and 
radiation-related side effects, including delayed, progressive and irreversible cognitive 
dysfunction in long-term survivors (Lin and DeAngelis 2015). In patients who received 
WBRT alone, median survival rates of 2.4 to 4.8 months have been reported (Fan et al 
2014). In addition, the recent QUARTZ study suggests that WBRT offers no substantial 
benefit to most patients with brain metastases secondary to NSCLC in terms of improved 
survival, overall quality of life (QoL) or reduction in steroid use (Mulvenna et al 2016).
Surgical resection for single brain lesions and stereotactic radiosurgery for oligometastatic 
disease is also used to manage brain metastases. However, good performance status and 
control of the extra-cranial disease is required in order to implement these techniques, and 
patients with CNS metastasis secondary to NSCLC are often not considered suitable 
candidates for surgery or radiosurgery (Fan et al 2014, Zimmermann et al 2014). 
As demonstrated in Section 2.3 osimertinib has demonstrated compelling activity in the 
CNS in patients with EGFR TKI NSCLC and in patients with ≥second-line T790M 
positive NSCLC.
Given the poor prognosis of patients who develop brain metastases, in this study 
osimertinib has the potential to improve PFS and OS by delaying or preventing the 
development of CNS metastases. In addition, it may provide clinically meaningful benefit 
by avoiding consequences of neurological deficits from brain metastasis or by 
delaying/preventing long-term side effects associated with steroid use and brain 
irradiation. Time to CNS PFS will be assessed using BICR assessments according to 
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(Gd-DTPA) contrast enhancement currently is the procedure of choice, because MRI is 
more sensitive and specific than other imaging modalities in determining the presence, 
location, and number of metastases (Kruger et al 2011,Schellinger et al 1999,Yokoi et al 
1999).
As such all patients will have Gd-DTPA contrast-enhanced T1w MRI brain scans at 
baseline and at the time of each RECIST tumor assessment to provide the most accurate 
assessment of time to CNS PFS.
4.3
Justification for dose
Osimertinib 80 mg or matching placebo will be administered PO, QD. This dose was 
initially selected for evaluation in clinical trials on the basis of the totality of the safety, PK 
and preliminary efficacy data in a Phase I study (Janne et al 2015).
Osimertinib 80 mg QD is the approved dose for use in patients with locally advanced or 
metastatic EGFR T790M mutation-positive NSCLC whose disease has progressed on or 
after EGFR TKI therapy and is the dose that has been evaluated in additional Phase III 
trials in the first line setting (FLAURA) and in the adjuvant setting (ADAURA). The 
safety profile of this dose is considered acceptable for use in the setting of maintenance 
post chemoradiation.
4.4
End of study definition
For the purpose of Clinical Trial Transparency (CTT) the definition of the end of the study 
differs under FDA and EU regulatory requirements:
!
European Union requirements define study completion as the last visit of the last 
subject for any protocol related activity.
!
Food and Drug Administration requirements defines two completion dates:
!
Primary Completion Date – the date that the final patient is examined or receives 
an intervention for the purposes of final collection of data for the primary outcome 
measure, whether the clinical study concluded according to the pre-specified 
protocol or was terminated. In the case of clinical studies with more than one 
primary outcome measure with different completion dates, this term refers to the 
date on which data collection is completed for all of the primary outcomes.
!
Study Completion Date – the date the final patient is examined or receives an 
intervention for purposes of final collection of data for the primary and secondary 
outcome measures and AEs (for example, last patient’s last visit), whether the 
clinical study concludes according to the pre-specified protocol or is terminated.
A patient is considered to have completed the study if they have completed all phases of 
the study including the last scheduled visit or last scheduled assessment, as shown in the 
SoA (Table 1), including OS determination.

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The end of the study is defined as the last expected visit/contact of the last patient 
undergoing the study.  
The study is expected to start patient enrolment June 2018 and to end by approximately 
May 2025. 
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 is slow. 
AstraZeneca may also terminate the entire study prematurely if concerns for safety arise 
within this study or in any other study with osimertinib.
See Appendix A 6 for guidelines for the dissemination of study results.
5
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for 
this study in order to be assigned/randomized to a study intervention.  Under no 
circumstances can there be exceptions to this rule. Patients who do not meet the entry 
requirements are screen failures; refer to Section 5.5.
In this protocol, “enrolled” patients are defined as those who sign the informed consent 
form (ICF) in this study at screening. “Randomized” patients are defined as those who 
undergo randomization and receive a randomization number.  
As per standard, patient number (E-code) is assigned to the patient via an interactive voice
response system/interactive web response system (IVRS/IWRS) once consent for 
screening is obtained and Investigator or delegate should perform screening call in 
IVRS/IWRS.
For procedures for withdrawal of incorrectly enrolled patients see Section 5.6.
5.1
Inclusion Criteria 
5.1.1
Part I Screening 
Part I screening applies only to patients that do not have a pre-existing local EGFR test 
result, derived from a tissue-based FDA-approved CDx for TAGRISSO (i.e., cobas® 
EGFR Mutation Test v2 or FoundationOne® CDx test), performed  in a CLIA-certified 
(USA sites) or an accredited  local laboratory (sites outside of the USA) and conducted 
according to the manufacturer’s instructions for use. 
Patients are eligible to be included in Part I of the study only if all of the following 
inclusion criteria, and none of Part II screening exclusion criteria numbers 1, 2, 7, 9-11 and 
15-20 apply:

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Informed consent
1.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol
2.
Provision of signed and dated written informed consent for Part I screening form prior 
to any mandatory provision of tumor samples for testing of EGFR mutation status. 
The ICF process is described in Appendix A 3.
Age and Sex
3.
Male and Female patient must be aged at least 18 years. Patients from Japan aged at 
least 20 years.
Type of patient and disease characteristics
4.
Patients with histologically documented NSCLC of predominantly non-squamous 
pathology* who present with locally advanced, unresectable (Stage III) disease 
(according to Version 8 of the IASLC Staging Manual in Thoracic Oncology). 
*Patients with a stage III tumor of squamous histology who have a pre-existing local positive 
test result (Ex19del or L858R), irrespective of EGFR test used or lab accreditation, are 
eligible for Part I screening.
It is recommended but not required that except for overt cT4 disease, nodal status N2 
or N3 should have been proven by biopsy, via endobronchial ultrasound, 
mediastinoscopy, or thoracoscopy or in absence of biopsy, should have been 
confirmed with whole body 18F-fluoro-deoxyglucose PET plus contrast-enhanced CT 
in addition to or in combination with PET.
5.
Patient who can provide an unstained formalin-fixed paraffin embedded tumor tissue* 
sample in a quantity sufficient to allow for prospective central analysis of EGFR 
mutation status.
* An archived tissue or new biopsy specimen, when no archived tissue is available, is 
acceptable. Patients should only have a new biopsy if it is considered a medically acceptable 
risk by the investigator.
Further information is provided in Section 8.1.1 and in the laboratory manual.
5.1.2
Part II Screening 
Part II screening applies to: (i) patients that have a pre-existing local EGFR mutation-
positive (Ex19del or L858R) test result, derived from a tissue-based FDA-approved CDx 
for TAGRISSO (i.e., cobas® EGFR Mutation Test v2 or FoundationOne® CDx test), 
performed in a CLIA-certified (USA sites) or an accredited local laboratory (sites outside 
of the USA) and conducted according to the manufacturer’s instructions for use; or (ii) 
patients who completed Part I screening and have centrally-confirmed EGFR mutation 
(Ex19del or L858R) positive NSCLC. 

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Patients are eligible to be included in the study only if all of the following inclusion 
criteria and none of the exclusion criteria apply:
Informed consent
1.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol.
2.
Provision of signed and dated, written ICF for the main study prior to any mandatory 
study specific procedures, sampling, and analyses. 
3.
Provision of signed and dated written genetic informed consent prior to collection of 
sample for genetic analysis for inclusion in the optional genetic research. 
Note: If a patient declines to participate in any voluntary exploratory research and/or 
genetic component of the study for optional test, there will be no penalty or loss of benefit 
to the patient and he/she will not be excluded from other aspects of the study.
Age and Sex
4.
Male and Female patient must be aged at least 18 years. Patients from Japan aged at 
least 20 years.
Type of patient and disease characteristics
5.
Patients with histologically documented NSCLC of predominantly non-squamous 
pathology* who present with locally advanced, unresectable (Stage III) disease 
(according to Version 8 of the IASLC Staging Manual in Thoracic Oncology).
*Patients with a Stage III tumor of squamous histology who have a pre-existing local positive 
test result (Ex19del or L858R), irrespective of EGFR test used or lab accreditation, and 
confirmed by central testing during Part I screening, are eligible for Part II screening.
It is recommended but not required that except for overt cT4 disease, nodal status N2 
or N3 should have been proven by biopsy, via endobronchial ultrasound, 
mediastinoscopy, or thoracoscopy or in absence of biopsy, should have been 
confirmed with whole body 18F-fluoro-deoxyglucose PET plus contrast-enhanced CT 
in addition to or in combination with PET.
6.
The tumor harbors one of the two common EGFR mutations known to be associated 
with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with 
other EGFR mutations, as assessed by a tissue-based FDA-approved CDx for 
TAGRISSO (i.e., cobas® EGFR Mutation Test v2 or FoundationOne® CDx test), 
performed  in a CLIA-certified (USA sites) or an accredited local laboratory (sites 
outside of the USA); or by central testing (using the cobas® EGFR Mutation Test v2).
7.
Patients must not have had disease progression during or following definitive 
platinum-based, chemoradiation therapy.

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8.
Patients must have received either CCRT or SCRT regimens as defined below:
!
CCRT:  Patients must have received at least 2 cycles of platinum-based 
chemotherapy (or 5 doses of weekly platinum–based chemotherapy) concurrent 
with radiation therapy, which must be completed ≤6 weeks prior to 
randomization. The final chemotherapy administration must be completed prior 
to, or concurrently with, the final dose of radiation. Note: A final cycle of 
chemotherapy is permitted up to 7 days after the last dose of radiation, if at least 2 
cycles have already been given concurrently. Consolidation chemotherapy after 
radiation is not permitted but administration of chemotherapy prior to CCRT is 
permitted.
!
SCRT:  SCRT is defined as chemotherapy followed by radiation therapy and not 
radiation therapy followed by chemotherapy. Patients must have received at least 
2 cycles of platinum-based chemotherapy prior to radiation treatment, which must 
be completed ≤6 weeks prior to randomization. Consolidation chemotherapy after 
radiation is not permitted
!
If a patient has received at least 2 cycles of platinum-based chemotherapy and 
subsequently receives one cycle of platinum-based chemotherapy or < 5 doses of 
weekly platinum–based chemotherapy concurrent with radiation therapy, this will 
be considered SCRT
!
If a patient has received 1 cycle of platinum-based chemotherapy and 
subsequently receives one cycle of platinum-based chemotherapy or < 5 doses of 
weekly platinum–based chemotherapy concurrent with radiation therapy, this will 
not be considered CCRT or SCRT and the patient will not be eligible
9.
The platinum-based chemotherapy regimen must contain one of the following agents: 
etoposide, vinblastine, vinorelbine, paclitaxel, docetaxel, or pemetrexed, according to 
the local SoC regimens. Gemcitabine is permitted if used prior to radiation but not 
with radiation.
Where possible, chemotherapy regimens should be given according to NCCN or 
ESMO guidelines.
10. Patients must have received a total dose of radiation of 60 Gy ±10% (54 to 66 Gy) as 
part of the chemoradiation therapy in order to be randomized. It is recommended but 
not required that patients eligible for randomization have a:
!
Mean lung dose <20 Gy and/or V20 <35%
!
Mean esophagus dose <34 Gy
!
Heart V50 <25%, V30 <50%, and V45 <35%

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11. World Health Organization (WHO) performance status of 0 or 1 at Part II screening 
and Day 1.
12. Life expectancy >12 weeks at Day 1.
Reproduction
13. Female patients who are not abstinent (in line with the preferred and usual lifestyle 
choice of the patient) and intend to be sexually active with a male partner must be 
using adequate contraceptive measures, must not be breast feeding, and must have a 
negative pregnancy test prior to first dose of study drug; or female patients must have 
an evidence of non-child-bearing potential by fulfilling one of the following criteria at 
screening:
!
Post-menopausal defined as aged more than 50 years and amenorrhoeic for at 
least 12 months following cessation of all exogenous hormonal treatments
!
Female patients less than 50 years old would be consider postmenopausal if they 
have been amenorrhoeic for 12 months or more following cessation of exogenous 
hormonal treatments and with luteinizing hormone (LH) and follicle-stimulating 
hormone (FSH) levels in the post-menopausal range for the institution
Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy but not tubal ligation
14. Male patients must  be willing to use barrier contraception, i.e., condoms (see Section 
5.3).
5.2
Exclusion Criteria 
5.2.1
Part I Screening
Patients are eligible to be included in Part I of the study only if none of the following 
Part II Screening exclusion criteria: 1, 2, 7, 9-11, and 15-20.
5.2.2
Part II Screening 
Patients are eligible to be included in Part II screening process only if none of the 
exclusion criteria apply:
Medical conditions
1.
Mixed small cell and NSCLC histology
2.
History of ILD prior to chemoradiation 
3.
Symptomatic pneumonitis following chemoradiation. 
4.
Any unresolved toxicity CTCAE > Grade 2 from the prior chemoradiation therapy. 
Patients with irreversible toxicity that is not reasonably expected to be exacerbated by 

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study drug may be included (e.g. hearing loss) after consultation with the AstraZeneca 
medical monitor. 
5.
Any of the following cardiac criteria:
!
Mean resting QTc >470 msec, obtained from 3 ECGs
!
Any clinically important abnormalities in rhythm, conduction, or morphology of 
resting ECG, e.g., complete left bundle branch block, third-degree heart block, 
second-degree heart block.
!
Patient with any factors that increase the risk of QTc prolongation or risk of 
arrhythmic events such as electrolyte abnormalities including*:
-
Serum/plasma potassium <lower limit of normal (LLN)
-
Serum/plasma magnesium <LLN
-
Serum/plasma calcium <LLN 
-
heart failure, congenital long QT syndrome (CLQTS), 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 (TdP).
* Correction of electrolyte abnormalities to within normal ranges can be performed 
during the screening period. 
6.
Inadequate bone marrow reserve or organ function, as demonstrated by any of the 
following laboratory values:
!
Absolute neutrophil count <1.5 x 109/L
!
Platelet count <100 x 109/L
!
Hemoglobin <90 g/L
!
Alanine aminotransferase (ALT) >2.5x the upper limit of normal (ULN)
!
Aspartate aminotransferase (AST) >2.5x ULN
!
Total bilirubin (TBL) >1.5x ULN or >3x ULN in the presence of documented 
Gilbert’s Syndrome (unconjugated hyperbilirubinemia)
!
Creatinine >1.5x ULN concurrent with creatinine clearance <30 mL/min 
(measured or calculated by Cockcroft and Gault equation); confirmation of 
creatinine clearance is only required when creatinine is >1.5xULN

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7.
History of other malignancies, except: adequately treated non-melanoma skin cancer 
or lentigo maligna, curatively treated in-situ cancer, or other solid tumors curatively 
treated with no evidence of disease for > 5 years following the end of treatment and 
which, in the opinion of the treating physician, do not have a substantial risk of 
recurrence of the prior malignancy.
8.
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 patient to participate in the trial or which would jeopardise 
compliance with the protocol. Active infection including hepatitis B virus (HBV), 
hepatitis C and human immunodeficiency virus (HIV). Active infection will include 
any patients receiving treatment for infection. Participants with a resolved or chronic 
HBV infection are eligible if they are: 
!
Negative for HBsAg and positive for hepatitis B core antibody [anti-HBc IgG]; or
!
Positive for HBsAg, negative for HBeAg but for >6 months have had 
transaminases levels below ULN and HBV deoxyribonucleic acid (DNA) levels 
below 2000 IU/mL (i.e., are in an inactive carrier state).
Refer to Section 5.3.3 for further details. Screening for chronic conditions is not 
required. 
9.
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
10. Prior treatment with any chemotherapy, radiation therapy, immunotherapy or 
investigational agents for NSCLC outside of that received in the definitive setting for 
Stage III disease (chemotherapy and radiotherapy in SCRT and CCRT regimens is 
allowed for treatment of Stage III disease). Prior surgical resection (i.e., Stage I, II or 
III) is permitted. 
11. Prior treatment with EGFR-TKI therapy. 
12. Major surgery as defined by the investigator within 4 weeks of the first dose of study 
drug. 
13. Patients currently receiving (unable to stop use prior to receiving the first dose of 
study treatment) medications or herbal supplements known to be strong inducers of 
cytochrome P (CYP)3A4 (at least 3 weeks prior to receiving the first dose of study 
drug). All patients must try to avoid concomitant use of any medications, herbal 
supplements and/or ingestion of foods with known inducer effects on CYP3A4.

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Prior/concurrent clinical study experience
14. Participation in another clinical study with an investigational product administered in 
the 4 weeks prior to randomization.  Patients in the follow-up period of an 
interventional study are permitted.
Other exclusions
15. Patient with involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site).
16. Judgment by the investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions and requirements.
17. Patient was previously randomized in the present study. 
18. For female patients only - currently pregnant (confirmed with positive pregnancy test) 
or breast-feeding.
19. Contraindication to MRI, including but not limited to, claustrophobia, pace makers, 
metal implants, intracranial surgical clips and metal foreign bodies.
20. History of hypersensitive to active or inactive excipients of osimertinib or drugs with a 
similar chemical structure or class to osimertinib. 
In addition, the following are considered criteria for exclusion from the exploratory genetic 
research:
1.
Prior allogeneic bone marrow transplant.
2.
Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample 
collection.
5.3
Lifestyle restrictions
The following restrictions apply while the patient is receiving study drug (osimertinib or 
matching placebo) and for the specified times before and after:
5.3.1
Pregnancy
Female patients of child-bearing potential who are not abstinent (in line with the preferred 
and usual lifestyle choice of the patient) and intend to be sexually active with a male 
partner must use a highly effective contraceptive measure  from the time of Part II 
screening until 6 weeks after discontinuing study drug. Acceptable methods of highly 
effective contraception are provided in Appendix J.
Male patients 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 4 
months after discontinuing study drug. In addition patients should refrain from donating 

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sperm from the start of dosing until 4 months after discontinuing study drug.
5.3.2
Blood donation
Patients are prohibited from donating blood from the date of randomization until 28 days 
after the last dose of study treatment.
5.3.3
Chronic HBV infection
In patients with chronic HBV infection (inactive carrier state) on treatment with 
osimertinib:
!
where ALT exceeds 2 x ULN and 2 x baseline, measurement of HBV DNA as per 
local practice and/or hepatologist consultation is recommended.
!
if biochemical or clinical signs of liver disease or viral reactivation occur, careful 
monitoring is required.
5.4
Meals and dietary restrictions
Osimertinib can be taken without regard to food. However, patients should avoid taking 
dietary supplements or herbal medicines with known strong inducers of CYP3A4 
whenever feasible (see Section 6.5.1).
5.5
Screen failures
Screen failures are defined as patients who signed the ICF of part I and/or part II to 
participate in the clinical study but are not subsequently entered to Part II screening or 
randomly assigned to study treatment in the study.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure patients 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 SAE).
Individuals who do not meet the criteria of screening for participation in this study (screen 
failure) may be rescreened, with the exception of patients in Part I screening with a central 
EGFR test negative for Ex19del or L858R. Rescreened patients should use the same 
patient number assigned previously at the first time of screening via IVRS/IWRS. 
However rescreening should be documented so that its effect on study results, if any, can 
be assessed.  
These patients should have the reason for study withdrawal recorded in the source 
documents and electronic case report form (eCRF).
5.6
Procedures for handling incorrectly enrolled or randomized patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study drug. There can be no exceptions to this rule. Where a patient 
does not meet all the eligibility criteria but is randomized in error, or incorrectly started on 
treatment, the Investigator should inform the AstraZeneca Study Physician immediately, 

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and a discussion should occur between the AstraZeneca Study Physician and the 
Investigator regarding whether to continue or discontinue the patient from treatment. The 
Study Physician must ensure all decisions are appropriately documented. The investigator 
should make documentation in medical record as appropriate. 
6
STUDY TREATMENTS
Study treatment is defined as any investigational product(s) (IP; including placebo) 
intended to be administered to a study participant according to the study protocol. Study 
treatment in this study refers to osimertinib and matching placebo.
6.1
Treatments administered 
6.1.1
Investigational products
AstraZeneca will supply osimertinib and matching placebo. See Table 4 further details on 
the IPs.
Table 4
Study treatments
Osimertinib
Placebo
Study treatment name:
Osimertinib (AZD9291)
Placebo
Dosage formulation:
80 mg tablet for oral administration
80 mg placebo tablet matching 
osimertinib in size, color, weight, 
and appearance for oral 
administration
Dosage formulation, dose 
reduction:
40mg tablet for oral administration
40mg placebo tablet matching 
osimertinib in size, color, weight, 
and appearance for oral 
administration
Route of administration 
Oral
Oral
Dosing instructions:
One tablet of 80 mg per day
One tablet of 80 mg placebo per day
Dosing instructions, dose 
reduction
One tablet of 40 mg per day
One tablet of 40 mg placebo per day
Packaging and labelling
Osimertinib will be provided in in 
high-density polyethylene (HDPE) 
bottles with child-resistant closures.
Each bottle will be labelled in 
accordance with Good 
Manufacturing Practice (GMP) 
Annex 13 and per country 
regulatory requirement.
Osimertinib matching placebo will 
be provided in high-density 
polyethylene (HDPE) bottles with 
child-resistant
closures. Each bottle will be 
labelled in accordance with Good 
Manufacturing Practice (GMP) 
Annex 13 and per country 
regulatory requirement.
Provider
AstraZeneca
AstraZeneca
Patients should swallow one tablet QD. Tablet can be taken whole with approximately 240 
mL water, with or without regard to food. 
Study drug will be distributed as following:

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!
Randomization to week 24 – enough study drug for 4 weeks. 
!
Week 24 to week 48 – enough study drug for 8 weeks 
!
Week 48 onwards – enough study drug for 12 weeks
Individual bottles will be dispensed in accordance with the medication identification 
numbers provided by the IVRS/IWRS.
Study drug will only be dispensed to patient at randomization day (visit 2) after all study 
procedures and assessments have been performed as described in Table 1 and all eligibility 
criteria have been met.   
Randomization will be made in IVRS/IWRS system as soon as all the eligibility criteria 
are met as confirmed by the investigator. It should be documented in the medical records 
in a proper manner.
Every effort should be made to minimize the time between randomization and starting 
study treatment. It is recommended that patients commence study treatment as soon as 
possible after randomization and whenever possible within one day. (i.e., on the same day 
after randomization in the IVRS/IWRS) 
The initial dose of osimertinib/placebo 80 mg QD can be reduced to 40 mg QD to allow 
for management of IP-related toxicities (see Section 6.6 and Section 8.4.4). Once the dose 
of osimertinib/placebo is reduced to 40 mg QD, the patient will remain with the reduced 
dose until termination from study treatment. Re-challenge of 80 mg/placebo is not allowed 
in this study.  
On site visit days on which PK samples are scheduled, the dosing should be delayed until 
arrival at the site. Patients should not take their dose until instructed to do so by site 
personnel.
Doses should be taken approximately 24 hours apart at the same time point each day. 
Doses should not be missed. If a patient misses taking a scheduled dose, within a window 
of 12 hours, it is acceptable to take the dose. If it is more than 12 hours after the scheduled 
dose time, the missed dose should not be taken, and patients should be instructed to take 
the next dose at the next scheduled time. If a patient vomits after taking their study drug, 
they should not make up for this dose, but should take the next scheduled dose.
The reason for a missed dose should be documented in the source document. 
Any change from the dosing schedule, dose interruptions, or dose reductions should be 
recorded in the eCRF. 
Open-label osimertinib will be supplied by AstraZeneca. See Section 7.6 for further details 
of drug supply following the final OS analysis. 

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Additional information about osimertinib may be found in the Investigator’s Brochure.
6.2
Preparation/handling/storage/accountability 
6.2.1
Preparation and Handling 
No additional preparation and handling is required for osimertinib or placebo.
6.2.2
Storage
All study drugs should be kept in a secure place under appropriate storage conditions. The 
investigational product label on the bottles specifies instruction of appropriate storage.
6.2.3
Accountability  
The investigator or delegated site staff must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
Only patients enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment.  All study treatments 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 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
accountable for all study drugs received at the site, unused study drugs and for appropriate 
destruction. Certificates of delivery, destruction should be signed. 
Used/unused study drug will be disposed of at site and not returned to AstraZeneca for 
disposal. Disposal will be performed as per local procedures.  
For Japan: Study drugs will not be distributed to the study site until the contract is 
concluded between the study site and AstraZeneca. The Investigational Product Storage 
Manager is responsible for managing the study drug from receipt by the study site until the 
return of all unused study drug to AstraZeneca. AstraZeneca will provide the study 
documents, ‘Procedures for Drug Accountability’ and ‘Procedures for Drug Storage,’ 
which describe the specific requirements. The Investigator(s) is responsible for ensuring 
that the patient has returned all unused study drug.  
6.3
Measures to minimize bias: randomization and blinding 
6.3.1
Methods For Randomization 
Patients must not be randomized unless all eligibility criteria have been met.
All patients will be centrally assigned to randomized study treatment in a 2:1 ratio 
osimertinib: placebo respectively using an IVRS/IWRS.
Randomization will be performed within 6 weeks of completion of chemoradiation. All 
patients will be stratified at randomization based on prior chemoradiation strategy (CCRT 

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vs SCRT), tumor stage prior to chemoradiation (IIIA vs IIIB/IIIC) and China cohort 
(enrolled at a Chinese site and patient declaring themselves of Chinese ethnicity vs. 
enrolled at Non-Chinese site or patient declaring themselves of non-Chinese ethnicity).  
Before the study is initiated, the telephone number and call-in directions for the IVRS 
and/or the log-in information and directions for the IWRS will be provided to each site.
If a patient withdraws from the study, then the IVRS/IWRS assigned patient number 
cannot be reused.  
The IVRS/IWRS will provide to the Investigator(s) or pharmacists the bottles 
identification number to be allocated to the patient at the dispensing visit. Routines for this 
will be described in the IVRS/IWRS user manual that will be provided to each center. 
6.3.2
Methods For Blinding  
Study drug will be labelled using a unique material pack code, which is linked to the 
randomization code. The IVRS/IWRS will assign the bottles of study material to be 
dispensed to each patient. This is a double-blind study wherein each patient will receive 
either the active osimertinib or osimertinib-matching placebo. The active and placebo 
tablets will be identical and presented in the same packaging to ensure blinding of the 
medication.
6.3.3
Blind Break   
The IVRS/IWRS will be programmed with blind-breaking instructions. The treatment code 
should not be broken except in medical emergencies when the appropriate management of 
the patient requires knowledge of the treatment randomization. Additionally, patients with 
BICR- confirmed progression of disease may be unblinded. 
AstraZeneca must be notified before the blind is broken unless identification of the study 
treatment is required for a medical emergency in which the knowledge of the specific 
blinded study treatment will affect the immediate management of the patient’s condition. 
In this case, AstraZeneca must be notified within 24 hours after breaking the blind. The 
date and reason that the blind was broken must be recorded in the source documentation 
and eCRF as applicable. AstraZeneca retains the right to break the code for SAEs that are 
unexpected and are suspected to be causally- related to an investigational product and that 
potentially require expedited reporting to regulatory authorities. 
Study unblinding should not occur until database lock and all decisions on the evaluability 
of the data from each individual patient have been made and documented.
The personnel analyzing the pharmacokinetic samples will be unblinded to the 
investigational treatment for each patient. 
6.4
Treatment compliance 
The administration of all study drugs including placebo should be recorded in the source 

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document and appropriate sections of the eCRF. Any change and the reasons for changing 
the dosing schedule, dose interruption, dose reduction, dose discontinuation, overdosing or 
omission will also be recorded in the source document and eCRF. This information plus 
drug accountability for all study drugs at every visit will be used to assess compliance with
the treatment. 
The study drugs should be completely reconciled with supportive evidence provided in the 
source document such as drug accountability log or equivalent documents. 
The delegated site staff is responsible for managing the IP from receipt by the study site 
until the destruction or return of all unused IP. The Investigator(s) or designee(s) is 
responsible for ensuring that the patient has returned all unused IP.
Osimertinib/matching placebo compliance will be calculated by the sponsor based on the 
drug accountability documented in the source document and eCRF by the site staff and 
monitored by the sponsor/designee (tablet counts). The objective is 100% compliance, and 
Investigators and the site staff should evaluate and review treatment compliance with 
patient at each visit and take appropriate steps to optimize compliance.
6.5
Concomitant therapy 
Any concomitant treatment, procedures, medication or vaccine including over-the-counter 
or prescription medicines, vitamins, and/or herbal supplements that the patient is receiving 
within 4 weeks prior to the first dose of study drug or receives during the study until 
28-day follow-up visit (28 days after last dose of study drug) must be recorded in the 
source document and the applicable section of eCRF. If any concomitant therapy is 
administered due to new or unresolved AE, it should be recorded until the related AE is 
resolved, stabilized, is otherwise explained or patient is lost to follow-up.  
6.5.1
Restricted and prohibited concomitant medications 
Restricted and prohibited concomitant medications are described below: 
!
Once enrolled, all patients must try to avoid concomitant use of medications, herbal 
supplements and/or ingestion of foods with known strong inducers of CYP3A4 
whenever feasible; but patients may receive any medication that is considered 
essential for patient management. Such drugs must have been discontinued for an 
appropriate period before the first dose of study treatment and for a period of 2 weeks 
after the last dose of osimertinib or matching placebo. All concomitant medications 
should be captured on the eCRF. Guidance on medicines to avoid, medications that 
require close monitoring, and on washout periods is provided (See Appendix I). 
!
If medically feasible, patients taking regular medication, with the exception of strong 
inducers of CYP3A4 (see above), should be maintained on it throughout the study 
period. Patients taking concomitant medications whose disposition is dependent upon 
Breast Cancer Resistance Protein (BCRP) and/or P-glycoprotein (P-gp) with a narrow 
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result of increased exposure of the concomitant medication whilst receiving 
osimertinib. (See Appendix I).
!
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.
!
Other anti-cancer therapies, investigational agents, and radiotherapy should not be 
given while the patient is on study drug.
!
Pre-medication will be allowed after, but not before, the first dose of study drug. This 
includes management of diarrhea, nausea, and vomiting, which should be 
administered as directed by the Investigator.
6.5.1.1
Drugs known to prolong QTc interval
Current information on drugs known to prolong QTc interval can be found on the Arizona 
Center for Education and Research on Therapeutics website 
https://www.crediblemeds.org/.
The website categorizes drugs based on the risk of inducing TdP. During screening the 
drugs that patients are currently prescribed should be checked opposite the ArizonaCert 
website. Drugs that prolong the QT interval and are clearly associated with a known risk 
of TdP, even when taken as recommended must have been discontinued prior to the start 
of administration of study treatment in accordance with guidance provided in Appendix I. 
These drugs should not be co-administered with study treatment (osimertinib/placebo) and 
for a period of two weeks after discontinuing study treatment. 
Patients 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 patient management and the patient 
has been stable on therapy. Close monitoring with ECGs and electrolytes is recommended.
Patients with congenital long QT syndrome (CLQTS) are excluded from this study.
Following study treatment initiation if it is considered essential for patient management to 
give drugs known to prolong QTc interval, regardless of TdP risk category, close 
monitoring with ECGs and electrolytes is recommended.
6.5.2
Other concomitant treatment
Medication other than that described above, which is considered necessary for the patient’s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
source document and appropriate sections of eCRF.

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6.6
Dose modification
Dose modifications are permitted for the management of adverse reactions, as described in 
Table 5. Further information is provided in Section 8.4.4.
Table 5
Study treatment dose adjustment information for adverse reactions
Target Organ
Adverse Reactions a
Dose Modification 
Pulmonary 
Pneumonitis b
Refer to pneumonitis guidelines provided in 
Table 10 in Section 8.4.4.2.
Cardiac 
Patients with QTc prolongation (i.e., 
confirmed QTc prolongation to >500 
msec absolute) at 2 separate ECGs. 
Withhold TAGRISSO until QTc interval is 
< 481 msec or recovery to baseline if 
baseline QTc is ≥ 481 msec within 3 weeks 
of interruption, then restart at a reduced dose 
(40 mg) or at 80 mg (at the discretion of the 
investigator, to allow for situations where 
causality in relation to osimertinib may be 
difficult to determine).
If the toxicity does not resolve to ≤grade 1 
within 3 weeks of interruption the patient 
will be permanently withdrawn from study 
treatment.
QTc interval prolongation in 
combination with any of the 
following: Torsade de pointes, 
polymorphic ventricular tachycardia, 
signs/symptoms of serious arrhythmia
Permanently discontinue study treatment
Cutaneous
Stevens Johnson Syndrome; Toxic 
epidermal necrolysis
Permanently discontinue study treatment
Blood and 
lymphatic system
Aplastic anemia
Permanently discontinue study treatment
Other 
Grade 3 or higher adverse reaction 
Withhold study treatment up to 3 weeks 
If Grade 3 or higher adverse reaction 
improves to Grade 0-2 after 
withholding study treatment for up to 
3 weeks 
Study treatment may be restarted at the same 
dose (80 mg/placebo) or the lower dose 
(40 mg/placebo) 
Grade 3 or higher adverse reaction 
that does not improve to Grade 0-2 
after withholding for up to 3 weeks
Permanently discontinue study treatment
a.
The intensity of the clinical AEs graded by the National Cancer Institute (NCI) CTCAE version 5.0
b.
Including pneumonitis/ILD and radiation pneumonitis
6.7
Treatment after the end of the study 
After the final OS analysis, the study blind will be broken at the site and patient level.
AstraZeneca will continue to supply osimertinib in the continued access phase of this study 
and after completion of this study while, in the opinion of the Investigator, the patient is 
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In the event that product development reaches a point where alternative product supply 
options become available, then these alternative product supply options will be discussed 
by AstraZeneca with the Investigator. AstraZeneca will work with the Investigator to 
transition the patient(s) to alternative supply, where possible.
In the event that a roll-over or safety extension study is available at the time of the final 
DCO and database closure, patient(s) currently receiving treatment with osimertinib may 
then be transitioned to such a study, and the current study may reach its end. The roll-over 
or extension study would ensure treatment continuation with visit assessments per its 
protocol, as applicable. Any patient who would be eligible to move to such a study would 
be given a new informed consent, as applicable.
7
DISCONTINUATION OF TREATMENT AND PATIENT 
WITHDRAWAL
7.1
Discontinuation of study treatment
Patients may be discontinued from IP in the following situations. Note that discontinuation 
from study treatment is NOT the same thing as a complete withdrawal from the study. 
Patients will continue in follow-up per the protocol. 
!
Patient decision. The patient is at any time free to discontinue treatment, without 
prejudice to further treatment
!
Patients experiencing any of the following AEs will be discontinued from study 
treatment: 
-
Grade 3 or higher pneumonitis
-
Grade 2 pneumonitis where symptoms have not resolved and treatment has not 
been restarted within 4 weeks after interrupting study treatment
-
Recurrent symptomatic pneumonitis following prior dose interruption and study 
treatment re-challenge
-
QTc interval prolongation with signs/symptoms of serious arrhythmia
-
Grade 3 or higher adverse reaction that does not improve to Grade 0-2 and 
treatment has not been restarted within 3 weeks of interrupting study treatment 
-
Any AE that, in the opinion of the Investigator or AstraZeneca, contraindicates 
further dosing
!
Severe non-compliance with the Clinical Study Protocol (CSP) as judged by the 
Investigator and/or AstraZeneca representative
!
Pregnancy

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!
Initiation of alternative anticancer therapy including another investigational agent
!
Prior to primary PFS analysis: Objective disease progression as per RECIST v1.1 
assessed by BICR  
!
Post-primary PFS analysis: Disease progression as assessed by investigator
!
Patients who are incorrectly initiated on study treatment. 
See the SoA (Table 1) for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed.
7.1.1
Procedures for discontinuation of study treatment
At any time, patients are free to discontinue study treatment or withdraw from the study 
without prejudice to further treatment. The investigator or delegated site staff should 
instruct the patient to contact the site before or at the time if study treatment is 
permanently stopped. A patient that decides to discontinue study treatment will always be 
asked about the reason(s) and the presence of any AEs. The date of last intake of study 
treatment should be documented in the source document and eCRF. All study treatment 
should be returned by the patient at their next on-site study visit or unscheduled visit. 
Patients permanently discontinuing study treatment should be given locally available SoC 
therapy, at the discretion of the Investigator.
Discontinuation of study treatment, for any reason, does not impact on the patient´s 
participation in the study.  The patients should continue attending subsequent study visits 
and data collection should continue according to the study protocol. If the patient does not 
agree to continue in-person study visits, a modified follow-up must be arranged to ensure 
the collection of endpoints and safety information including new AEs and follow up on 
any ongoing AEs and concomitant medications. This could be a telephone contact with the 
patient at 28 days (+ 7 days) after study treatment is discontinued, a contact with a relative 
or treating physician, or information from medical records.  The approach taken should be 
recorded in the medical records.  A patient that agrees to modified follow-up is not 
considered to have withdrawn consent or to have withdrawn from the study.
The discontinuation visit should be performed as soon as patient permanently discontinues 
from study treatment and/or study. See SoA (Table 1) for study of assessments to be 
performed at treatment discontinuation visit. The reason for discontinuation should be 
documented in the source document and the appropriate section of the eCRF. 
7.1.1.1
Progression follow-up 
7.1.1.1.1
Prior to primary PFS analysis 
Prior to the primary PFS analysis patients who discontinue study drug for reasons other 
than RECIST v1.1 defined progression as assessed by BICR will continue RECIST v1.1 
assessments every 8 weeks for the first 48 weeks and every 12 weeks afterwards (relative 
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occurs.
In addition to tumor assessments, the following assessments are also required during the 
follow-up period (as detailed in the SoA [Table 1]): 
!
WHO Performance Status
!
Plasma samples for circulating tumor DNA (ctDNA) and blood borne biomarkers
!
Anti-cancer and surgical treatments
!
HRU Module
!
SAEs and AESIs considered related to study treatment and study procedures
!
Electronic Patient Reported Outcomes (ePROs) to be carried out at the same 
frequency as treatment period:
-
European Organisation for Research and Treatment of Cancer (EORTC) 
Quality of Life Questionnaire- Lung Cancer 13 items (QLQ-LC13)
-
EORTC Quality of Life Questionnaire – Core 30 items (QLQ-C30)
-
Patients Global Impression of Severity (PGIS)
-
PRO-CTCAE
-
EuroQoL 5-Deimension 5-Levels (EQ-5D-5L)
7.1.1.1.2
Post primary PFS analysis
After the primary PFS analysis, patients who are in progression follow-up will have 
progression assessed in accordance with local clinical practice. Formal RECIST v 1.1 
measurements will not be collected. 
ePROs, HRU, WHO performance status, ctDNA and blood borne biomarkers will no 
longer be required. The patients should return the ePRO devices to site at their next visit 
and site staff should perform the “End LogPad Use”, so that this is recorded in the 
database. Only AESIs and SAEs considered related to prior study treatment will be 
captured. 
Patients will enter survival follow-up as described in Section 7.1.1.2. Visits will occur 
every 12 weeks relative to their last progression follow up visit prior to the primary 
analysis data cut-off date.
7.1.1.2
Survival follow-up
Survival follow-up is applicable for:
!
Patients who have had BICR confirmed RECIST v1.1 defined progression prior to the 

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primary PFS analysis
!
Patients who have withdrawn consent and have agreed to be followed up for survival
!
Patients remaining in progression follow-up after the primary PFS analysis (as 
described in Section 7.1.1.1.2)
7.1.1.2.1
Prior to primary PFS analysis 
Patients will be followed up for survival status every 12 weeks until death, withdrawal of 
consent or the end of the study i.e., at the time of final OS analysis, whichever occurs first. 
Survival information may be obtained via telephone contact with the patient, patient’s 
family or by contact with the patient’s current physician. In addition to the survival status, 
the following assessments are also required:
!
Anti-cancer and surgical treatments 
!
Subsequent response/progression until the first disease progression as assessed by the 
investigator occurs on a subsequent treatment.
!
HRU Module
!
SAEs and AESIs, if considered related to prior study treatment or open-label 
osimertinib
!
ePROs to be completed at RECIST v1.1 defined progression as assessed by BICR, and 
week 8, 16 and 32 post-progression, relative to the treatment discontinuation visit:
-
EORTC QLQ-LC13
-
EORTC QLQ-C30
-
PGIS
-
PRO-CTCAE
-
EQ-5D-5L
Patients should be contacted in the week following the data cut-off at the time of primary 
PFS analysis to provide complete survival data.
For patients who have not actively withdrawn consent, the status of those ongoing, 
withdrawn (from the study), and “lost to follow-up” at the time of the first OS analysis 
should be obtained by the site personnel by checking the patients notes, hospital records, 
contacting the patients general practitioner, and checking publicly available death 
registries. In the event that the patient has actively withdrawn consent to the processing of 
their personal data, the vital status of the patient can be obtained by site personnel from 
publicly available resources where it is possible to do so under applicable local laws.

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7.1.1.2.2
Post primary PFS analysis 
Patients will be followed up for survival status every 12 weeks until death, withdrawal of 
consent or the end of the study i.e., at the time of final OS analysis. Survival information 
may be obtained via telephone contact with the patient, patient’s family or by contact with 
the patient’s current physician. In addition to the survival status, the following assessments 
are also required:
!
Anti-cancer and surgical treatments 
!
SAEs and AESIs, if considered related to open-label osimertinib
Patients should be contacted in the week following the data cut-off for the final OS 
analysis to provide complete survival data.
For patients who have not actively withdrawn consent, the status of those ongoing, 
withdrawn (from the study), and “lost to follow-up” at the time of the final OS analysis 
should be obtained by the site personnel by checking the patients notes, hospital records, 
contacting the patients general practitioner, and checking publicly available death 
registries. In the event that the patient has actively withdrawn consent to the processing of 
their personal data, the vital status of the patient can be obtained by site personnel from 
publicly available resources where it is possible to do so under applicable local laws.
7.2
Treatment with open-label osimertinib
Treatment assignment may be unblinded for each patient with BICR-confirmed 
progression per RECIST v1.1 if progression occurs prior to the primary PFS analysis, or 
based on investigator-assessed progression after the primary PFS analysis. Patients may 
receive open-label osimertinib if:
!
Progression is confirmed by BICR, or, if progression occurs after the primary PFS 
analysis, investigator-assessed progression has been diagnosed.
!
In the opinion of the treating physician, they are continuing to derive clinical benefit 
(for patients assigned to the osimertinib treatment arm), or, treatment is in accordance 
with local clinical practice and the judgement of their treating physician (for patients 
assigned to the placebo arm).
!
They have not received any other anti-cancer therapy following the discontinuation of 
study treatment. Palliative radiotherapy is allowed.
!
Disease extent has been characterized by CT or MRI scan at the time of progression.
All patients receiving open-label osimertinib post-progression will enter survival follow-up 
as described in Section 7.1.1.2. During treatment with open-label osimertinib, the 
investigator should monitor the patient per local clinical guidance.
Treatment with open-label osimertinib may continue until the patient stops deriving 

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clinical benefit (as judged by the investigator). 
7.3
Lost to follow-up
A patient will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a patient fails to return to the clinic for a required 
study visit: 
!
The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule.
!
Before a patient is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the patient or next of kin by e.g. repeat telephone 
calls, certified letter to the patient´s last known mailing address or local equivalent 
methods. These contact attempts should be documented in the patient’s medical record. 
!
Efforts to reach the patient should continue until the end of the study. Should the 
patient be unreachable at the end of the study the patient should be considered to be 
lost to follow up with unknown vital status at end of study and censored at latest follow 
up contact.
7.4
Withdrawal from the study
A patient may withdraw from the study (e.g. withdraw consent), at any time 
(investigational product and assessments) at his/her own request, without prejudice to 
further treatment.
A patient who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options (e.g. telephone contact, a contact with a relative or 
treating physician, or information from medical records).
If the patient withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
If a patient withdraws from the study, he/she may request destruction of any samples taken 
and/or analysis including optional testing, and the investigator must document this in the 
site study records. The AstraZeneca study team should be informed of withdrawn patient 
sample destruction by the site or at the central laboratory in a prompt manner.   
A patient who withdraws consent will always be asked about the reason(s) and the 
presence of any AE. The Investigator will follow up patients until 28 days after 
discontinuation of study treatment or beyond as medically indicated. The patient or the 
representative will return all unused study treatment and ePRO devices.
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vital status (dead or alive; date of death when applicable) during survival follow up until 
the final OS analysis from publicly available sources, in accordance with local regulations. 
Knowledge of the vital status in all patients is crucial for the integrity of the study. 
See SoA (Table 1), for data to be collected at the time of study discontinuation and follow-
up and for any further evaluations that need to be completed.  
7.5
Patient management post primary PFS analysis and up to final OS 
analysis
The primary analysis of PFS will occur when approximately 120 progression events 
confirmed by BICR have been observed out of the globally randomized patients. 
Following the primary PFS analysis, patients still on study treatment should continue to 
receive study treatment. Study assessments will continue as per the SoA (see Table 1). 
Disease status will be monitored as per standard local practice and formal RECIST 
measurements will not be collected. Patients can continue to receive study treatment until 
disease progression occurs as judged by the investigator, or until meeting any other 
discontinuation criteria defined in Section 7.1. Patients with investigator-assessed disease 
progression may be unblinded and offered open-label osimertinib consistent with the 
guidance in Section 7.2.
For all patients receiving open-label osimertinib, treatment with open-label osimertinib 
should continue until radiological or clinical disease progression or unacceptable toxicity 
as determined by the investigator, at which point open-label osimertinib may be 
discontinued. Treatment with open-label osimertinib may continue post-progression if the 
treating physician considers the patient to still be deriving clinical benefit. 
AstraZeneca will collect information (during the treatment period and for 28 [+ 7] days 
after last dose) on SAEs and AESIs related to study treatment, overdose and pregnancy (as 
per Section 8.4) via paper and emailed (preferably) or faxed directly to TCS DES (also 
known as AZ DES). Drug accountability information will be recorded in the source 
documents.
7.6
Patient management post-final OS analysis
The final analysis of OS will be conducted at approximately 60% data maturity, when 
approximately 120 death events (across both arms) have occurred. At this time point, the 
clinical study database will close to new data. 
Patients will be monitored in accordance with the investigator’s standard clinical practice 
or national product label. Dispensing of osimertinib post-final OS analysis will be done 
outside of IVRS/IWRS. At routine clinic visits, patients will return used and unused 
medication, and a thorough drug accountability assessment will be performed at the site. 
AstraZeneca will collect information (during the treatment period and for 28 [+ 7] days 
after last dose) on SAEs, AESIs, overdose and pregnancy (as per Section 8.4) via paper 
and emailed (preferably) or faxed directly to TCS DES (also known as AZ DES). Drug 

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accountability information will be recorded in the source documents.
If an investigator learns of any SAEs or AESIs, 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). Additionally, as stated in Section 8.3.3, any 
SAE or non-serious AE that is ongoing at the time of this data cut off, must be followed up 
to resolution unless the event is considered by the investigator to be unlikely to resolve, or 
the patient is lost to follow up.
For details regarding study treatment after the final OS analysis, see Section 6.7.
8
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timings are summarized in the SoA (Table 1). The investigator 
will ensure that data are recorded in the eCRF. The RAVE Web Based Data Capture 
(WBDC) system will be used for data collection and query handling. The investigator 
ensures the accuracy, completeness, of the eCRF 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. A copy of the 
completed eCRF will be archived at the study site at study end.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
treatment.
Adherence to the study design requirements, including those specified in the SoA (Table 
1), are essential and required for study conduct.
All evaluations in Part I and Part II screening must be completed and reviewed to confirm 
that potential patients meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all patients screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
Procedures conducted as part of the patient’s routine clinical management (e.g. blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes, provided that the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA (Table 1).  
8.1
Efficacy assessments 
8.1.1
Screening tumor sample for EGFR mutation analysis
8.1.1.1
Biopsied tissue samples for EGFR mutation testing 
8.1.1.1.1
Patients without a positive local tissue-based EGFR mutation test result 
Mandatory provision of a FFPE tumor tissue sample is required for prospective central 

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analysis of EGFR mutation status in Part I screening. The sample will also be used for 
exploratory biomarker analysis (except in China as per local regulations).
Cytology samples including fine-needle aspirates (FNA), transbronchial needle aspirates 
(TBNA), bronchial washings, bronchial lavage, bone marrow aspirates and expectorated 
sputum are NOT acceptable samples and should not be sent. Needle biopsies in which the 
tissue architecture is maintained are acceptable.
The Investigator will be asked to provide:
!
Formalin-fixed, paraffin-embedded (FFPE) tumor tissue blocks, not older than 
12 months or
!
Preferably at least 12 re-cut unstained sections from FFPE tumor tissue block (except 
in China) (see the Laboratory Manual for the minimum number of slides required), 
presented on slides and not older than 60 days. Each section is to be 5 μm thick.
Note: Blocks should be provided wherever possible.*
* 
Note: China study sites will not submit tumor tissue blocks, and only unstained sections from the 
tissue block will be submitted for further analysis. Mutation testing residual tissue samples collected 
in China will be destroyed or repatriated maximally 5 years after study indication approval for 
marketing in China.
If the first tissue sample submitted for central testing is not confirmed as EGFR mutation 
positive due to test failure, a further tissue sample may be submitted for central testing. 
Central retests on a new tissue sample can only be performed if the original testing failed. 
Re-tests are not permitted if the central EGFR tissue testing result is EGFR mutation 
negative for Ex19del and/or L858R.
Whilst eligible EGFR mutations for this study are Ex19del and L858R, other EGFR 
mutations (including T790M) will be reported as part of the cobas® EGFR Mutation Test 
v2.
8.1.1.1.2
Patients with a positive local tissue-based EGFR mutation test result 
Investigators should provide a FFPE tumor tissue sample (where available) for 
retrospective central analysis of EGFR mutation status in Part II screening. The sample 
will also be used for exploratory biomarker analysis (except in China as per local 
regulations).
If patients have results from a local tumor tissue cobas® EGFR Mutation Test v2 test 
conducted in a central Covance laboratory following its instructions for use for other 
AstraZeneca studies, retrospective central analysis of EGFR mutation status will not be 
needed.
Whilst eligible EGFR mutations for this study are Ex19del and L858R, other EGFR 
mutations (including T790M) will be reported as part of the local EGFR test. Similarly 

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Ex19del, L858R and other EGFR mutations (including T790M) will be reported from the 
central retrospective testing of sample if provided.
The local EGFR test results should be collected and maintained as source document and 
captured in the eCRF entirely by the site.  
Tissue sample requirements are as per Section 8.1.1.1.1*.
* 
Note: China study sites will not submit tumor tissue blocks, and only unstained sections from the 
tissue block will be submitted for further analysis. Mutation testing residual tissue samples collected 
in China will be destroyed or repatriated maximally 5 years after study indication approval for 
marketing in China.
8.1.1.2
Plasma samples for EGFR mutation testing 
Mandatory provision of 20 ml of blood is required for retrospective EGFR mutation 
testing from patients at Part II screening. Blood should be processed to plasma and frozen 
as soon as possible (within 4 hours), sites should then ship directly to the testing lab. For 
China, the volume of blood required is 10 ml*.
Further guidance is provided in the laboratory manual.
* 
Note: Mutation testing residual plasma samples collected in China will be destroyed or repatriated 
maximally 5 years after study indication approval for marketing in China.
8.1.2
RECIST v1.1
All subjects should continue to receive randomized study treatment until objective 
radiological disease progression per RECIST v1.1 and as assessed by BICR, or until 
another discontinuation criterion is met as per Section 7.1. 
Tumor assessments will be performed using (i) contrast enhanced CT of the chest and 
abdomen (including liver and adrenal glands) as the preferred method. However, if 
subjects are contraindicated to CT contrast agents a non-contrast CT otherwise MRI will 
be acceptable; and (ii) Contrast enhanced T1w MRI of the brain as the preferred method. 
However in those subjects who are contraindicated to Gd-DTPA based contrast agents a 
non-contrast MRI would be sufficient. 
CT (preferred) or MRI of chest and abdomen and MRI of the brain will be performed at all 
tumor imaging visits. The baseline assessment is part of the screening procedures and 
should be performed ≤28 days prior to randomization. The imaging modality used for 
baseline tumor 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. 
Efficacy for all patients will be assessed by objective tumor assessments every 8 weeks 
(relative to the date of randomization) until 48 weeks, then every 12 weeks thereafter, until 
confirmed objective radiological disease progression as defined by RECIST v1.1 and as 
assessed by BICR. These assessments should occur irrespective of whether a patient is 

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receiving study treatment or has previously discontinued study treatment for another 
discontinuation criterion and may have started alternative anticancer treatment. Additional 
scans should be performed if clinically indicated, i.e., if disease progression is suspected. 
An MRI scan with contrast should be performed in the event of suspected CNS 
progression. If an unscheduled assessment is performed, and the patient’s disease has not 
progressed, every attempt should be made to perform the subsequent assessments at their 
scheduled visits. 
All imaging assessments (including unscheduled visit scans, radiotherapy planning scan, 
and high resolution CT) will be sent to AstraZeneca appointed central reader on an 
ongoing basis. Assessment of scans by BICR will be triggered only upon investigator-
assessed progression and the results of the BICR will be reported back promptly to sites. If 
the BICR confirms disease progression study treatment will be discontinued and the 
patients will enter survival follow up. If the BICR does not confirm disease progression, 
study treatment should be continued and tumor assessments continued in line with the 
SoA. Since the primary analysis of the study is based on BICR, it is important that study 
treatment and scheduled imaging assessments continue until progression confirmed by 
BICR. 
If at the time of primary PFS analysis it is identified that a patient has disease progression 
by BICR that has not been identified by the investigator, AstraZeneca will contact the 
investigator to discuss whether continued treatment with study medication is appropriate.
8.1.2.1
Central reading of scans
All imaging scans for tumor assessments including unscheduled visit scans should be 
duplicated and collected on an ongoing basis and sent to the appointed CRO to enable 
BICR. 
Following BICR-confirmed progression patients should have tumor assessments as per 
standard local practice for assessment of PFS2 (see Section 8.1.2.2).These local-practice 
scans should not be sent to the appointed CRO.
The radiotherapy planning scans from the definitive radiation treatment delivered prior to 
randomization are to be submitted to the AZ appointed imaging CRO to assist in the 
selection of target lesions (TLs) and in the interpretation of scans during study treatment 
and to facilitate the interpretation of radiological findings consistent with pneumonitis 
(radiation vs drug induced pneumonitis). 
Information collected in the eCRF regarding prior radiotherapy will also be provided to the 
BICR to allow the selection of the appropriate TLs.
RECIST v1.1 criteria will be used to assess each patient’s tumor response to treatment and 
allow calculation of PFS, ORR, DoR, DCR, tumor shrinkage and time to death or distant 
metastases (TTDM). The RECIST v1.1 guidelines for measurable, non-measurable, TLs 
and non-target lesions (NTLs), and the objective tumor response criteria (CR, PR, SD, or 

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progression of disease [PD]) are presented in Appendix F). 
8.1.2.2
Assessment of second progression
Following objective progression that is confirmed by BICR, patients will have their 
progression status recorded every 12 weeks per local standard clinical practice to assess 
PFS2. A patient’s progression status is defined according to the local practice and may 
involve any of: objective radiological progression (preferred), symptomatic progression, or 
death. Scans will be performed according to the local practice and formal RECIST 
measurements will not be collected for assessment of PFS2. The second progression event 
must have occurred during or after treatment with a subsequent treatment after the 
progression event used for the primary variable PFS or death. The date of PFS2 assessment 
and Investigator opinion of progression status (progressed or non-progressed) at each 
assessment will be recorded in the source documents and the eCRF.
Assessment of PFS2 will no longer be collected after the primary PFS analysis.
8.1.3
Clinical outcome assessments
A Clinical Outcome Assessment (COA) is any assessment that may be influenced by 
human choices, judgement, or motivation and may support either direct or indirect 
evidence of treatment benefit. PROs is one of the types of COAs. A PRO is any report of 
the status of a patient’s health condition that comes directly from the patient, without 
interpretation of anyone else. PROs have become a significant endpoint when evaluating 
effectiveness of treatments in clinical trials. The following PROs will be collected: EORTC 
QLQ-C30, EORTC QLQ-LC13, PGIS, PRO-CTCAE and EQ-5D-5L (See Appendix G). 
PROs will be collected for all patients throughout the study period via a hand-held 
electronic device. See SoA (Table 1) for the timing of collection. The PRO devices should 
be administered prior to first dose at visit 2/randomization. Site staff should stress that the 
information is confidential. 
After randomization, ePRO questionnaires are available on electronic devices (LogPads) 
for a period of up to 7 days for each assessment (i.e., it will be available three days before 
the designated “Study Day” and three days after the designated “Study Day”) for 
completion. ePRO questionnaires can only be completed once within the 7-day period of 
availability. ePRO completion is mandatory to those sites that have it approved by health 
authority/ethic committee/independent review board. In case a patient is not eligible to 
complete the ePROs e.g., due to sight impairment, illiteracy, sites are required to still 
assign the LogPad and then immediately perform the “End LogPad Use”, so that this is 
recorded in the database. The relevant actions should be recorded in source document.
For patients who discontinue study treatment prior to BICR-confirmed progression, PROs 
should be collected at the study treatment discontinuation visit and continue to be collected 
at the same frequency as the treatment period during progression follow-up until BICR-
confirmed disease progression, then at the disease progression visit and at week 8, week 16 
and week 32, relative to the disease progression visit.

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For patients who have had BICR-confirmed RECIST v1.1 defined progression prior to the 
primary PFS analysis, ePROs should be completed at week 8, 16 and 32 post-progression, 
relative to the date of the treatment discontinuation visit. PROs will not be collected for 
any patient after the primary PFS analysis.
8.1.3.1
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire – Core 30 items (EORTC QLQ-C30) 
The EORTC QLQ-C30 was developed by the EORTC Quality of Life Group 1993. It 
consists of 30 items and measures cancer patients’ functioning (Health Related Quality of 
Life [HRQoL]) and symptoms (Aaronson et al 1993) for all cancer types. Questions can be 
grouped into 5 multi-item functional scales (physical, role, emotional, cognitive, and 
social); 3 multi-item symptom scales (fatigue, pain, nausea, and vomiting); a 2-item global 
HRQoL scale; 5-single items assessing additional symptoms commonly reported by cancer 
patients (dyspnea, loss of appetite, insomnia, constipation, diarrhea) and 1 item on the 
financial impact of the disease. The EORTC QLQ-C30 is a valid and reliable PRO 
instrument in this patient population. 
8.1.3.2
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire – Lung Cancer 13 items (EORTC QLQ-LC13) 
The EORTC QLQ-LC13 is a well-validated complementary module measuring lung 
cancer associated symptoms and side effects from conventional chemotherapy and 
radiotherapy (Bergman et al 1994). Refer to Appendix G. The EORTC QLQ-LC13 
includes questions assessing cough, hemoptysis, dyspnea, site specific pain (symptoms), 
sore mouth, dysphagia, peripheral neuropathy, and alopecia (treatment-related side effects) 
and pain medication.
8.1.3.3
Patients Global Impression of Severity (PGIS)
The PGIS item is included to assess how a patient perceives his/her overall current severity 
of cancer symptoms. Patients will choose from response options from “no symptoms” to 
“very severe.”
8.1.3.4
Patient Reported Outcomes version of the Common Terminology Criteria 
for Adverse Event (PRO-CTCAE)
The PRO-CTCAE system was developed by the National Cancer Institute (NCI) in 
recognition that collecting potential treatment-related symptoms directly from patients can 
improve the accuracy and efficiency. This was based on findings from multiple studies 
demonstrating that physicians and nurses underestimate symptom onset, frequency, and 
severity in comparison with patient ratings (Sprangers & Aaronson 1992; Litwin et al 
1988; Basch et al 2009). The PRO-CTCAE will only be administered in those countries 
where a linguistically validated version exists. The PRO-CTCAE is an item-bank of 
symptoms experienced by patients while undergoing treatment of their cancer. To date, 
81 symptoms of the CTCAE have been identified to be amenable to patient reporting but 
not all items are administered in any one clinical trial. Response options vary from 
frequency, severity, and interference with usual activities. For this study, 14 items are 
considered relevant for this cancer treatment (See Appendix G). 

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8.1.3.5
EuroQoL 5-Dimension 5-Levels (EQ-5D-5L)
The EuroQoL 5-Dimension (EQ-5D) is a standardized measure of health status developed 
by the EuroQol Group in order to provide a simple, generic measure of health for clinical 
and economic appraisal (EuroQol Group 1990). Applicable to a wide range of health 
conditions and treatments, it provides a simple descriptive profile and a single index value 
for health status that can be used in the clinical and economic evaluation of health care as 
well as in population health surveys. The questionnaire assesses 5 dimensions as follows: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each 
dimension has 5 response options (“no problems,” “slight problems,” “moderate 
problems,” “severe problems,” and “extreme problems”) that reflect increasing levels of 
difficulty (EuroQol Group 2015).
Since 2009, the EuroQol Group has been developing a more sensitive version of the EQ-
5D (the EQ-5D-5L) that expands the range of responses to each dimension from 3 to 5 
levels of increasing severity (Herdman et al 2011). Preliminary studies indicate that the 5L 
version improves upon the properties of the 3L measure in terms of reduced ceiling effect, 
increased reliability, and an improved ability to differentiate between different levels of 
health (Janssen et al 2008a, Janssen et al 2008b, Pickard et al 2007).
The patient will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions. The questionnaire also includes a visual 
analog scale, where the patient will be asked to rate current health status on a scale of 0 to 
100, with 0 being the worst imaginable health state (see Appendix G).
8.1.3.6
Administration of electronic Patient Reported Outcomes
The order of ePRO completion via hand-held electronic device will be as following: 
EORTC QLQ-LC13, EORTC QLQ-C30, PGIS, PRO-CTCAE and EQ-5D-5L. 
The following best practice guidelines should be followed when collecting PRO data via 
an electronic device:
!
Site staff to explain that it is important to hear directly from the patients how they feel. 
Investigator or delegated site staff should also stress that the information is 
confidential. Therefore, if the patient has any medical problems he/she should discuss 
them with the investigator or site staff separately from the ePRO assessment.
!
Remind patients that there are no right or wrong answers; avoid bias by not clarifying 
items.
!
Train the patient on how to use the ePRO device using the materials and training 
provided by the ePRO vendor. Also provide guidance on whom to call if there are 
problems with the device by providing the patient information pamphlet provided by 
the ePRO vendor.
!
The investigator or delegated site staff should review the compliance of ePRO 

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completion with subjects at each study visit. Any compliance issue should be discussed 
with subjects and is encouraged to work on a solution to enhance/resolve the issue. 
Certain discussion and compliance review should be reflected in source document.
!
Electronic devices (LogPads) used for ePRO collection should be return to site at the 
nearest visit as soon as the last assessment is completed by patient. 
Monitor compliance: minimizing missing data is a key aspect of study success. 
Compliance must be checked at each study visit and should be checked more frequently to 
identify problems early. If compliance drops below 85%, a check-in call from the site to 
ask the patient if he/she has any difficulties is highly recommended.
8.1.4
Health Resource Use Module
HRU Module will be completed by the investigational site for any healthcare resource use 
between visits. Up to the point of primary PFS analysis, the site will ask patients for any 
HRU between visits (i.e., excluding routine follow-up clinic visits associated with the 
clinical trial but including both planned and unplanned admissions) at study visits as per 
Table 1. 
Patients who discontinue study treatment for a reason other than BICR-confirmed 
progression should have information collected at that time of study treatment 
discontinuation, 28-day follow-up and every 8 weeks up to week 48 and then every 12 
weeks (relative to the date of randomization) afterwards until BICR-confirmed 
progression. 
Following BICR-confirmed progression, information will be collected every 12 weeks 
during survival follow-up. Assessments for Healthcare resource will no longer be collected 
after the primary PFS analysis.
For the purposes of economic evaluation, it is necessary to capture healthcare resource use 
related to the treatment and the underlying disease. Within the study, the following 
resource use will be captured:
!
Hospital episodes including the type of contact (hospitalizations, outpatient, day case), 
reason, length of stay (including intensive care unit), and concomitant medications and 
procedures. 
!
Symptoms for admission.
The above resource use data will mainly come from the source document including but not 
limited to medical record and patient interview. The delegated site staff will record it in the 
Hospital Admissions Details module in the eCRF. 

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8.2
Safety assessments 
8.2.1
Clinical safety laboratory assessments 
See Table 6 for the list of clinical safety laboratory tests to be performed for clinical 
chemistry, hematology and urinalysis and refer to the SoA (Table 1) for the timing and 
frequency. Additional safety samples may be collected if clinically indicated at the 
discretion of the Investigator. All protocol-required laboratory assessments, as defined in 
the table, must be conducted in accordance with the laboratory manual and the SoA (Table 
1). If clinical chemistry, hematology, and urinalysis assessments have been performed 
within 7 days prior to commencing study treatment, they do not have to be repeated on 
Visit 2 (Day 1/Week 1) if the patient’s condition has not changed (i.e., no new treatment 
during this period of time, no new complication, or aggravation). 
The Investigator should make an assessment of the available results with regard to 
clinically relevant abnormalities in documentation. The laboratory results should be signed 
and dated and retained at center as source data for laboratory variables and applicable 
section of eCRF in a promptly manner.  
For information on how AEs based on laboratory tests should be recorded and reported, 
see Section 8.3.7.
The clinical chemistry, hematology and urinalysis will be performed at a local laboratory 
at or near to the Investigator site. Sample tubes and sample sizes may vary depending on 
laboratory method used and routine practice at the site. The numbers of samples and blood 
volumes is therefore subject to site-specific change.

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Table 6
Laboratory safety variables
Hematology/Hemostasias (whole blood)
Clinical Chemistry (serum or plasma)
B-Hemoglobin (Hb)
S/P-Albumin 
B-Red Blood Cell (RBC) count
S/P-Alanine aminotransferase (ALT)
B-Hematocrit
S/P-Aspartate aminotransferase (AST)
B-Reticulocytes
S/P-Alkaline phosphatase (ALP)
B-Leukocyte count
S/P-Bilirubin, total (TBL)
B-Absolute leukocyte differential count b:  
S/P-Calcium, total
Neutrophils
S/P-Creatinine
Lymphocytes
S/P-Glucose
Monocytes
S/P-Lactate dehydrogenase (LDH)a
Basophils
S/P-Magnesium 
Eosinophils
S/P-Potassium
B-Platelet count 
S/P-Sodium
Urinalysis (dipstick) c
S/P-Urea/Blood Urea Nitrogen
U-Glucose
U-Protein
U-Blood
NB. In case a patient shows an AST or ALT ≥3xULN together with TBL ≥2xULN please refer to Appendix E for 
further instructions. 
a      LDH is an additional variable collected at Part II screening visit only. 
b      The value is to be provided as percentage of the leukocyte count if the absolute leukocyte differential counts 
are not available.
c      Note: Either dipstick and local lab testing are acceptable methods of urinalysis. The results are to be reported 
as qualitative outcomes to be comparable to the dipstick results. 
8.2.2
Volume of blood 
Total mandatory blood volume in the first 12 weeks (up to Visit 6) is approximately 300 
mL including optional pharmacogenetics (PGx) sample (see Table 7).
Table 7
Approximate blood sample volumes (mL) d
Visit 
Safety a
PK analysis
Plasma b
PGx c
Part I Screening 
NA
NA
NA
NA
Visit 1/Part II 
Screening
15
NA
50
6
(Optional)
Subsequent treatment 
Visit, Visit 2, 3 and 5
15
NA
30
NA
Visit 4 and 6
15
2
30
NA
Subtotal at Visit 6
90
4
200
6
NA= not applicable; PGx=pharmacogenetics; PK=pharmacokinetics.
a      For safety, assumes 6 mL clinical chemistry and 9 mL hematology per visit. Sample tubes and sample sizes 
may vary depending on laboratory method used and routine practice at the site. The blood volume might be 

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higher at some sites who collects serum samples for pregnancy test. The number of samples/blood volumes is 
therefore subject to site-specific change.
b      Plasma samples collected for retrospective central EGFR mutation testing and Plasma sample for ctDNA and 
blood borne biomarkers
c      Pharmacogenetic testing should occur during Part II screening (subject to consent). However  if for any reason 
the sample is not drawn prior to dosing, it may be taken at any visit after visit 2 until the last study visit.
d     The approximate blood sample volume summarized in the table above might not be applicable for China.  
Additionally, at Part II Screening, a pregnancy test (blood or urine tests are acceptable 
based on the site’s standard clinical practice) will be collected from all women of 
child-bearing potential only. 
8.2.3
Physical examinations
A complete physical examination will be performed and include an assessment of the 
following: general appearance, respiratory, cardiovascular, abdomen and additional 
systems as deemed clinically appropriate (e.g., skin). 
Height will only be measured during the Part II screening, and it will be documented in the 
eCRF. Weight will be documented in the eCRF. Physical examination and weight will be 
performed at timelines as specified in the SoA (Table 1).
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 or disease progression, see Sections 8.3.9
and 8.3.10.
8.2.4
Vital signs
Vital signs (to be taken before blood collection for laboratory tests) will be measured in a 
supine position (or sitting, if supine is not feasible) after 10 minutes rest for the patient in a 
quiet setting and will include systolic and diastolic blood pressure, and pulse rate.  
Any clinically significant changes in vital signs (pulse and blood pressure) should be 
recorded as an AE if applicable.
8.2.5
Electrocardiograms
Twelve-lead ECG will be performed at the visits indicated in the SoA (Table 1) and in 
addition should be performed in the event of any cardiac AE.
Twelve-lead ECGs will be obtained after the patient has been resting semi-supine for at 
least 10 minutes prior to times indicated. All ECGs should be recorded with the patient in 
the same physical position. For each time point three ECG recordings should be taken at 
approximately 5 minute intervals. A standardized ECG machine should be used and the 
patient should be examined using the same machine throughout the study if possible. 
After paper ECGs have been recorded, the investigator or designated physician will review 
each of the ECGs and may refer to a local cardiologist if appropriate. A paper copy should 
be filed in the patient’s medical records as source document. If an abnormal ECG finding 

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at screening or baseline is considered to be clinically significant by the investigator, it 
should be reported as a concurrent condition. For all ECGs details of rhythm, ECG 
intervals and an overall evaluation will be recorded.
ECG data will be collected digitally and will be transferred electronically for central 
analysis as described in the study specific ECG manual. The investigator may choose to 
perform a non-digital ECG at the time of the screening visit in order to identify patients 
eligible for study entry. If a non-digital ECG is performed at the screening visit it cannot 
subsequently be used as a baseline recording, in this situation an ECG will need to be 
collected on the baseline visit in digital form. If no digital ECG is captured prior to the 
start of study treatment, where an appropriate non-digital ECG is available, the non-digital 
ECG will be used as a baseline recording.
Heart rate, PR, R-R, QRS, QT intervals and QT corrected by Fridericia’s formula (QTcF) 
will be determined and reviewed by an external cardiologist. ECG data used for patient 
eligibility will be reviewed and determined based on investigator or delegated 
cardiologist’s judgement.  
Fridericia’s formula is applied to calculate the corrected QT interval. 
If there is a clinically significant abnormal ECG finding during the Treatment period, this 
should be recorded in the source document and the AE section of eCRF, according to 
standard AEs collection and reporting processes. A 28-day follow-up assessment will be 
required if an on treatment assessment showed a clinically significant abnormality at the 
time of discontinuation of study therapy, to confirm reversibility of the abnormality.
After the primary PFS analysis, there is a potential to move from centrally reviewed to 
locally reviewed ECGs depending upon the analysis of cardiac data. AstraZeneca will 
notify sites if local ECG assessment is to be instituted, at which point, ECG assessments 
will be performed locally (triplicate 12-lead ECG, with paper printouts of 10 seconds for 
Investigator review) and a paper copy will be stored in the patient’s medical records. ECG 
information will continue to be recorded in the eCRF. If there is a clinically significant 
abnormal ECG findings during this period, this should be recorded on the AE eCRF, 
according to standard AEs collection and reporting processes. After final OS analysis, 
ECG assessments will be performed according to routine clinical practice as defined by the 
Investigator.
8.2.6
Echocardiogram/MUGA scan
An ECHO 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 within a 
patient i.e., if ECHO is used for the screening assessment then ECHO should also be used 

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for subsequent scans. The patients should also be examined using the same machine and 
operator whenever possible, and quantitative measurements should be taken.
ECHO/MUGA assessment at week 36 should be carried out additionally to align the 
assessment frequency every 12 weeks relative to the date of randomization.
8.2.7
WHO performance status
Performance status will be assessed at the scheduled visits indicated in the SoA (Table 1) 
according to WHO criteria as follows:
0 = Fully active, able to carry out all pre-disease activities without restrictions.
1 = Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work.
2 = Ambulatory and capable of self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours.
3 = Capable of only limited self-care, confined to bed or chair more than 50% of 
waking  hours.
4 = Completely disabled, cannot carry on self-care, totally confined to bed or chair.
8.3
Collection of 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.
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legally authorized representative).  
The investigator and any designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. For information on how to 
follow/up AEs see section 8.3.3.  
An AESI is one of scientific and medical interest specific to understanding of the 
investigational product and may require close monitoring and rapid communication by the 
Investigator to the sponsor. An AESI may be serious or non-serious. The rapid reporting of 
AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of this investigational product.
The AESIs for the study are:
!
Pneumonitis
!
Interstitial lung disease

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!
Radiation pneumonitis
Guidelines for dose modifications and management of pneumonitis (including radiation 
pneumonitis) are provided in Section 8.4.4.2 (See Table 10) of this protocol.
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended 
and non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.  
8.3.2
Time period and frequency for collecting AE and SAE information 
All AEs will be collected from the time of signature of the Screening Part II ICF 
throughout the treatment period and including the 28-day follow-up (28 days after last 
dose of study drug), as shown in Table 8. In addition, any AEs related to study procedures 
occurring during Screening Part I will be collected. Any new or unresolved AE observed at 
28-day follow-up should be followed until resolution, stabilization, the event is otherwise 
explained, or the subject is lost to follow-up. 
SAEs will be recorded during the course of the study from the time of signing the first ICF. 
AESIs will be recorded from the time of signing the Screening Part II ICF. The time period 
for AE and SAE collection is described in Table 8. 
Table 8
Time period and collection of AEs and SAEs  
Part I Screening 
until Part II 
Screening
Part II Screening 
until 28-day 
follow-up visit
Progression 
follow-up
Survival 
follow-up 
Post final OS 
analysis for 
patients on 
osimertinib
All SAEs, and 
AEs related to 
study procedures
All AEs, SAEs, and 
AESIs
SAEs and AESIs, 
if related to study 
treatment 
AND
SAEs related to 
study procedures
SAEs and AESIs, 
if related to prior 
study treatment or 
open-label 
osimertinib a
All SAEs b
a
Additional safety assessments may be performed as per local clinical practice, but will not be collected as part of study data 
capture.
b     AstraZeneca will collect information (during the treatment period of osimertinib and for 28 [+ 7] days after last dose of 
osimertinib) on SAEs, overdose and pregnancy (as per Section 8.4) via paper and emailed (preferably) or faxed directly to TCS 
DES (also known as AZ DES). 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix B.  The investigator will submit any updated SAE data to the 
sponsor within 24 hours of it 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 

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treatment or study participation, the investigator may notify the sponsor in accordance with 
the SAE reporting timelines where relevant.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
For those patients who are continuing to receive osimertinib after the final OS analysis, 
AstraZeneca will collect information (during the treatment period and for 28 (+ 7) days 
after last dose) on SAEs, overdose and pregnancy (as per Section 8.4) via paper and 
emailed (preferably) or faxed directly to TCS DES (also known as AZ DES). Drug 
accountability information will be recorded in the source documents.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
patient at subsequent visits/contacts. All SAE/non-serious AEs/AEs of special interest (as 
defined in Section 8.3), will be followed until resolution, stabilization, the event is 
otherwise explained, or the patient is lost to follow-up.
Any AEs/AESIs that are unresolved at the patient’s last AE assessment or other 
assessment/visit as appropriate in the study are followed up by the Investigator for as long 
as medically indicated, but with further recording in the CRF for AESIs only. AstraZeneca 
retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
8.3.4
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
!
Investigator causality rating against the IP(s) (yes or no)
!
Action taken with regard to IP(s)
!
AE caused patient’s withdrawal from study treatment 
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for serious AE
!
Date Investigator became aware of serious AE
!
AE is serious due to
!
Date of hospitalization
!
Date of discharge

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!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to Study procedure(s)
!
Causality assessment to other medication
!
Description of SAE
8.3.5
Causality collection
The Investigator will assess causal relationship between IP 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 IP?’
For SAEs, causal relationship will also be assessed for other medication and study 
procedures.  Note that for SAEs that could be associated with any study procedure the 
causal relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the CSP.
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or care provider or reported in response to 
the open question from the study site staff: ‘Have you had any health problems since the 
previous visit ?’, or revealed by observation will be collected and recorded in the Clinical 
Report Form (CRF).  When collecting AEs, the recording of diagnoses is preferred (when 
possible) to recording a list of signs and symptoms.  However, if a diagnosis is known and 
there are other signs or symptoms that are not generally part of the diagnosis, the diagnosis 
and each sign or symptom will be recorded separately.
8.3.7
Adverse events based on examinations and tests
The results from the CSP mandated laboratory tests and vital signs will be summarized in 
the CSR. Deterioration as compared to baseline in protocol-mandated laboratory values 
and vital signs (pulse and blood pressure) should therefore only be reported as AEs if they 
fulfill any of the SAE criteria, are the reason for discontinuation of treatment with the 
investigational product, or are considered to be clinically relevant as judged by the 
investigator.
If deterioration in a laboratory value, vital sign, ECG, ECHO/MUGA, or WHO 
performance is associated with clinical signs and symptoms, the sign or symptom will be 
reported as an AE and the associated laboratory value/vital sign will be considered as 
additional information.  Wherever possible the reporting Investigator uses the clinical, 
rather than the laboratory term (e.g., anemia vs low hemoglobin value).  In the absence of 
clinical signs or symptoms, clinically relevant deteriorations in non-mandated parameters 
should be reported as AE(s).

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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, see Sections 8.3.9 and 8.3.10.
8.3.8
Hy’s law
Cases where a patient shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3xULN together with TBL ≥2xULN may 
need to be reported as SAEs.  Please refer to Appendix E for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s Law (HL).
8.3.9
Disease-under study (DUS)
Symptoms of DUS are those which might be expected to occur as a direct result of locally 
advanced unresectable 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 investigational product.
8.3.10
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable 
to the disease for which the investigational product is being studied.  It may be an increase 
in the severity of the disease under study and/or increases in the symptoms of the disease.  
The development of new, or progression of existing metastasis to the primary cancer under 
study should be considered as disease progression and not an AE.  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 not be reported as a SAE. Hospitalization due to signs and symptoms of disease 
progression should not be reported as SAE.
8.3.11
New cancers
The development of a new cancer should be regarded as an AE and will generally meet at 
least one of the serious criteria. New cancers are those that are NOT the primary reason for 
the administration of the study drug and have been identified after the patient’s inclusion 
in this study. They do not include metastases of the original cancer.
8.3.12
Handling of deaths
All deaths that occur during the study, or within the follow-up period after the 
administration of the last dose of study drug, should be reported as follows:
!
Death, which is unequivocally due to disease progression, should be communicated to 
the study monitor at the next monitoring visit and should be documented in the eCRF 

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module (in the Statement of Death Page), but should not be reported as a SAE during 
the study.
!
Where death is not clearly due to disease progression of the DUS, the AE causing the 
death should be reported to the study monitor 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 progression of disease, if 
appropriate, and should assign a single primary cause of death together with any 
contributory causes.
!
Deaths with an unknown cause should always be reported as a SAE, but every effort 
should be made to establish a cause of death. A post-mortem may be helpful in the 
assessment of the cause of death, and if performed, a copy of the post-mortem results 
(with translation of important parts into English) should be reported in an expedited 
fashion to an AstraZeneca representative within the usual timeframes.
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 IP, or to the 
study procedure(s). All SAEs will be recorded in the medical record and eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel 
inform the appropriate AstraZeneca representatives within one day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative 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 
within one calendar day i.e., 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 RAVE 
WBDC system, an automated email alert is sent to the designated AstraZeneca 
representative.
If the RAVE WBDC system is not available, then the Investigator or other delegated study 
site staff reports a SAE to the appropriate AstraZeneca representative through alternative 
reporting way in writing as instructed.
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proceed.  
The reference document for definition of expectedness/listedness is Section 3 (Emerging 
Safety Information) of the Investigator’s Brochure for the AstraZeneca drug, osimertinib
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 should be reported to AstraZeneca except for:
If the pregnancy is discovered before the study patient has received any study drug
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.4.2.1
Maternal exposure
If a patient becomes pregnant during the course of the study the IP should be discontinued 
immediately and the pregnancy reported to AstraZeneca.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP 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 patient was discontinued from the study.
If any pregnancy occurs from the date of first dose of study treatment until 6 weeks after 
the last dose of study treatment, then the Investigator or other site personnel informs the 
appropriate AstraZeneca representatives within one day i.e., immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative 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 8.4.1) and within 30 days for all other 
pregnancies.
The same timelines apply when outcome information is available.
8.4.2.2
Paternal exposure 
Pregnancy of the patient’s partners is not considered to be an AE. However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
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treatment until 4 months after the last dose of study treatment should be followed up and 
documented in the medical record and provided to AstraZeneca Patient Safety data entry 
site. Consent from the partner must be obtained before the information is collected and 
reported to AstraZeneca.
The local study team should adopt the master pregnant partner form in line with local 
procedures/requirements and submit it to the relevant Regulatory Authority /Independent 
Ethics Committees (IECs)/Institutional Review Boards (IRBs) prior to use. 
8.4.3
Overdose
In the context of a clinical study, an overdose is any dose which exceeds the daily dose of 
80 mg or 40 mg for patients that have dose reduced, that is defined in the CSP.
A maximum tolerated dose has not been established for osimertinib.
There is no known antidote. Investigators are advised that any patient, who receives a 
higher dose than intended should be monitored closely, managed with appropriate 
supportive care, and followed up expectantly.
!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on 
the relevant AE modules in the eCRF and on the Overdose eCRF module.
!
An overdose without associated symptoms is only reported on the Overdose 
CRF module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, no matter it 
is AEs associated or not, then the Investigator or other site personnel inform appropriate 
AstraZeneca representatives immediately via eCRF, or no later than 24 hours of when he 
or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see 
Section 8.3.2.  For other overdoses, reporting must occur within 30 days.
8.4.4
Management of IP-related toxicities 
8.4.4.1
General dose adjustments for adverse events
There will be no individual modifications to dosing schedule in response to toxicity, only 
potential dose reduction or dose interruption.
If a patient experiences a CTCAE grade 3 or higher toxicity and/or unacceptable toxicity 
(any grade) not attributable to the disease or disease-related processes under investigation, 
where the investigator feels that there is a reasonable possibility of a causal relationship to 
osimertinib/matching placebo, dosing of osimertinib/matching placebo will be interrupted 
and supportive therapy administered as required in accordance with local 

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practice/guidelines. If a toxicity resolves or reverts to <CTCAE grade 2 within 3 weeks of 
interruption, treatment with osimertinib / matching placebo may be restarted at the same 
dose (osimertinib 80 mg / matching placebo) or a lower dose (osimertinib 40 mg / 
matching placebo), using the rules below for dose modifications (see Table 9), and with 
discussion and agreement with the AstraZeneca Study Team Physician as needed. If 
restarting at the same dose level, patients should be closely monitored for 3 days following 
the restart of treatment. If within 3 days there is recurrence of same toxicity, a dose 
reduction should be considered at the Investigator’s discretion.
Table 9
Dose reduction levels
Study Treatment
Starting Dose
80 mg osimertinib/ matching placebo
Reduced Dose
40 mg osimertinib/ matching placebo
If the toxicity does not resolve to ≤CTCAE grade 2 after 3 weeks, then the patient should 
be withdrawn from the study drug and observed until resolution of the toxicity.
If an AE subsequently requires dose interruption, study treatment may restart at the same 
dose or the reduced dose, on resolution/improvement of the AE at the discretion of the 
Investigator.
Permanent discontinuation due to toxicity
If patients experience any of the following, they will not be permitted to restart study 
treatment:
!
Grade 3 or higher pneumonitis
!
Grade 2 pneumonitis where symptoms have not resolved within 4 weeks after 
interrupting study treatment
!
Recurrent symptomatic pneumonitis following prior dose interruption and study 
treatment re-challenge
!
QTc interval prolongation with signs/symptoms of serious arrhythmia
!
Any AE that, in the opinion of the Investigator or AstraZeneca, contraindicates further 
dosing
8.4.4.2
Pneumonitis   
Whilst recognizing that radiographic changes coinciding with radiation portals would 
favor the diagnosis of radiation pneumonitis, differentiating a potential drug-induced 
pneumonitis from radiation pneumonitis can be challenging. The diagnosis of both events 
can be very subjective and is typically dependent on physician’s judgement based on their 
clinical experiences and the use of EGFR TKI therapies. Moreover given that the time to 
onset of such events and their treatment is likely to be similar, a single guidance on dosing 

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modification and toxicity management for ‘pneumonitis’ is provided in Table 10 which 
covers both pneumonitis / ILD and radiation pneumonitis, rather than having two separate 
guidance.
If new or worsening pulmonary symptoms (e.g., dyspnea, cough) or radiological 
abnormality suggestive of pneumonitis is observed, guidance on investigations and 
toxicity management, as described in detail in Table 10 will be applied. It is recommended 
to perform a full diagnostic work-up, to exclude alternative causes such as lymphangitic 
carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage.  The 
results of diagnostic work-up (including high-resolution computed tomography [HRCT], 
blood and sputum culture, hematological parameters, etc.) will be captured in the eCRF. 
The investigator will be asked to consider whether the signs /symptoms/radiological 
findings are consistent with radiation pneumonitis, drug-induced pneumonitis/ILD, or 
other diagnosis.

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Table 10
‘Pneumonitis’a Dosing modification and Toxicity Management Guideline
Grade of the Event 
(NCI CTCAE version 5.0)
Dose modification
Toxicity management
Any Grade
-
!
Monitor patients for signs and symptoms of pneumonitis 
(new onset or worsening shortness of breath or cough).  
Patients should be evaluated with imaging and pulmonary 
function tests, including other diagnostic procedures, as 
described below.
!
Initial work up may include clinical evaluation, monitoring 
of oxygenation via pulse oximetry (resting and exertion) 
laboratory work-up and high resolution CT scan.
Grade 1
Asymptomatic, clinical or 
diagnostic observations only, 
intervention not indicated.
No dose modification required however
!
Holding study drug may be considered as 
clinically appropriate and during diagnostic 
work-up for other etiologies.
For Grade 1 (radiographic changes only) 
!
Perform investigations as clinically appropriate 
!
Monitor the patient and closely follow-up in 2 to 4 days 
for clinical symptoms +/- additional assessments and 
continue to monitor closely thereafter; 
!
Additional imaging on continued treatment may be 
considered  

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Table 10
‘Pneumonitis’a Dosing modification and Toxicity Management Guideline
Grade of the Event 
(NCI CTCAE version 5.0)
Dose modification
Toxicity management
Grade 2
Symptomatic, medical intervention 
indicated b, limiting instrumental 
ADL.
Hold study drug until resolution of symptoms c
The decision to re-initiate study drug will be 
based upon treating physician’s clinical 
judgement and following endorsement from the 
AstraZeneca study physician.
!
If clinically appropriate to re-initiate, it is
recommended that corticosteroids are 
administered concomitantly and subsequently 
tapered/withdrawn as clinically appropriate. 
!
Re-initiation at either 80mg/placebo once 
daily or at a reduced dose of 40 mg once 
daily/placebo can be considered, as clinically 
appropriate, and in agreement with the 
AstraZeneca study physician
!
If ≥Grade 2 pneumonitis (symptomatic) 
occurs following re-initiation of study drug, 
permanently discontinue study drug.
For Grade 2 (mild to moderate new symptoms)
!
Treat in accordance with local clinical practice.
!
Following study drug re-initiation, monitor and closely 
follow-up in 2 to 4 days for recurrence of symptoms and at 
frequent intervals thereafter
!
Additional imaging may be considered following re-
initiation of study drug
Grade 3 or 4
Grade 3
Severe symptoms, limiting self-care 
ADL; oxygen indicated d
Grade 4
Life-threatening respiratory 
compromise, urgent intervention 
indicated, e.g., tracheostomy or 
intubation.
Permanently discontinue study drug
Severe or new symptoms, new/worsening hypoxia, life 
threatening
Treat in accordance with local clinical practice.
ADL=Activities of daily living
a      Includes pneumonitis/ILD and radiation pneumonitis
b      Patients given treatment for asymptomatic changes are not mandated to interrupt trial therapy and guidance for Grade 1 should be followed
c      Study treatment should be permanently discontinued if symptoms have not resolved within 4 weeks after interrupting study treatment   
d      Patients given oxygen in the absence of symptoms do not require permanent discontinuation of study drug

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8.4.4.3
QTc prolongation
In light of the potential for QT changes associated with osimertinib, electrolyte abnormalities 
(hypokalemia, hypomagnesemia, hypocalcemia) must be corrected to be within normal ranges 
prior to first dose and electrolyte levels should be monitored during study treatment.
Patients with QTc prolongation (i.e., confirmed QTc prolongation to >500 msec absolute) at 
2 separate readings should have study drug interrupted and regular monitoring of ECGs 
performed until resolution to <481 msec, or recovery to baseline if baseline QTcF is 
≥481 msec. If the toxicity resolves or reverts to ≤CTCAE grade 1 within 3 weeks of 
interruption, study drug may be restarted at the same dose or reduced dose using the dose 
reduction levels in Table 9 with discussion and agreement with the AstraZeneca Study Team 
Physician as needed. If the toxicity does not resolve to ≤CTCAE grade 1 within 3 weeks of 
interruption, the patient will be permanently withdrawn from study drug. Study treatment 
must be permanently discontinued in patients who develop QTc interval prolongation in 
combination with any of the following: Torsade de pointes, polymorphic ventricular 
tachycardia, signs/symptoms of serious arrhythmia.
Following study treatment initiation if it is considered essential for patient management to 
give drugs known to prolong QTc interval, regardless of TdP risk category as noted in the 
current guidance in the ArizonaCert website https://www.crediblemeds.org/, close monitoring 
with ECGs and electrolytes is recommended.
Close monitoring with ECGs and electrolytes is also recommended in patients with congestive 
heart failure, and/or electrolyte abnormalities.Keratitis
Patients 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. 
8.4.4.5
Changes in cardiac contractility
Patients who develop relevant cardiac signs and symptoms should be managed as clinically 
appropriate, in line with the general toxicity management (Section 8.4.4.1). 
8.4.4.6
Erythema multiforme, and Stevens-Johnson syndrome, and Toxic epidermal 
necrolysis
Case reports of Erythema multiforme (EM) and toxic epidermal necrolysis (TEN) have been 
uncommonly reported, and Stevens-Johnson syndrome (SJS) have been rarely reported, in 
association with osimertinib treatment. Before initiating study treatment, patients should be 
advised of signs and symptoms of EM, SJS, and TEN. If signs and symptoms suggestive of 
EM develop, close patient monitoring and drug interruption or discontinuation of study 
treatment should be considered. If signs and symptoms suggestive of SJS appear, study 
treatment should be interrupted. Osimertinib should be discontinued immediately if SJS or 

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TEN is diagnosed.
8.4.4.7
Aplastic anaemia
Rare reports of aplastic anemia have been reported in association with osimertinib treatment. 
Some cases had a fatal outcome. If signs and symptoms suggestive of aplastic anemia 
develop, close patient monitoring and drug interruption or discontinuation of osimertinib 
should be considered. Osimertinib should be discontinued in patients with confirmed aplastic 
anemia.
8.4.5
Medication error, drug abuse, and drug misuse
8.4.5.1
Timelines
If an event of medication error, drug abuse or drug misuse occurs during the study, then the 
Investigator or other site personnel informs the appropriate AstraZeneca representatives within 
one calendar day i.e., immediately but no later than 24 hours of when they become aware of 
it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within one (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 8.3.2) and within 30 days for all other 
events.
8.4.5.2
Medication error
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an IMP/study intervention or AstraZeneca NIMP that either causes 
harm to the patient or has the potential to cause harm to the patient.
The full definition and examples of a Medication Error can be found in Appendix B.
8.4.5.3
Drug abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect.
The full definition and examples of drug abuse can be found in Appendix B.
8.4.5.4
Drug misuse
Drug misuse is the intentional and inappropriate use (by a study patient) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorized product information, or 
for unauthorized IMPs/study intervention(s) or AstraZeneca NIMPs, outside the intended use 
as specified in the protocol and includes deliberate administration of the product by the wrong 
route.

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The full definition and examples of drug misuse can be found in Appendix B.
8.5
Pharmacokinetics
Plasma samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of osimertinib as specified in the SoA (Table 1) at pre-dose on day 29 
(visit 4/week 4), day 85 (visit 6/week 12) and day 169 (visit 9/week 24). Samples may be 
collected at additional time points during the study if warranted and agreed upon between the 
investigator and the sponsor, and align local regulations. Instructions for the collection and 
handling of biological samples will be provided by the sponsor or analytical test site. The 
actual date and time (24-hour clock time) of each sample will be recorded.
Samples will be used to evaluate the PK of osimertinib. Pre-dose PK samples should be 
collected within 1 hour before the dose on the day of collection. The sample collection time 
and date should be recorded in source document and central lab form. The collection of the 
plasma sample for PK can be omitted if the patient did not have exposure to IP for at least 
7 days prior to the visit. 
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
Only osimertinib dosed patients will be analyzed in the bioanalytical lab (Covance labs, 
Harrogate, UK or its affiliate) using validated bioanalytical method. The unblinding to identify 
the samples will only be available to the bioanalytical lab and this information along with the 
concentration data will not be shared with any other study personnel until after Database lock.
8.5.1
Determination of drug concentration
Samples for determination of osimertinib (and AZ5104) concentrations in plasma will 
analyzed by Covance on behalf of AstraZeneca. Full details of the analytical method used will 
be described in a separate bioanalytical report. All samples still within the known stability of 
the analytes of interest (i.e., osimertinib and AZ5104) at the time of receipt by the 
bioanalytical laboratory will be analyzed.
In addition, the PK samples may be subjected to further analyses by AstraZeneca in order to 
further investigate the presence and/or identity of additional drug metabolites and correlate PK 
with other primary, secondary, and exploratory endpoints in patients treated with osimertinib. 
These additional analyses are not applicable for China as per local regulations.
Any results from such analyses may be reported separately from the CSR, if warranted.
Details on sample processing, handling, shipment, and storage are provided in the Laboratory 
Manual.

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Full details of the analytical method used will be described in a separate bioanalytical report.
8.5.2
Storage and destruction of pharmacokinetic samples
PK samples will be disposed of after the Bioanalytical Report finalization or six months after 
issuance of the draft Bioanalytical Report (whichever is earlier), unless requested for future 
analyses.  
PK samples may be disposed of or anonymized by pooling.  Any results from such analyses 
may be reported separately from the CSR, if warranted.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the CSR but may be 
reported separately in a bioanalytical report.
All PK samples and PK testing residual samples collected in China will be managed according 
to local laws and regulations, and will be destroyed maximally 12 months after the final CSR 
release.
8.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7
Genetics
8.7.1
Optional exploratory genetic sample
Approximately 6 mL blood sample for DNA isolation will be collected from patients who 
have consented to participate in the genetic analysis component of the study.  Participation is 
optional.  Patients who do not wish to participate in the genetic research may still participate 
in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the patient.  Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent.
See Appendix D for Information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in Appendix D or in 
the Laboratory Manual.
Blood samples for genetic analyses will be obtained during the study, except in China as per 
local regulations.
8.7.2
Storage and destruction of genetic samples
The processes adopted for the coding and storage of samples for genetic analysis are 

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important to maintain patient confidentiality. Samples may be stored for a maximum of 
15 years or as per local regulations from the date of the Last Patient’s Last Visit, after which 
they will be destroyed. DNA is a finite resource that may be used up during analyses. The 
results of any further analyses will be reported either in the CSR itself or as an addendum, or 
separately in a scientific report or publication.
No personal details identifying the individual will be available to AstraZeneca or designated 
organizations working with the DNA.
8.8
Biomarkers & Exploratory Research 
Mandatory collection of blood samples and analysis of residual tumor from samples provided 
for EGFR mutation testing, for biomarker research is also part of this study*. Samples will be 
collected as specified in the SoA (Table 1).
In addition, an optional fresh tumor biopsy sample at the time of disease progression may be 
collected from patients.
Tumor and blood samples will be collected and will be tested for exploratory biomarkers to 
evaluate their association with observed clinical responses to study treatment, including time 
to progression (the primary endpoint of the study) and ORR. 
Further details of exploratory biomarkers are provided in Section 8.8.1.
*
Blood and tissue samples for biomarker & exploratory research will be obtained during the study, except 
in China and other selected countries and study sites, as per local regulations. Details for collection, 
volumes, storage, and shipment of biologic samples are presented in a separate Laboratory Manual.
8.8.1
Exploratory biomarkers 
Tumor markers
Based on availability of tissue, tumor material at baseline after central testing of EGFR 
mutation status (see Section 8.1.1) will be used to assess exploratory biomarkers. Baseline 
measures will be correlated with outcomes including time to progression and ORR. Markers 
tested may include but will not be limited to EGFR mutations (sensitizing and non-
sensitizing), Human Epidermal Growth Factor Receptor-2 (HER2), and Tyrosine-protein 
kinase Met (MET) mutations, expression, and amplification.
Tumor material from an optional fresh biopsy at the time of disease progression will be used 
to understand resistance mechanisms to study treatment. Markers tested may include but will 
not be limited to the identification of alterations in genes known or potentially involved in 
EGFR signaling. Tissue requirements for this sample are provided in Section 8.1.1.  

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Soluble markers
A series of blood samples to generate plasma samples will be collected from all patients. 
These samples will be used for the extraction and analysis of ctDNA and will be used to 
explore the relationship between emergence of EGFR sensitizing mutations in ctDNA and 
time to progression. In addition, resistance mechanisms will be explored. Markers tested may 
include but will not be limited to T790M, C797S, EGFR amplification, MET amplification, 
HER2 amplification, and alterations in other genes involved in EGFR signaling. Similarly the 
relationship between blood-borne biomarkers and drug response and/or disease progression 
will be explored. These markers may include but will not be limited to growth factors or 
cytokines. 
8.8.2
Additional research
Residual tumor and plasma samples from that provided for mandatory research may be used 
to explore factors that may influence susceptibility to/development of NSCLC/cancer or 
and/or response to osimertinib (where response is defined broadly to include efficacy, 
tolerability or safety).  In addition the samples may be used to support the development of 
diagnostics. This additional research is optional and is subject to additional patient consent.
8.8.3
Storage, re-use and destruction of biomarker samples
Samples will be stored for a maximum of 15 years from the date of the Last Subject’s Last 
Visit, after which they will be destroyed.  The results of this biomarker research will be 
reported either in the CSR itself or as an addendum, or separately in a scientific report or 
publication. The results of this biomarker research may be pooled with biomarker data from 
other studies with the study drug to generate hypotheses to be tested in future research.
Mutation testing residual plasma and tissue samples collected in China will be destroyed or 
repatriated maximally 5 years after study indication approval for marketing in China.  
9
STATISTICAL CONSIDERATIONS
9.1
Statistical hypotheses
The formal statistical analyses will be performed to test the main hypothesis:
!
H0: No difference between osimertinib and placebo.
!
H1: Difference between osimertinib and placebo.
The primary objective of this study is to assess the efficacy of osimertinib compared with 
placebo in terms of PFS as assessed by BICR. Key secondary endpoints are CNS PFS by 
BICR and OS. 

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In order to strongly control the type I error at 5% 2-sided significance level, a sequential 
testing procedure will be implemented and after the testing of PFS, OS, and CNS PFS will be 
tested (in that order). The hypothesis on OS will only be tested if the null hypothesis is 
rejected for PFS. The hypothesis on CNS PFS will only be tested if the null hypothesis is 
rejected for OS, either at the time of the PFS analysis or at the time of the final OS analysis. 
9.2
Sample size determination 
Approximately 200 patients in a 2:1 ratio (osimertinib to placebo) will be randomized into the 
study. Patients will be stratified at randomization based on prior chemoradiation strategy 
(CCRT vs SCRT), tumor stage prior to chemoradiation (IIIA vs IIIB/IIIC) and China cohort 
(enrolled at a Chinese site and patient declaring themselves of Chinese ethnicity vs enrolled at 
Non-Chinese site or patient declaring themselves of non-Chinese ethnicity).  
The primary endpoint for this study is PFS by BICR in the FAS population. The primary 
analysis will occur when approximately 120 PFS BICR events have been observed. With 
120 PFS (BICR) events the study has 90% power to show a statistically significant difference 
in PFS at the 2-sided 5% level if the assumed true treatment effect is a HR 0.53; this translates 
to an approximate 7 month improvement from a median 8 month PFS on placebo. The 
smallest treatment difference that would be statistically significant is a PFS HR of 0.68 
(translating to an approximate 4 month improvement). 
In order to provide strong control of the type I error rate, α=0.05 (two-sided), the primary 
endpoint of PFS (BICR in FAS), OS (FAS), and CNS PFS (FAS) will be tested in this 
sequential order. If any previous analysis in the sequence is not statistically significant, the 
alpha will not be transferred to subsequent analyses. 
The analyses of PFS, CNS PFS and OS endpoints will occur at the time of the primary 
analysis of PFS. One analysis of the primary endpoint (PFS by BICR) is planned. Two 
analyses of OS are planned; one interim at the time of PFS and a final analysis. The final OS 
analysis is planned to be conducted when the OS data are approximately 60% mature 
(approximately 120 deaths). The secondary endpoint of OS will be tested at both the interim 
and final analysis. The alpha level allocated to OS will be controlled at the interim and final 
timepoints by using the Lan-DeMets spending function for OS that approximates an O’Brien 
Fleming approach, where the alpha level applied at the interim depends upon the proportion of 
information available.
Approximately 200 patients will be randomized. Of those, it is planned that approximately 
30 to 40 patients will be recruited in China. This is being done to ensure adequate Chinese 
patient participation to satisfy China Regulatory Authority requirements. The China cohort 
will support standalone safety and efficacy analyses of patients from China.

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9.3
Populations for analyses
9.3.1
Full Analysis Set
The FAS will include all randomized patients (see Section 9.6). The FAS will be used for all 
efficacy analyses and treatment groups will be compared on the basis of randomized study 
treatment, regardless of the treatment actually received. This is also known as the Intent to 
Treat (ITT) analysis set. 
9.3.2
Safety Analysis Set
The safety analysis set (SAF) will consist of all randomized patients who received at least one 
dose of study treatment (see Section 9.6). Safety data will not be formally analyzed but 
summarized using the SAF, according to the treatment received; i.e., erroneously treated 
patients (e.g., those randomized to treatment A but actually given treatment B) will be 
summarized according to the treatment they actually received.
9.3.3
Pharmacokinetic Analysis Set
PK Analysis Set is defined as patients in the SAF who have at least one measurable PK 
concentration, supported by the relevant date and time of this sample; and for each time a PK 
sample was taken, the dosing data for that day; and for samples taken after multiple dosing, 
the dosing data for 7 continuous days of osimertinib dosing prior to the sample day as well as 
the sample day. For any individual sample to be included in the PK analysis set, the full 
sample data and dosing data need to be present for that sample.
The Pharmacokineticist will agree to the strategy for dealing with data affected by protocol 
deviations before any formal statistical analysis is performed. Important protocol deviations 
include changes to the procedures that may impact the quality of the data or any circumstances 
that can alter the evaluation of the PK. Examples include, but not limited to, vomiting 
following oral dosing occurring within the timeframe of 2 times the median time to reach 
maximum concentration (tmax); sample processing errors that lead to inaccurate bioanalytical 
results; incomplete dose administered; incomplete PK profile collected; and/or use of 
disallowed concomitant medication. In the case of an important protocol deviation or event, 
affected PK data collected will be excluded from the summaries and statistical analyses, but 
will still be reported in the study result listings. Important deviations will be listed and 
summarized in the CSR.
9.3.4
Evaluable for Response Analysis Set
The evaluable for response analysis set will be all patients in the FAS who have measurable 
disease at baseline according to the BICR of baseline imaging data.
The primary analysis of PFS, and other RECIST-based outcomes by independent central 
review in the FAS population will be repeated using the evaluable for response analysis set as 

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sensitivity analyses. 
9.4
Statistical analyses
Analyses will be performed by AstraZeneca or its representatives. A comprehensive statistical 
analysis plan (SAP) will be developed and finalized before database lock and will describe the 
subject populations to be included in the analyses, and procedures for accounting for missing,
unused, and spurious data.  This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints.  Any deviations from this plan will be reported in the CSR.
9.4.1
Efficacy analyses
All efficacy analyses will be performed on the FAS population. Results of all statistical 
analyses will be presented using a 95% CI and 2-sided p-value. 
9.4.1.1
Analysis of the primary variable
9.4.1.1.1
Primary analysis of PFS
PFS (per RECIST 1.1 as assessed by BICR) is defined as the time from randomization until 
the date of objective disease progression or death (by any cause in the absence of progression) 
regardless of whether the patient withdraws from randomized therapy or receives another 
anti-cancer therapy prior to progression. PFS per BICR for patients in the FAS will be 
analyzed using a log rank test stratified by chemoradiation strategy (CCRT vs SCRT), disease 
stage prior to chemoradiation (IIIA vs IIIB/IIIC), and China cohort (enrolled at a Chinese site 
and patient declaring themselves of Chinese ethnicity vs enrolled at Non-Chinese site or 
patient declaring themselves of non-Chinese ethnicity) for generation of the p-value and using 
the Breslow approach for handling ties. The HR and CI will be obtained directly from the U 
and V statistics as follows (Berry et al 1991; Robins et al 1991; Robins 1993; Selke and 
Siegmund 1983):
Where 
is the stratified log-rank test statistic (with d1ki and e1ki, the 
observed and expected events in group 1, stratum k) and 
is the standard deviation 
of the log-rank test statistic obtained from the LIFETEST procedure with a STRATA term for 
the stratification variable.
If the resulting number of events per stratum is too small, the strata will be collapsed. Further 
details are provided in the SAP. A KM plot and summaries of PFS will be presented by 

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treatment group.
The assumption of proportionality will be assessed. In the event of non-proportionality, the 
HR will be interpreted as an average HR over the observed extent of follow-up. 
Proportionality will be tested firstly by examining the plots of complementary log-log (event 
times) vs log (time) and, if necessary, a time dependent covariate will be fitted to assess the 
extent to which this represents random variation.  
9.4.1.1.2
Sensitivity analyses
(a) Quantitative Interactions
The presence of quantitative interactions will be assessed by means of an overall global 
interaction test. This will be performed in the overall population by comparing the fit of a Cox 
proportional hazards model including treatment, all covariates, and all covariate-by-treatment 
interaction terms, with one that excludes the interaction terms and will be assessed at the 
2-sided 10% significance level. If the fit of the model is not significantly improved, then it 
will be concluded that overall, the treatment effect is consistent across the subgroups. If the 
global interaction test is found to be statistically significant, an attempt to determine the cause 
and type of interaction will be made. Stepwise backwards selection will be performed on the 
saturated model, whereby (using a 10% level throughout) the least significant interaction 
terms are removed one-by-one and any newly significant interactions re-included until a final 
model is reached where all included interactions are significant and all excluded interactions 
are non-significant. Throughout this process, all main effects will be included in the model 
regardless of whether the corresponding interaction term is still present. This approach will 
identify the factors that independently alter the treatment effect and prevent identification of 
multiple correlated interactions.
Any quantitative interactions identified using this procedure will then be tested to rule out any 
qualitative interaction using the approach of Gail and Simon (Gail & Simon 1985).
(b) Ascertainment bias
The possibility of bias in assessment and measurement of PFS by BICR will be assessed using 
the Investigator assessment of disease progression by RECIST. The HR from BICR 
assessment and Investigator assessment of PFS will be assessed. Further details will be 
provided in the SAP.
(c) Evaluation-time bias
In order to assess possible evaluation-time bias that could occur if scans are not performed at 
the protocol-scheduled time points, the midpoint between the time of progression and the 
previous evaluable RECIST assessment will be analyzed using a log rank test stratified 

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chemoradiation (concurrent vs sequential),  disease  stage prior to chemoradiation (IIIA vs 
IIIB/IIIC) and China cohort (enrolled at a Chinese site and patient declaring themselves of 
Chinese ethnicity vs enrolled at Non-Chinese site or patient declaring themselves of non-
Chinese ethnicity), as described for the primary analysis of PFS.
(d) Attrition bias
Possible attrition bias will be assessed by repeating the primary PFS analysis, except that the 
actual PFS event times rather than the censored times of patients who progressed or died in 
the absence of progression immediately following 2 or more non-evaluable tumor 
assessments, will be included. In addition, patients who take subsequent therapy prior to 
progression or death will be censored at their last evaluable assessment prior to taking the 
subsequent therapy. A KM plot of the time to censoring, where the censoring indicator of the 
primary PFS analysis is reversed, will be presented.
9.4.1.1.3
Subgroup analyses
In addition to the analysis of PFS described above, the following subgroup analyses will be 
conducted by comparing PFS between treatments (i.e., using a Cox-Proportional Hazards 
Model) in the following groups:
!
Chemoradiation (concurrent vs sequential)
!
Disease stage prior to chemoradiation (IIIA vs IIIB/IIIC) 
!
Patients enrolled at a Chinese site and declaring themselves of Chinese ethnicity vs 
patients enrolled at non-Chinese site or patients declaring themselves of non-Chinese 
ethnicity 
!
Central plasma ctDNA EGFR (Ex19del and L858R) mutation status at screening (positive 
vs negative vs unknown)
!
Tissue EGFR mutation at screening (Ex19del vs L858R)
!
Race (Asian vs Non-Asian)
The results of these analyses will be presented in terms of a HR together with its associated 
95% CI separately for each subgroup in the comparison. Further details will be outlined in the 
SAP.
9.4.1.2
Analysis of secondary variables
9.4.1.2.1
Hierarchical testing of key secondary variables
The secondary endpoints of OS and CNS PFS in the overall population will be tested after the 

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primary PFS analysis in a hierarchical procedure at the time of the PFS analysis, following the 
primary analysis (see Section 9.1).
9.4.1.2.2
Analysis of overall survival
OS is defined as the time from the date of randomization until death due to any cause. Any 
patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the subject was known to be alive.
The analysis of OS will be conducted at 2 time points: At the time of the primary analysis of 
PFS; and At approximately 60% maturity (when approximately 120 death events across both 
arms have occurred). OS data will be analyzed using the same methodology and model as for 
the analysis of PFS provided there are sufficient events (≥ 20 deaths across both treatment 
groups with at least 5 events per arm) available for a meaningful analysis otherwise 
descriptive summaries will be provided.
9.4.1.2.3
Analysis of Objective Response Rate
ORR is defined as the percentage of patients with at least one BICR-assessed visit response of 
CR or PR. ORR by BICR will be analyzed using a logistic regression stratified by 
chemoradiation (concurrent vs sequential), disease stage prior to chemoradiation (IIIA vs 
IIIB/IIIC) and China cohort (enrolled at a Chinese site and patient declaring themselves of 
Chinese ethnicity vs enrolled at Non-Chinese site or patient declaring themselves of non-
Chinese ethnicity). The results of the analysis will be presented in terms of an OR together 
with its associated 95% profile likelihood CI and 2-sided p-value.
9.4.1.2.4
Analysis of Duration of Response
DoR will be defined as the time from the date of first documented response until date of 
documented progression or death in the absence of disease progression. The expected DoR 
(EDoR) is the product of the proportion of patients responding to treatment and the mean DoR 
in responding patients, and provides an estimate based on all randomized patients. Treatments 
will be compared by calculating the ratio of EDoRs using an appropriate probability 
distribution for DoR in responding patients. The choice of probability distribution will be 
detailed in the SAP. The analysis of DoR will be stratified by the same stratifiers as the 
primary analysis, weighting each stratum inversely proportional to the within stratum variance 
of the log of the ratio of EDoRs. Additionally, descriptive data will be provided for the DoR in 
responding patients, including associated KM curves (without any formal comparison or p-
value attached).
9.4.1.2.5
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.

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DCR, by BICR, will be analyzed using a logistic regression. The results of the analysis will be 
presented in terms of an OR together with its associated 95% profile likelihood CI and 2-sided 
p-value.
DCR [DCR: CR + PR + SD] and OS.
9.4.1.2.6
Analysis of tumor shrinkage
Depth of response (i.e., tumor shrinkage / change in tumor size) by BICR will be examined by 
summarizing the absolute change in TL tumor size from baseline, and percentage change in 
TL tumor size from baseline using descriptive statistics and presented at each time point and 
by randomized treatment group. The effect of osimertinib on best percentage change in tumor 
size will be estimated from an analysis of covariance (ANCOVA) model. The number of 
patients, unadjusted mean, and least squares means for each treatment group will be presented, 
together with the difference in least squares means, 95% CI and corresponding p-value.
9.4.1.2.7
Analysis of time to death or distant metastases
Distant metastases free survival, by BICR, for patients in the FAS will be analyzed using a log 
rank test stratified by chemoradiation (concurrent vs sequential), disease stage prior to 
chemoradiation (IIIA vs IIIB/IIIC) and China cohort (enrolled at a Chinese site and patient 
declaring themselves of Chinese ethnicity vs enrolled at Non-Chinese site or patient declaring 
themselves of non-Chinese ethnicity) for generation of the p-value and using the Breslow 
approach for handling ties. The HR and CI will be obtained as for progression free survival.
TTDM will be defined as the time from the date of randomization until the first date of distant 
metastasis or date of death in the absence of distant metastasis. Distant metastasis is defined as 
any new lesion that is outside of the radiation field according to RECIST 1.1 or proven by 
biopsy. Patients who have not developed distant metastasis or died at the time of analysis will 
be censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 
assessment. 
However, if the patient has distant metastasis or dies after 2 or more missed visits, the patient 
will be censored at the time of the latest evaluable RECIST 1.1 assessment prior to the 2 
missed visits. If the patient has no evaluable visits or does not have baseline data, he/she will 
be censored at Day 1 (date of randomization) unless they die within 2 visits of baseline.
9.4.1.2.8
Analysis of time to CNS PFS
Time to CNS PFS, is the time to the earlier event of CNS progression or death using BICR 
assessments, according to RECIST v1.1. Patients in the FAS will be analyzed using a log rank 
test stratified by chemoradiation (concurrent vs sequential), disease stage prior to 
chemoradiation (IIIA vs IIIB/IIIC) and China cohort (enrolled at a Chinese site and patient 

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declaring themselves of Chinese ethnicity vs enrolled at Non-Chinese site or patient declaring 
themselves of non-Chinese ethnicity) for generation of the p-value and using the Breslow 
approach for handling ties. The HR and CI will be obtained as for progression free survival.
Cumulative incidence of brain metastases, by BICR, will be summarized using appropriate 
summary statistics, and further details will be provided in the SAP. Cumulative incidence rate 
of CNS PFS by BICR at 12 and 24 months will be presented. 
9.4.1.2.9
Time to study treatment discontinuation 
Time to study treatment discontinuation or death (TTD), for patients in the FAS will be 
analyzed using a log rank test stratified by chemoradiation (concurrent vs sequential), disease 
stage prior to chemoradiation (IIIA vs IIIB/IIIC) and China cohort (enrolled at a Chinese site 
and patient declaring themselves of Chinese ethnicity vs enrolled at Non-Chinese site or 
patient declaring themselves of non-Chinese ethnicity) for generation of the p-value and using 
the Breslow approach for handling ties. The HR and CI will be obtained as for progression 
free survival.
TTD is defined as the time from randomization to the earlier of the date of study treatment 
discontinuation (regardless of the reason for study treatment discontinuation) or death (i.e. 
date of study treatment discontinuation/death or censoring – date of randomization + 1). Any 
patient not known to have died at the time of analysis and not known to have discontinued 
study treatment will be censored based on the last recorded date on which the patient was 
known to be alive. Patients who have not been treated will be censored at the date of 
randomization.
9.4.1.2.10 Analysis of post progression outcomes
PFS2, time to first subsequent therapy (TFST) and time to second subsequent therapy (TSST) 
patients in the FAS will be analyzed using a log rank test stratified by chemoradiation 
(concurrent vs. sequential), disease stage prior to chemoradiation (IIIA vs IIIB/IIIC) and 
China Cohort (enrolled at a Chinese site and patient declaring themselves of Chinese ethnicity 
vs enrolled at Non-Chinese site or patient declaring themselves of non-Chinese ethnicity) for 
generation of the p-value and using the Breslow approach for handling ties. The HR and CI 
will be obtained as for progression free survival. 
For details of PFS2 refer to section 8.1.2.2. Analysis of PFS2 will only take place at the time 
of the primary PFS analysis. Patients alive and for whom a second disease progression has not 
been observed should be censored at the last time known to be alive and without a second 
disease progression; i.e., censored at the last progression assessment date if the patient has not 
had a second progression or death.
TFST or death is defined as the time from the date of randomization to the earlier of start date 

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of the first subsequent anti-cancer therapy following discontinuation of randomized treatment, 
or death.  Any patient not known to have had a subsequent therapy or not known to have died 
at the time of the analysis will be censored at the last known time to have not received 
subsequent therapy; i.e., the last follow-up visit where this was confirmed.
TSST or death is defined as the time from the date of randomization to the earlier of the start 
date of the second subsequent anti-cancer therapy following discontinuation of randomized 
treatment, or death.  Any patient not known to have died at the time of the analysis and not 
known to have had a second subsequent therapy will be censored at the last known time to 
have not received second subsequent therapy, i.e., the last follow-up visit where this was 
confirmed.
9.4.1.2.11 Analysis of EORTC QLQ-C30 and QLQ-LC13
Symptoms and overall QoL will be assessed using EORTC QLQ-C30 and QLQ-LC13 
(secondary endpoints). Questionnaires will be scored according to published guidelines or the 
developer’s guidelines, if published guidelines are not available. All PRO analyses will be 
based on the FAS, and will only take place at the time of the primary PFS analysis. Further 
details of the statistical analyses including details of Mixed effect Models for Repeated 
Measures (MMRM) modelling will be given in the SAP.
The EORTC QLQ-C30 consists of 30 questions that can be combined to produce 5 functional 
scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and 
nausea/vomiting), 5 individual items (dyspnea, insomnia, appetite loss, constipation, and 
diarrhea), and a global measure of health status. The QLQ-LC13 is a lung cancer-specific 
module from the EORTC for lung cancer comprising 13 questions to assess lung cancer 
symptoms (cough, hemoptysis, dyspnea, and site-specific pain), treatment-related symptoms 
(sore mouth, dysphagia, peripheral neuropathy, and alopecia), and pain medication. With the 
exception of a multi-item scale for dyspnea, all are single items. The dyspnea scale will only 
be used if all 3 items have been scored; otherwise, the items are treated as single-item 
measures.
An outcome variable consisting of a score from 0 to 100 will be derived for each of the 
symptom scales/symptom items, the functional scales and the global health status/QoL scale 
according to the EORTC QLQ-C30 Scoring Manual (EORTC QLQ-C30 Scoring Manual, 
Third Edition) and EORTC QLQ-LC13 instructions.
Higher scores on the global health status/QoL and functioning scales indicate better health 
status/function, but higher scores on symptom scales/items represent greater symptom 
severity. Changes in score compared with baseline will be evaluated. For each subscale, if 
<50% of the subscale items are missing, then the subscale score will be divided by the number 
of non-missing items and multiplied by the total number of items on the subscales. If at least 

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50% of the items are missing, then that subscale will be treated as missing. Missing single 
items are treated as missing. The reason for any missing questionnaire will be identified and 
recorded. If there is evidence that the missing data are systematic, missing values will be 
handled to ensure that any possible bias is minimized.
Definition of compliance and evaluability rates
Compliance rates for the PRO questionnaires should be at least 85%; this rate will be 
monitored as the trial goes on. Compliance with the EORTC QLQ-C30 and EORTC 
QLQ-LC13 will be calculated, separately for each questionnaire:
Compliance rate = number of evaluable forms
number of expected forms × 100
Evaluability rates for the EORTC QLQ-C30 and EORTC QLQ-LC13 will also be calculated, 
separately for each questionnaire:
Evaluability rate = number of evaluable forms
number of received forms × 100
An expected form = a questionnaire that is expected to be completed at a scheduled 
assessment time, i.e., a questionnaire from a patient who has not withdrawn from the study at 
the scheduled assessment time but excluding patients in countries with no available 
translation. 
An evaluable form = a questionnaire with a completion date and at least one subscale that is 
non-missing. 
A received form = a questionnaire that has been received and has a completion date and at 
least one individual item completed.
Definition of clinically meaningful changes
Changes in score compared to baseline will be evaluated. A minimum clinically relevant 
change is defined as a change in the score from baseline of ≥10 for scales/items from the 
QLQ-C30 and the QLQ-LC13 (Osoba et al 1998). For example, a clinically relevant 
deterioration or worsening in chest pain (as assessed by QLQ-LC13) is defined as an increase 
in the score from baseline (defined as Day 1, pre-dose) of ≥10. A clinically relevant 
improvement in fatigue (as assessed by QLQ-C30) is defined as a decrease in the score from 
baseline of ≥10. At each post-baseline assessment, change in symptoms/functioning from 
baseline will be categorized as improved, stable, or worsening as shown in Table 11. Patients 
with no baseline data will be excluded from analyses. 

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Table 11
Visit responses for symptoms and HRQoL
Score Change from baseline 
Visit response
Score Change from baseline 
Visit response
Score Change from baseline 
Visit response
QLQ-C30/QLQ-LC13 symptom 
scales/items
≥+10
≤-10
Otherwise
Worsened
Improved
Stable
QLQ-C30 functional scales and 
global health status/QoL
≥+10
≤-10
Otherwise
Improved
Worsened
Stable
HRQoL=Health-related quality of life; QLQ C30 30-Item core quality-of-life questionnaire; QLQ-LC13 13-Item lung 
cancer quality-of-life questionnaire.
Time to symptom and HRQoL/function deterioration (QLQ-C30 and QLQ-LC13)
Time to deterioration in symptoms, functioning and global health status/QoL will be 
evaluated, more details will be specified in the SAP.
Improvement in symptom and HRQoL (QLQ-C30 and QLQ-LC13)
Improvement in symptoms, functioning and global health status/QoL will be evaluated, more 
details will be specified in the SAP. 
9.4.1.2.12 Safety
Safety data will be summarized using appropriate summary statistics and further details will 
be provided in the SAP. The safety endpoints are:
!
AEs (graded by CTCAE v5, including AESIs);
!
Clinical chemistry, hematology and urinalysis;
!
Vital signs (pulse and blood pressure), physical examination, weight;
!
ECG parameters;
!
LVEF by ECHO/MUGA scan;
!
WHO Performance Status.
9.4.1.2.13 Pharmacokinetics
PK data from this study will be analyzed using a population PK approach and may also form 
part of a pooled analysis with other osimertinib studies; results from these analyses may also 
be reported separately from the CSR. Pharmacokinetic concentration data will be summarized 
using appropriate summary statistics, and further details will be provided in the SAP.

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9.4.1.3
Exploratory analysis
9.4.1.3.1
Relationship between PK and other variables
Correlation of PK with other primary, secondary or exploratory endpoints in patients treated 
with osimertinib.  Results from such analyses may be reported separately from the CSR, if 
warranted.
Data from this study may also form part of a pooled analysis with other osimertinib studies.
9.4.1.3.2
Patient Reported Outcome version of the Common Terminology Criteria for 
Adverse Event System 
PRO version of the CTCAE data will be presented using summaries and descriptive statistics 
and further details will be provided in the SAP.
9.4.1.3.3
Patients Global Impression of Severity 
PGIS data will be presented using summaries and descriptive statistics. Further details will be 
provided in the SAP.
9.4.1.3.4
EQ-5D-5L health state utility index
EQ-5D-5L health state utility index data will be presented using summaries and descriptive 
statistics. Further details will be provided in the SAP.
9.4.1.3.5
Healthcare Resource Use Module
HRU data will be presented using summaries and descriptive statistics, based on the FAS and 
further details will be provided in the SAP.
9.4.1.3.6
Comparison of baseline tumor EGFR mutation status
Baseline tumor EGFR mutation status will be compared between tumor DNA and plasma 
ctDNA using the Kappa coefficient. Analysis will be carried out separately for each 
sensitizing mutation, Ex19del and L858R. Analysis will be in all Part II screened patients 
with evaluable results from baseline plasma samples.
Baseline tumor EGFR mutation status will also be compared between local and central 
(cobas® EGFR mutation test v2) tests, using the Kappa coefficient, in subjects with evaluable 
results from baseline tumor samples. Analysis will be carried out separately for each 
sensitizing mutation, Ex19del and L858R, and as well as in aggregate.
9.4.2
Methods for multiplicity control
The multiple testing procedure will define which significance levels should be applied to the 
interpretation of the raw p-values for the primary endpoint of PFS and key secondary 
endpoints, OS and CNS PFS. The family-wise error rate is strongly controlled at 

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5% (two sided) for these endpoints. 
The testing procedure is sequential in that it starts with testing the primary endpoint of PFS. If 
the PFS analysis is significant at the primary analysis, then 5% alpha will be recycled to the 
OS endpoint and then CNS PFS endpoint.  
To provide strong control of the type I error rate, α=0.05 (two-sided), the primary endpoint of 
PFS, and endpoints of OS and CNS PFS, will be tested in this sequential order. If any previous 
analysis in the sequence is not statistically significant, the alpha will not be transferred to 
subsequent analyses.
The analyses of PFS, OS, and CNS PFS endpoints will occur at the time of the primary 
analysis of PFS. If the OS analysis is statistically significant at the time of the PFS analysis or 
the final OS analysis, then the significance testing of CNS PFS will be performed at the full 
α=0.05 significance level (two-sided). If the OS analysis is not statistically significant at the 
time of the PFS analysis or the final OS analysis then the significance testing of CNS PFS will 
be not be performed. 
Since two analyses of OS are planned, the Lan DeMets approach that approximates the 
O’Brien and Fleming spending function will be used to maintain an overall 2-sided 5% type I 
error across the two planned analyses of OS.
The significance level for the OS analyses will be calculated using the statistical software 
package EAST by specifying the information fraction for each analysis. The information 
fraction is calculated as the number of OS events at the analysis time-point divided by the 
total number of events at the final analysis time-point. For example, assuming a median OS on 
the placebo arm of 40 months and a median OS of 50 months on the osimertinib arm, 48 OS 
events were observed at the interim analysis, the information fraction would be 0.40 (48/120 
events) for the interim analysis and 1.00 for the final analysis. This would result in a 
significance level for the interim analysis of 0.0008 (2-sided) and a significance level for the 
final analysis of 0.0497 (2-sided).
The information fraction is calculated as the number of events at the analysis time-point 
divided by the total number of events at the final analysis time-point.
Any non-statistically significant OS analyses at the time of the primary analysis of PFS will 
not preclude further testing of OS.
9.5
Interim analyses 
The SAP will describe the planned interim analyses in greater detail.

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9.5.1
Independent data monitoring committee 
An IDMC will be convened, and will meet to review unblinded safety data, initially 
approximately 6 months after the study has started, as long as a minimum of 20 patients have 
been randomized and treated for >1 month. Three subsequent meetings will take place every 6 
months and then meetings will be held yearly thereafter until completion of the primary 
analysis. Further meetings for review of safety data from all patients may be convened at the 
discretion of the IDMC. Following each meeting the IDMC will evaluate whether the trial 
should continue without change, be modified or stopped due to potential harm to patients. 
Full details of the IDMC procedures and processes can be found in the IDMC Charter.
9.6
China Cohort
Approximately 200 patients will be randomized. Of those, it is planned that approximately 
30 to 40 patients will be recruited in China. This is being done to ensure adequate Chinese 
patient participation to satisfy China Regulatory Authority requirements. The China cohort 
will support standalone safety and efficacy analyses of patients from China.
The China cohort consists of all Chinese patients from Chinese sites accredited by Chinese 
regulation. 
Hence a patient randomized in the China cohort will be included in the China FAS.
The analysis of PFS in the China cohort will be conducted at the same time as the analysis of 
PFS for the overall population.  
The final OS analysis in the China cohort will be conducted at the same time as the final OS 
analysis for the overall population. 
Per China Regulatory Authority guidance, in addition to the evaluation of global cohort data 
for primary, secondary and safety objectives, evaluation of consistency in efficacy and safety 
in China and Asia population is required to facilitate the benefit-risk assessment for Chinese 
patients. Hence, the safety and efficacy data in China cohort will be analyzed separately where 
the same endpoint definitions and the same analysis methods (as detailed in Section 9.4) are 
applied.
The China FAS (China FAS) will include all patients randomized in China sites and claimed 
themselves as ethnicity Chinese, China FAS will be used for all China only efficacy analyses.
The China SAF is defined as patients in the China FAS and who received at least 1 dose of 
study treatment and for whom post-dose data are available. 
The China Pharmacokinetic Analysis Set is defined as patients in the China FAS who have 

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at least one evaluable PK concentration.
All statistical analyses will be considered exploratory and only performed if sufficient 
numbers of events or patients are available, otherwise descriptive statistics only will be 
presented. No adjustment for multiplicity will be made and so the procedure for hierarchical 
testing detailed in Section 9.4 will not be followed. PFS efficacy evaluation for China cohort 
will be performed only once.
Details of China cohort analysis, including vendor to perform the analysis, will be specified in 
China supplementary SAP, which is to be finalized before global cohort data lock for analysis.

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10
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11
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 (CIOMS) International Ethical Guidelines
!
Applicable International Council for Harmonisation (ICH) GCP Guidelines
!
Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, 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 approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients.  
AstraZeneca will be responsible for obtaining the required authorizations to conduct the study 
from the concerned Regulatory Authority. This responsibility may be delegated to a CRO but 
the accountability remains with AstraZeneca.
The investigator will be responsible for providing oversight of the conduct of the study at the 
site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
Regulation 536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local regulations.
Regulatory Reporting Requirements for SAEs 
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, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators. 
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.

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!
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations 
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 and will notify the 
IRB/IEC, if appropriate according to local requirements. 
Regulatory Reporting Requirements for Serious Breaches 
Prompt notification by the investigator to the sponsor of any (potential) serious breach of the 
protocol or regulations is essential so that legal and ethical obligations are met.
!
A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a subject or the reliability and robustness of the data generated in the 
clinical trial.
If any (potential) serious breach occurs in the course of the study, investigators or other site 
personnel will inform the appropriate AstraZeneca representatives immediately after he or she 
becomes aware of it.
In certain regions/countries, the sponsor has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches.
!
The sponsor will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. If EU Clinical 
Trials Regulation 536/2014 applies, the sponsor is required to enter details of 
serious breaches into the European Medicines Agency (EMA) Clinical Trial 
Information System (CTIS). It is important to note that redacted versions of serious 
breach reports will be available to the public via CTIS.
The investigator should have a process in place to ensure that:
!
the site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach
!
a (potential) serious breach is promptly reported to the sponsor or delegated party, 
through the contacts (e-mail address or telephone number) provided by the sponsor
A 2
Financial disclosure
Investigators and sub-investigators will provide AstraZeneca 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.  

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Investigators are 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 patient or 
his/her legally authorized representative and answer all questions regarding the study.  
Patients must be informed that their participation is voluntary.  Patients or their legally 
authorized representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center.  
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date and time the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the ICF.
Patients 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 patient or the patient’s legally authorized 
representative.  
If a patient declines to participate in any voluntary exploratory genetic research component of 
the study, there will be no penalty or loss of benefit to the patient and he/she will not be 
excluded from other aspects of the study.
If a patients partner becomes pregnant, the partner is asked to sign the "Adult Study Informed 
Consent Form for Pregnant Partners of Study Patients" and provide information about the 
pregnancy accordingly. Patients who are rescreened are required to sign a new ICF. Any 
intention and embarkation of re-screening should be well communicated with AstraZeneca 
study team and reflected the reason in the medical records. Both the previous signed ICF and 
re-screened ICF should be retained in original copy at study site. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research.  The investigator or authorized designee will 
explain to each patient the objectives of the exploratory research and potential diagnostic 
development.  Patients will be told that they are free to refuse to participate and may withdraw 
their consent at any time and for any reason during the storage period.  The patient will give a 
separate agreement to allow any remaining specimens to be used for exploratory research.  
Patients who decline to participate in this optional research will indicate this in the ICF.  If a 
patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples already have been analyzed at 
the time of the request, AstraZeneca will not be obliged to destroy the results of this research.

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A 4
Data protection
Patients will be assigned a unique identifier by AstraZeneca. Any patient records or data sets 
transferred to the AstraZeneca will contain the identifier only; patient names or any 
information which would make the patient identifiable will not be transferred.  
The patient must be informed that his/her personal study-related data will be used by 
AstraZeneca in accordance with local data protection law. The level of disclosure and use of 
their data must also be explained to the patient in the informed consent.  
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the AstraZeneca, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
The patient must be informed that data will be collected only for the business needs. We will 
only collect and use the minimum amount of personal data to support our business activities 
and will not make personal data available to anyone (including internal staff) who is not 
authorized or does not have a business need to know the information.
The patient must be informed that in some cases their data may be pseudonymized. The 
General Data Protection Regulation (GDPR) defines pseudonymization as the processing of 
personal data in such a way that the personal data can no longer be attributed to a specific 
individual without the use of additional information, provided that such additional information 
is kept separately and protected by technical and organizational measures to ensure that the 
personal data are not attributed to an identified or identifiable natural person.
Personal Data Breaches
A ‘personal data breach’ means a breach of security leading to the accidental or unlawful 
destruction, loss, alteration, unauthorized disclosure of, or access to, personal data transmitted, 
stored or otherwise processed.
!
In compliance with applicable laws, the Data Controller1 for the processing activity 
where the personal data breach occurred (AstraZeneca or respectively the site), will 
notify the data protection authorities without undue delay within the legal terms 
provided for such notification and within the prescribed form and content.
!
Whilst AstraZeneca has processes in place to deal with personal data breaches it is 
important that investigators that work with AstraZeneca have controls in place to 
protect patient data privacy.
The Investigator should have a process in place to ensure that:
                                               
1 The data controller determines the purposes for which and the means by which personal data is processed, as 
defined by the European Commission

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!
allow site staff or service providers delegated by the investigator/institution to 
identify the occurrence of a (potential) personal data breaches.
!
any (potential) personal data breach is promptly reported to AstraZeneca or 
delegated party, through the contacts (e-mail address or telephone number) 
provided by AstraZeneca.
AstraZeneca and the site must demonstrate that they:
!
have taken all necessary steps to avoid personal data breaches and
!
have undertaken measures to prevent such breaches from occurring in the first place 
and to mitigate the impact of occurred data breaches (e.g., applying encryption, 
maintaining and keeping systems and IT security measures up-to-date, regular 
reviews and testing, regular training of employees, and developed security policies 
and standards).
!
where possible, have developed an internal data breach reporting and investigation 
process and internal protocols with guidance on how to respond swiftly and 
diligently to the occurrence of a personal data breach.
!
where it has not been possible to develop an internal data breach reporting and 
investigation process, the site follows AstraZeneca’s instructions.
Notification of personal Data Breach to patients:
!
notification to patients is done by the site for the data breaches that occurred within 
the processing activities for which the site is the Data Controller and for data 
breaches occurred within the processing activities of AstraZeneca as the Data 
Controller, the notification is done in collaboration with the site and is performed by 
the site and/or Principal Investigator, acting on behalf of AstraZeneca, so that 
AstraZeneca has no access to the identifying personal information of the patients. 
The site and/or Principal Investigator shall conduct the notification by contacting 
the patients using the information that they gave for communication purposes in
clinical research.
!
If a personal data breach occurs in a processor’s systems, engaged by AstraZeneca, 
the processor under contractual obligations with AstraZeneca promptly and in due 
course after discovering the breach notifies AstraZeneca and provides full 
cooperation with the investigation. In these cases, to the extent AstraZeneca is the 
Data Controller for the processing activity where the breach occurred, it will be 
responsible for the notification to data protection authorities and, if applicable, to
patients. If the personal data breach needs to be notified to the patients, the 
notification to patients is done in collaboration with the site and is performed by the 
site and/or Principal Investigator, acting on behalf of the Sponsor, so that 
AstraZeneca has no access to the identifying personal information of the patients.

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!
If a personal data breach involving an AstraZeneca's representative device (i.e., 
Study Monitor laptop), AstraZeneca representative will provide AstraZeneca with 
all of the information needed for notification of the breach, without disclosing data 
that allows AstraZeneca directly or indirectly to identify the patients. The 
notification will be done by AstraZeneca solely with the information provided by 
the Study Monitor and in no event with access to information that could entail a risk 
of re-identification of the patients. If the data breach must be notified to the data 
subjects, the notification will be done directly by the Study Monitor in collaboration 
with the site and/or Principal Investigator, acting on behalf of the Sponsor, so that 
AstraZeneca has no access to the identifying personal information of the patients. 
The contract between AstraZeneca and the Study Monitor shall expressly specify 
these conditions.
!
The contract between the site and AstraZeneca for performing the clinical research 
includes the provisions and rules regarding who is responsible for coordinating and 
directing the actions in relation to the breaches and performing the mandatory 
notifications to authorities and patients, where applicable
A 5
Committees structure
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
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS 
within a year from global End of Trial Date in all participating countries, due to scientific 
reasons as otherwise statistical analysis is not relevant.
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com, 
http://www.clinicaltrials.gov, and https://euclinicaltrials.eu/ as will the summary of the study 
results when they are available. The clinical trial 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 patient data relating to the study will be recorded on printed or electronic 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 CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  

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The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
Monitoring details describing strategy, including definition of study-critical data items and 
processes (e.g., 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 included in the Monitoring Plan(s). 
The sponsor or designee is responsible for medical oversight throughout the conduct of the 
study which includes clinical reviews of study data in accordance with the currently approved 
protocol. Monitoring details describing clinical reviews of study data from a medical 
perspective are included in more detail in the Medical Oversight Plan.
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.
AstraZeneca assumes accountability for actions delegated to other individuals (e.g., CROs).
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients 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 a minimum of 25 years after study archiving, or as required 
by the local regulations, according to the AstraZeneca Global Retention and Disposal (GRAD) 
Schedule.  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. 
A 8
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator’s site.
Data reported on the CRF 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
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 
multicenter studies only in their entirety and not as individual site data.  In this case, a 
coordinating 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 event definitions and additional safety information
B 1
Definition of adverse events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
patient (other than progression of the malignancy under evaluation) administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavorable and unintended sign (e.g.  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 medicinal product.  
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 treatment has been administered.
B 2
Definitions of serious adverse event
A SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout, follow-
up), that fulfills one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-patient hospitalization or prolongation of existing hospitalization 
!
Results in persistent or significant disability or incapacity.  
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardize the patient or may require 
medical treatment to prevent one of the outcomes listed above.
B 3
Life threatening
‘Life-threatening’ means that the patient 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 patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (e.g., hepatitis that resolved without hepatic failure).
B 4
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal edema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.

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B 5
Important medical event or medical treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the patient 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 
judgement must be used.
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (e.g., neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization
!
Development of drug dependency or drug abuse
B 6
Intensity rating scale: CTCAE
The grading scales found in the revised NCI CTCAE latest version will be utilized 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.
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 7
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

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!
Time Course.  Exposure to suspect drug.  Has the patient actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?
!
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
!
De-challenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?
!
No alternative cause.  The AE cannot be reasonably explained by another etiology 
such as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience.  Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped? AstraZeneca would not normally 
recommend or support a re-challenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 8            Medication Error, Drug Abuse, and Drug Misuse
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant.  

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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 recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Drug name confusion
!
Dispensing error e.g., medication prepared incorrectly, even if it was not actually 
given to the participant
!
Drug not administered as indicated, e.g., wrong route or wrong site of 
administration
!
Drug not taken as indicated e.g., tablet dissolved in water when it should be taken as
a solid tablet 
!
Drug not stored as instructed e.g., kept in the fridge when it should be at room 
temperature 
!
Wrong participant received the medication (excluding IVRS/IWRS errors)
!
Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IVRS/IWRS - including those which lead to one 
of the above listed events that would otherwise have been a medication error 
!
Participant accidentally missed drug dose(s) e.g.  forgot to take medication
!
Accidental overdose (will be captured as an overdose)
!
Participant failed to return unused medication or empty packaging
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 

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non-therapeutic excessive use of IMP/study intervention or AstraZeneca NIMP for a perceived 
reward or desired non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Abuse Report Form. This form should be used both if the drug abuse 
happened in a study participant or if the drug abuse regards a person not enrolled in the study 
(such as a relative of the study participant).
Examples of drug abuse include but are not limited to:
!
The drug is used with the intent of getting a perceived reward (by the study 
participant or a person not enrolled in the study)
!
The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high.
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP/study 
intervention or AstraZeneca NIMP for medicinal purposes outside of the authorized product 
information, or for unauthorized IMPs/study interventions or AstraZeneca NIMPs, outside the 
intended use as specified in the protocol, and includes deliberate administration of the product 
by the wrong route.
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a study participant or if the drug misuse regards a person not enrolled in 
the study (such as a relative of the study participant).
Examples of drug misuse include but are not limited to:
!
The drug is used with the intention to cause an effect in another person
!
The drug is sold to other people for recreational purposes 
!
The drug is used to facilitate assault in another person
!
The drug is deliberately administered by the wrong route
!
The drug is split in half because it is easier to swallow, when it is stated in the 
protocol that it must be swallowed whole
!
Only half the dose is taken because the study participant feels that they were feeling 
better when not taking the whole dose

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!
Someone who is not enrolled in the study intentionally takes the drug.

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Appendix C
Handling of Human Biological Samples
C 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each center keeps full traceability of collected biological samples from the 
patients while in storage at the center until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca 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 AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire 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.
Biological samples collected in China will be stored and disposed of according to local laws 
and regulations.
Mutation testing residual tissue samples collected during Part I and Part II screening  in China 
will be destroyed or repatriated maximally 5 years after study indication approved for 
marketing in China. 
Mutation testing residual plasma samples collected during Part I and Part II screening  in 
China will be destroyed maximally 5 years after study drug indication approved for marketing 
in China.
All PK samples and PK testing residual samples collected in China will be managed according 
to local laws and regulations, and will be destroyed maximally 12 months after final CSR 
release.
C 2
Withdrawal of Informed Consent for donated biological samples 
AstraZeneca ensure that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the information consent.
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analyzed,
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological sample(s) is an integral part of the study, then the patient is 
withdrawn from further study participation. 

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The Investigator:
!
Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca
!
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented
!
Ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the 
action documented and the signed document returned to the study site
!
Ensures that the patient and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organizations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). For 
transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005). Infectious 
substances are now classified either as Category A, Category B or Exempt. There is no direct 
relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. Category A pathogens are eg, Ebola, Lassa fever virus:
!
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number 
and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

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!
Clinical trial samples will fall into Category B or exempt under IATA regulations
!
Clinical trial samples will routinely be packed and transported at ambient
!
temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm)
!
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content
!
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable
!
Samples routinely transported by road or rail are patient to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used.

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Appendix D
Genetics
D 1
Use/analysis of DNA
Genetic variation may impact a patient’s response to therapy, susceptibility to, and severity 
and progression of disease.  Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated.  Therefore, 
where local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis from consenting patients.
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications.  Genetic research may lead to better understanding of diseases, better diagnosis 
of diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications.  
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic research may consist of the analysis of the structure of the patient´s DNA, i.e., the 
entire genome. 
The results of genetic analyses may be reported in the CSR or in a separate study summary.
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be retained while research on Study treatment continues but no longer than 
15 years or other period as per local requirements.
D 2
Genetic research plan and procedures
Selection of genetic research population
Study selection record
All patients will be asked to participate in this genetic research.  Participation is voluntary and 
if a patient declines to participate there will be no penalty or loss of benefit.  The patient will 
not be excluded from any aspect of the main study.
Inclusion criteria
!
For inclusion in this genetic research, patients must fulfill all of the inclusion 
criteria described in the main body of the CSP and: Provide informed consent for 
the genetic sampling and analyses.
Exclusion criteria

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Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:
!
Prior allogeneic bone marrow transplant.
!
Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample 
collection.
Withdrawal of consent for genetic research:  
Patients may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study.  Voluntary withdrawal will not 
prejudice further treatment.  Procedures for withdrawal are outlined in Section 7 of the main 
CSP.
Collection of samples for genetic research
The blood  sample for genetic research will be obtained from the patients at Visit 1. Although 
DNA is stable, early sample collection is preferred to avoid introducing bias through 
excluding patients who may withdraw due to an AE, such patients would be important to 
include in any genetic analysis.  If for any reason the sample is not drawn at Visit 1, it may be 
taken at any visit until the last study visit.  Only one sample should be collected per patient for 
genetics during the study.  Samples will be collected, labelled, stored, and shipped as detailed 
in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 
15 years, from the date of last patient last visit, after which they will be destroyed.  DNA is a 
finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood sample either before or at the time of 
DNA extraction replacing the information on the sample tube.  Thereafter, the sample will be 
identifiable only by the second, unique number.  This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organization.  No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organizations working with the DNA).
The link between the patient enrolment/randomization code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organizations.  The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit, 
and permit tracing of samples for destruction in the case of withdrawal of consent.
Ethical and regulatory requirements

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The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix B.
Informed consent
The genetic component of this study is optional and the patient may participate in other 
components of the main study without participating in the genetic component.  To participate 
in the genetic component of the study the patient must sign and date both the consent form for 
the main study and the genetic component of the study.  Copies of both signed and dated 
consent forms must be given to the patient and the original filed at the study center.  The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 
patient understands that they may freely withdrawal from the genetic aspect of the study at 
any time.
Patient data protection
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient.  For example, in the case of 
a medical emergency, an AstraZeneca Physician or an investigator might know a patient’s 
identity and also have access to his or her genetic data.  In addition, Regulatory authorities 
may require access to the relevant files, though the patient’s medical information and the 
genetic files would remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyses the samples.
AstraZeneca and its designated organizations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as hospitals, academic organizations or health insurance companies.  This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease.  The researchers can 
only use this information for health related research purposes.  Researchers may see summary 
results but they will not be able to see individual patient data or any personal identifiers.  
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Statistical methods and determination of sample size
The number of patients that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 

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statistical evaluation or whether only descriptive statistics will be generated.  A SAP may be 
prepared where appropriate.

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Appendix E
Actions required in cases of increases in liver biochemistry 
and evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of HL.  It is not intended to be a comprehensive guide to the management of 
elevated liver biochemistries. Specific guidance on managing liver abnormalities can be found 
in Section 8.3.8 of the CSP.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met.  
HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug induced liver injury (DILI) caused by the IP.  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting AEs and SAEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
AST or ALT ≥ 3× ULN together with TBL ≥ 2×ULN at any point during the study following 
the start of study treatment  irrespective of an increase in alkaline phosphatase (ALP).  
Hy’s Law (HL)
AST or ALT ≥ 3 × ULN  together with TBL ≥ 2 ×ULN, where no other reason, other than 
the IP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified time frame within which the 
elevations in transaminases and TBL must occur.
E 3
Identification of potential Hy’s Law cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:
!
ALT ≥ 3 × ULN
!
AST ≥ 3 × ULN

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!
TBL ≥ 2 × ULN
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (and also to the 
AstraZeneca representative).  
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:
!
Notify the AstraZeneca representative
!
Request a repeat of the test (new blood draw) by the central laboratory
!
Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from local laboratory results the Investigator will 
without delay:
!
Determine whether the patient meets PHL criteria (see Appendix E 2 for definition) 
by reviewing laboratory reports from all previous visits (including both central and 
local laboratory results)
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Notify the AstraZeneca representative
!
Determine whether the patient meets PHL criteria (see Appendix E 2 for definition) 
by reviewing laboratory reports from all previous visits
!
Promptly enter the laboratory data into the laboratory CRF
E 4
Follow-up
E 4.1
Potential Hy’s Law criteria not met
If the patient does not meet PHL criteria the Investigator will:
!
Inform the AstraZeneca representative that the patient has not met PHL criteria.
!
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the CSP.

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E 4.2
Potential Hy’s Law criteria met
If the patient does meet PHL criteria the Investigator will:
Determine whether PHL criteria were met at any study visit prior to starting Study treatment 
(See Section 8.4 Safety Reporting)
!
Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will:
!
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 
!
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician.  
!
Complete the three Liver CRF Modules as information becomes available 
!
If at any time (in consultation with the Study Physician the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures.
E 5
Review and assessment of potential Hy’s Law cases
The instructions in this section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the IP.  
The AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will also be 
involved in this review together with other patient matter experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
!
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF
!
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes

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If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IP:
!
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.  
∀
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply
∀
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:
!
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above
!
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met.  Update the SAE report according to the 
outcome of the review amending the reported term if an alternative explanation for 
the liver biochemistry elevations is determined.
E 6
Actions required when potential Hy’s Law criteria are met before 
and after starting study treatment
This section is applicable to patients who meet PHL criteria on Study treatment having 
previously met PHL criteria at a study visit prior to starting Study treatment.
At the first on-study treatment occurrence of PHL criteria being met, the Investigator will 
determine if there has been a significant change in the patients’ condition# compared with the 
last visit where PHL criteria were met.#
!
If there is no significant change, no action is required
!
If there is a significant change, notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Appendix B 5.
!
A ‘significant’ change in the patient’s condition refers to a clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST or TBL) 
in isolation or in combination, or a clinically relevant change in associated 
symptoms.  The determination of whether there has been a significant change will 
be at the discretion of the Investigator, this may be in consultation with the Study 
Physician if there is any uncertainty.

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E 7
Actions required for repeat episodes of potential Hy’s Law
This section is applicable when a patient meets PHL criteria on study treatment, and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.  
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found to be 
the disease under study (e.g., chronic or progressing malignant disease, severe infection or 
liver disease), or did the patient meet PHL criteria prior to starting study treatment and at first 
on-study treatment visit, as described in Appendix E 6
If No: Follow the process described in Appendix E 4.1.
If Yes: Determine if there has been a significant# change in the patient’s condition compared 
with when PHL criteria were previously met.
If there is no significant change, no action is required.
If there is a significant change, follow the process described in Appendix E 4.
A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.

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Appendix F
Guidelines for evaluation of objective tumor response using 
RECIST 1.1 criteria (Response Evaluation Criteria in Solid 
Tumors)
Introduction
This appendix details the implementation of RECIST 1.1 guidelines (Eisenhauer et al 2009) 
for this study with regards to Investigator assessment of tumor burden including protocol-
specific requirements for this study. Additional special guidance is provided for determination 
of confirmation of radiologic progression.
Definitions of measurable, non-measurable, target and non-target lesions
Patients with measurable disease and/or non-measurable and/or no evidence of disease 
assessed at baseline by CT/ MRI will be entered in this study.
Measurable:
A lesion, that can be accurately measured at baseline as ≥10 mm in the longest diameter 
(except lymph nodes which must have short axis1 diameter of ≥15 mm) with CT or MRI and 
which is suitable for accurate repeated measurements
Non-measurable:
!
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis diameter at baseline2).
!
Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by CT or 
MRI.
!
Brain metastasis
1 The short axis is defined as the longest axis perpendicular to long axis
2 Nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded or followed as 
non-target lesions (NTLs).
Special cases:
!
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability. Blastic lesions are considered non-measurable.
!
Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present 
in the same patient, these should be selected as TL.

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Target lesions:
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as TLs 
at baseline. Lymph nodes, in any location, are collectively considered as a single organ, with a 
maximum of 2 lymph nodes as TLs. A bilateral organ (e.g., adrenal glands) is considered as a 
single organ. Each segmented organ (e.g., liver) or lobular organ (e.g., lung) is considered as a 
single organ.
Prior irradiated lesions may be considered measurable and selected as TLs provided they 
fulfill the other criteria for measurability. 
Non-target lesions:
Additional measurable and non-measurable lesions (or sites of disease) not recorded as TL 
should be identified as NTL at baseline.
Methods of assessment
The same method of assessment on the same imaging technique should be used to 
characterize each identified and recorded lesion at baseline and during follow-up visits.
A summary of the methods to be used for RECIST assessment is provided in Table 12, and 
those excluded from tumor assessments for this study are highlighted with the rationale 
provided.
Table 12
Summary of methods of assessment
Target lesions 
Non-target lesions
New lesions
CT (preferred)
MRI
CT (preferred)
MRI
Plain X-ray
Chest X-ray
CT (preferred)
MRI
Plain X-ray
Chest X-ray
Bone scan
FDG-PET
CT  Computed tomography; FDG-PET  18F-Fluoro-deoxyglucose positron emission tomography; MRI  Magnetic resonance 
imaging.
CT and MRI 
CT and MRI, each preferably with IV contrast, are generally considered to generate the best 
currently available and reproducible images for measurement of TL, assessment of NTL, and 
identification of any new lesions. 
It is recommended that CT examinations of the chest and abdomen (including the entire liver 
and both adrenal glands) will be used to assess tumor burden at baseline and follow-up visits. 
Any other areas of disease involvement should be additionally imaged based on the signs and 

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symptoms of individual patients. In patients who are sensitive to IV CT contrast, a 
non-contrast CT examination of the chest and an MRI with IV contrast of the abdomen is 
appropriate. In patients with severely compromised renal function a non-contrast CT 
examination of the chest and abdomen is appropriate. For brain lesion assessment, MRI with 
IV contrast is the preferred method over IV contrast enhanced CT*. It is strongly 
recommended to maintain use of the same imaging modality (CT or MRI), acquisition 
protocol, facility and scanner across all imaging timepoints per patient.
* In this study all patients will have MRI of brain at screening, at each RECIST tumor 
assessment following randomization and if CNS progression is suspected.
Clinical examination 
Clinical examination of skin lesions or surface tumors (by visual inspection or manual 
palpation) will not be used for RECIST assessments. Tumors identified by clinical 
examination will need to be assessed by correlative CT or MRI anatomical scans.
X-ray
Chest X-ray
Chest X-ray assessment will not be used for assessment of TL. Chest X-ray can, however, be 
used to assess NTL and to identify the presence of new lesions.
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTL and to identify the presence 
of new bone lesions. 
Ultrasound 
Ultrasound examination will not be used for RECIST assessment of tumors as it is not a 
reproducible method, does not provide an accurate assessment of tumor size, and it is 
subjective and operator dependent. Tumors identified by ultrasound examination will need to 
be assessed by correlative CT or MRI anatomical scans.
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated 
in the context of tumor assessment.
Tumor markers 
Tumor markers on cytological or histological (biopsy) samples will not be used for tumor 
response assessments as per RECIST 1.1.
Cytology and histology 
Histology on tumor biopsy samples will not be used as part of the tumor response assessment 
as per RECIST 1.1. 

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Results of cytological examination for the neoplastic origin of any effusion (e.g., ascites, 
pericardial effusion, pleural effusion) that appears or worsens during the study will not be 
used as part of the RECIST 1.1 tumor response assessments in this study. An effusion that 
appears or significantly worsens (from trace to large) radiologically by CT/MRI anatomical 
scans will be considered to be disease progression due to new lesions or progression of NTLs, 
respectively.
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 NTL and followed by the same method as per baseline 
assessment. 
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits. New lesions may be recorded in the event that positive 
hotspots appear on a bone scan that were not present on a previous bone scan; however, a 
newly observed equivocal hotspot on a bone scan that cannot be verified with correlative 
imaging (CT, MRI, X-ray) of the same anatomical region shall not be the only trigger for a 
progressive disease (PD) assessment at that timepoint.
FDG-PET scan
18F-Fluoro-deoxyglucose PET/CT (FDG-PET) scans may be used as a method for identifying 
new lesions, according to the following algorithm:  New lesions will be recorded where there 
is positive 18F-Fluoro-deoxyglucose uptake3 not present on the most recent FDG-PET scan or 
in a location corresponding to a new lesion on CT/MRI at the same follow-up visit. If there is 
no baseline or prior FDG-PET scan available, and no evidence of new lesions on CT/MRI 
scans, then follow-up CT/MRI assessments should be continued, scheduled as per protocol or 
clinical indicated, in order to verify new lesions.
At present, low dose or attenuation correction CT portions of a combined FDG-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 tumor 
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 tumor 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.
3 A positive FDG-PET scan lesion should be reported only when an uptake (e.g., SUV) greater than twice that of 
the surrounding tissue or liver is observed.

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Tumor response evaluation 
Schedule of evaluation
The methods of assessment of tumor burden used at baseline CT/MRI scans of the chest and 
abdomen (including liver and adrenal glands) must be used at each subsequent follow-up 
assessment. Additional imaging may be performed based on the signs and symptoms of the 
patient (e.g., new lesions) at follow-up. An MRI scan with contrast should be performed in the 
event of suspected CNS progression. 
Baseline assessments should be performed ≤28 days prior to randomization, and ideally 
should be performed as close as possible to the start of IP. Efficacy by RECIST 1.1 for all 
patients will be assessed according to the schedules of assessments. If an unscheduled 
assessment is performed, and the patient has not progressed, every attempt should be made to 
perform the subsequent assessments at their scheduled visits. 
For patients who discontinue IP due to toxicity in the absence of evidence of disease 
progression, tumor assessments should be continued according to the original imaging 
schedule. 
Target lesions
Documentation of target lesions
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 TL at baseline. TLs should be selected on the basis of their size 
(longest diameter for non-nodal lesions or short axis for nodal lesions), but in addition should 
be those that lend themselves to reproducible repeated measurements. It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion, which can be measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes). All measurements should be recorded in 
millimeters. At baseline the sum of the diameters for all TL will be calculated and reported as 
the baseline sum of diameters. At follow-up visits the sum of diameters for all TL will be 
calculated and reported as the follow-up sum of diameters.
Special cases:
!
For TL measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short 
axis. 
!
If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable 
disease at baseline should be twice the slice thickness of the baseline scan.

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!
If a TL  has completely disappeared, the longest 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 New lesion.
!
If a TL splits into two or more parts, then record the sum of the diameters of those 
parts. 
!
If two or more TLs merge then the sum of the diameters of the combined lesion 
should be recorded for one of the lesions and 0 mm recorded for the other lesion(s). 
!
If a TL is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned. If an accurate measure can be given, this 
should be recorded, even if it is below 5 mm.
!
If a TL cannot be measured accurately due to it being too large, provide an estimate 
of the size of the lesion. 
!
When a TL has had any intervention e.g., definitive radiotherapy, embolization, 
surgery etc. during the study, the size of the TL should still be provided where 
possible and the intervention recorded in the RECIST CRF for that timepoint and in 
all subsequent TL assessments (see ‘Not evaluable’ below). If a TL has been 
completely removed (surgery) or disappears following an intervention, the longest 
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 New lesion. 
Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TL (see Table 13).

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Table 13
Evaluation of target lesions
Complete response (CR)
Disappearance of all TLs since baseline. Any pathological lymph 
nodes selected as TLs must have a reduction in short axis to 
<10 mm.
Partial response (PR)
At least a 30% decrease in the sum of the diameters of TL, taking 
as reference the baseline sum of diameters
Stable disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD
Progression of disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.
Not evaluable (NE)
Only relevant if any of the TLs at follow-up were not assessed or 
not evaluable (e.g. missing anatomy) or had a lesion intervention 
at this visit. Note: if the sum of diameters meets the PD criteria, 
PD overrides not evaluable as a TL response
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; SD  Stable disease; TL  Target 
lesion.
Non-target lesions
Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline. Measurements are not required for these lesions, but their status should be followed 
at subsequent visits. At each visit an overall assessment of the NTL response should be 
recorded by the Investigator. This section provides the definitions of the criteria used to 
determine and record overall response for NTL at the investigational site at each visit (see 
Table 14).

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Table 14
Evaluation of non-target lesions
Complete response (CR)
Disappearance of all NTLs since baseline. All lymph nodes must 
be non-pathological in size (<10 mm short axis).
Non CR/non PD
Persistence of one or more NTL.
Progression (PD)
Unequivocal progression of existing NTLs. Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions. In all cases the progression MUST be 
clinically significant for the physician to consider changing (or 
stopping) therapy.
Not evaluable (NE)
Only relevant when one or some of the NTLs were not assessed 
and, in the Investigator’s opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit.
Note: for patients 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.
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; NTL  Non-target lesion; TL  
Target lesion.
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 tumor burden has increased sufficiently to merit discontinuation of therapy. A 
modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify for 
unequivocal progression status.
New lesions
Details of any new lesions will also be recorded with the date of assessment. The presence of 
one or more new lesions is assessed as RECIST 1.1 progression. The finding of a new lesion 
should be unequivocal; i.e., not attributable to differences in scanning technique, change in 
imaging modality, or findings thought to represent something other than tumor. If a new 
lesion is equivocal, for example because of its small size, the treatment and tumor assessments 
should be continued until the previously new lesion has been assessed as unequivocal and then 
the progression date should be declared using the date of the initial scan when the new lesion 
first appeared. 
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
Symptomatic deterioration
Symptomatic deterioration is not a descriptor of a radiological response; it is a reason for 
stopping study therapy.
Patients with symptomatic deterioration requiring discontinuation of treatment without 
objective radiologic evidence of disease progression at that time should continue to undergo 
tumor assessments where clinically feasible.

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Evaluation of overall visit response
The overall visit response will be derived using the algorithm shown in Table 15.
Table 15
Overall visit response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
CR
Non CR/Non PD 
No
PR
CR
NE
No 
PR
PR
Non PD or NE
No
PR
SD 
Non PD or NE
No
SD
NE
Non PD or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR  Complete response, PR  Partial response, SD  Stable disease, PD  Progression of disease, NE  Not evaluable, NA  Not 
applicable (only relevant if there were no target and/or non-target lesions at baseline).
Central Review
All tumor assessment images will be collected, quality checked, and stored centrally by an 
Imaging CRO appointed by AstraZeneca. Guidelines for image acquisition, storage at the 
Investigative site as source data, and transfer to the imaging CRO will be provided in a 
separate document. Assessment of scans  by BICR will be triggered only upon investigator-
assessed progression and the results of  the  BICR will be  reported back typically within two 
working days to sites. 
Further details of the BICR will be documented in the Independent Review Charter (IRC), 
(also referred to as ‘Imaging Charter’) and the CNS IRC.
Specifications for radiological imaging
These notes are recommendations for use in clinical studies. The use of standardized protocols 
for CT and MRI allows comparability both within and between different studies, irrespective 
of where the examination has been undertaken.
If specified, all images will be collected, quality checked and stored centrally by the imaging 
CRO appointed by AstraZeneca. Guidelines for image acquisition, anonymization, storage at 
the investigative site as source data and transfer to the imaging CRO will be provided in a 
separate document. 
Also if specified, further details of the BICR will be documented in the Independent Review 
Charter (also referred to as the ‘Imaging Charter’).

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CT Scan
CT scans of the chest and abdomen (and pelvis when indicated) should be contiguous 
throughout all the anatomic region of interest.
The most critical CT image acquisition parameters for optimal tumor evaluation using 
RECIST 1.1 are anatomic coverage, contrast administration, slice thickness, and 
reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumors is the chest, 
abdomen and 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 patients. Because a lesion later 
identified in a body part not scanned at baseline would be considered as a new lesion 
representing disease progression, careful consideration should be given to the extent of 
imaging coverage at baseline and at subsequent follow-up timepoints. This will enable better 
consistency not only of tumor measurements but also identification of new disease.
b. IV contrast administration: Optimal visualization and measurement of metastases in solid 
tumors requires consistent administration (dose and rate) of IV contrast as well as timing of 
scanning. Typically, most abdominal imaging is performed during the portal venous phase and 
(optimally) about the same time frame after injection on each examination. An adequate 
volume of a suitable contrast agent should be given so that the metastases are demonstrated to 
best effect and a consistent method is used on subsequent examinations for any given patient. 
It is very important that the same technique be used at baseline and on follow- up 
examinations for a given patient. For patients who develop contraindications to contrast after 
baseline contrast CT is done, the decision as to whether non-contrast CT or MRI (enhanced or 
non-enhanced) should be performed should also be based on the tumor type, anatomic 
location of the disease and should be optimized to allow for comparison to the prior studies if 
possible. Each case should be discussed with the radiologist to determine if substitution of 
these other approaches is possible and, if not, the patient should be considered not evaluable 
from that point forward. Care must be taken in measurement of TLs on a different modality 
and interpretation of non-target disease or new lesions, since the same lesion may appear to 
have a different size using a new modality. Oral contrast is recommended to help visualize 
and differentiate structures in the abdomen. 
If iodine contrast media is medically contraindicated at baseline or at any time during the 
course of the study then the recommended methods are: CT thoracic (chest) examination 
without contrast and abdominal and pelvis MRI with contrast. If MRI cannot be performed 
then CT without IV contrast is an option for the thorax, abdomen, and pelvis examination. For 
brain imaging, MRI with IV contrast is the preferred method.
c. Slice thickness and reconstruction interval: It is recommended that CT scans be 
performed at 5mm contiguous slice thickness and this guideline presumes a minimum 5 mm 
thickness in recommendations for measurable lesion definition. Exceptionally, particular 

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institutions may perform medically acceptable scans at slice thicknesses greater than 5 mm. If 
this occurs, the minimum size of measurable lesions at baseline should be twice the slice 
thickness of the baseline 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. All 
images from each examination should be included in the assessment and not “selected” 
images of the apparent lesion.
MRI Scan
MRI has excellent contrast, spatial and temporal resolution; 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. Generally, axial imaging of the abdomen and 
pelvis (and other anatomies e.g. neck) with T1 and T2 weighted imaging along with 
gadolinium-enhanced imaging can be performed. The field of view, matrix, number of 
excitations, phase encoding steps, use of fat suppression and fast sequences should be 
optimized for the specific body part being imaged as well as the scanner utilized. CT of the 
chest is typically recommended over MRI due to significant motion artifacts (heart, major 
blood vessels, breathing) associated with MRI. It is beyond the scope of this appendix to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts and diseases. 
Ideally, the same type of scanner should be used and the image acquisition protocol should be 
followed as closely as possible to prior scans. Body scans should be performed with breath-
hold scanning techniques if possible.
References
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47.

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Appendix G
Patient Reported Outcome
Patient Reported Outcomes questionnaires EORTC QLQ-C30 removed due to copyrights.

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Patient Reported Outcomes questionnaires EORTC QLQ-C30 removed due to copyrights.

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Patient Reported Outcomes questionnaires EORTC QLQ-LC13 removed due to copyrights.

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Patient Reported Outcomes questionnaires PGIS removed due to copyrights.

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Patient Reported Outcomes questionnaires PRO-CTCAE removed due to copyrights.

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Patient Reported Outcomes questionnaires PRO-CTCAE removed due to copyrights.

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Patient Reported Outcomes questionnaires PRO-CTCAE removed due to copyrights.

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Patient Reported Outcomes questionnaires EQ-5D-5L removed due to copyrights.

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Patient Reported Outcomes questionnaires EQ-5D-5L removed due to copyrights.

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Appendix H
Abbreviations 
Abbreviation or special term
Explanation
ADRs
Adverse Drug Reactions
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
AUCss
Area under plasma concentration-time curve during any dosing 
interval at steady state [amount·time/volume]
BCRP
Breast Cancer Resistance Protein
BICR
Blinded Independent Central Review
CCRT
Concurrent Chemoradiation
CDx
Companion diagnostic
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
CLIA
Clinical Laboratory Improvement Amendments
CLQTS
Congenital Long QT Syndrome
CLss/F
Apparent total body clearance at steady state
CNS
Central Nervous System
COA
Clinical Outcome Assessment
COCs
Combined Oral Contraceptives
CONSORT
CONsolidated Standards of Reporting Trials
CR
Complete Response
CRF
Case Report Form (electronic/paper)
CRO
Clinical Research Organization
CRT
ChemoRadioTherapy
CSP
Clinical Study Protocol 
CSR
Clinical Study Report

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Abbreviation or special term
Explanation
Css, max
Maximum plasma concentration at steady state
Css, min
Minimum plasma concentration at steady state
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
circulating tumor DeoxyriboNucleic Acid
CYP
Cytochrome P
DCR
Disease Control Rate
DTPA
Diethylenetriamine penta-acetic acid
DILI
Drug Induced Liver Injury 
DNA
DeoxyriboNucleic Acid 
DoR
Duration of Response
DUS
Disease-Under Study 
ECG
Electrocardiogram
ECHO
Echocardiogram
eCRF
electronic Case Report Form 
EGFR
Epidermal Growth Factor Receptor
EGFRm
EGFR mutation
EGFRwt
eEGFR wild type
EM
Erythema Multiforme
EOD
Every Other Day
EORTC QLQ LC13 
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire – Lung Cancer 13 items
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire – Core 30 items
ePRO
electronic Patient Reported Outcome
EQ-5D-5L
EuroQoL 5-Dimension 5-Levels 
ESMO
European Society for Medical Oncology
Ex19del
Exon 19 deletion
FAS
Full Analysis Set 
FDA
Food and Drug Administration
FDG-PET
18F-Fluoro-DeoxyGlucose Positron Emission Tomography
FFPE
Formalin Fixed and Paraffin Embedded 

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Abbreviation or special term
Explanation
FNA
Fine-Needle Aspirates 
FSH
Follicle-Stimulating Hormone 
GCP
Good Clinical Practice
Gd
Gadolinium
GMP
Good Manufacturing Practice
Hb
Hemoglobin
HBeAg
Hepatitis B e Antigen
HBsAg
Hepatitis B surface Antigen
HBV
Hepatitis B virus
HBc IgG
hepatitis B core antibody
HDPE
High-Density Polyethylene
HER2
Human Epidermal Growth Factor Receptor 2
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HL
Hy’s Law 
HR
Hazard Ratio 
HRCT
High-Resolution Computed Tomography 
HRQoL
Health-Related Quality of Life
HRU
Health Resource Use
IASLC
International Association for the Study of Lung Cancer 
IATA
International Airline Transportation Association
ICF
Informed Consent Form 
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee  
IEC
Independent Ethics Committee
ILD
Interstitial Lung Disease 
IMRT
Intensity-Modulated Radio Therapy 
IP/IMP
Investigational Product
IRB
Institutional Review Board
IRC
Independent Review Charter

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Abbreviation or special term
Explanation
ITT
Intent To Treat (population)
IUD
Intra-uterine Device 
IUS
Intra-uterine System
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
KM
Kaplan-Meier
L858R
An amino acid substitution at position 858 in EGFR, from a 
leucine (L) to a arginine (R)
LDH
Lactate DeHydrogenase 
LH
Luteinizing Hormone 
LLN
Lower limit of normal
LVEF
Left Ventricular Ejection Fraction
MET
Tyrosine-protein kinase Met
MMRM
Mixed effect Models for Repeated Measures
MRI
Magnetic Resonance Imaging
MUGA
Multigated Acquisition Scan
NA
Not Applicable 
NCCN
National Comprehensive Cancer Network 
NCI
National Cancer Institute 
NE
Not Evaluable
NIMP
Non-Investigational Medicinal Product
NSCLC
Non-Small Cell Lung Cancer
NTL
Non-Target Lesion 
OR
Odds ratio
ORR
Objective Response Rate 
OS
Overall Survival
PD
Progressive Disease
PD-1
Programmed death-1
PD-L1
Programmed Death Ligand 1
PET
Positron Emission Tomography

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Abbreviation or special term
Explanation
PFS
Progression-Free Survival
PFS2
Progression-Free Survival-Second (time to second progression on 
a subsequent treatment)
PGIS
Patients Global Impression of Severity
P-gp
P-glycoprotein
PGx
Pharmacogenetics
PHL
Potential Hy’s Law
PK
Pharmacokinetics
PO
Per Os (taken orally)
PR
Partial Response
PRO
Patient Reported Outcomes
PRO-CTCAE
Patient Reported Outcome-Common Terminology Criteria for 
Adverse Event 
PS
Performance Status
QD
Quaque Die (once a day)
QLQ-C30
30-Item Core Quality-of-Life Questionnaire
QLQ-LC13 
13-Item Lung Cancer Quality-of-Life Questionnaire
QoL
Quality of Life
QTc
corrected QT
QTcF
QT corrected by Fridericia’s formula
RBC
Red Blood Cell 
RECIST v 1.1 
Response Evaluation Criteria in Solid Tumors version 1.1
SAE
Serious Adverse Event 
SAF
Safety Analysis Set 
SAP
Statistical Analysis Plan
SCRT
Sequential Chemoradiation 
SD
Stable Disease
SJS
Stevens Johnson Syndrome
SoA
Schedule of Activities 
SoC
Standard of Care
tmax
Time – maximum (time to reach maximum concentration)

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Abbreviation or special term
Explanation
T790M
An amino acid substitution at position 790 in EGFR, from a 
threonine (T) to a methionine (M)
TBL
Total Bilirubin 
TBNA
TransBronchial Needle Aspirates 
TdP
Torsades de Pointes
TEN
Toxic Epidermal Necrolysis
TFST
Time to First Subsequent Therapy 
TKI
Tyrosine Kinase Inhibitor 
TL
Target Lesion
TNM
Tumor/Node/Metastasis
TSST
Time to Second Subsequent Therapy 
TTD
Time to Treatment Discontinuation or death
TTDM
Time to Death or Distant Metastases 
UK
United Kingdom
ULN
Upper Limit of Normal 
US(A)
United States (of America)
V
Visit 
vs
versus
w
Weeks
WBDC
Web Based Data Capture
WBRT
Whole Brain RadioTherapy 
WHO
World Health Organization
WoCBP
Women of Childbearing Potential

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Appendix I
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 CYP3A4 METABOLISM THAT ASTRAZENECA 
STRONGLY RECOMMEND ARE NOT COMBINED WITH STUDY 
TREATMENT
Osimertinib is metabolized by CYP3A4 and CYP3A5 enzymes.
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 patient 
receiving study treatment.
Table 16
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.  Please contact AstraZeneca with any queries you have on this issue.
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 P-gp substrates 
(concentration of the sensitive BCRP substrate, rosuvastatin and sensitive P-gp substrate, 
fexofenadine, are increased).
Table 17
Exposure, pharmacological action and toxicity may be increased by 
Osimertinib
Warning of possible interaction
Advice
Rosuvastatin

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Table 17
Exposure, pharmacological action and toxicity may be increased by 
Osimertinib
Warning of possible interaction
Advice
Sulfasalazine
Drugs are permitted but caution should be 
exercised and patients monitored closely for 
possible drug interactions.  Please refer to full 
prescribing information for all drugs prior to co-
administration with Study treatment.
Doxorubicin
Daunorubicin
Topotecan
Dabigatran
Aliskiren
DRUGS THAT PROLONG QT INTERVAL
The drugs listed in this section are taken from information provided by the Arizona Center for 
Education and Research on Therapeutics website: https://www.crediblemeds.org/. The website 
categorizes drugs based on the risk of inducing TdP.
During screening the drugs that patients are currently prescribed should be checked opposite 
the ArizonaCert 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. These drugs must have been discontinued prior to the 
start of administration of study treatment in accordance with guidance provided in Table 18
and should not be co-administered with study treatment (osimertinib/placebo) and for a period 
of two weeks after discontinuing study treatment. 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.
Table 18
Drugs with a known risk of TdP
Drug name
Withdrawal period prior to 
study treatment start
Aclarubicin, 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

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Table 18
Drugs with a known risk of TdP
Drug name
Withdrawal period prior to 
study treatment start
Azithromycin bepridil, citalopram, chlorpromazine, dronedarone, 
escitalopram, fluconazole, halofantrine, haloperidol, 
levomepromazine, levosulpiride, mesoridazine
14 days
Donepezil, terodiline
3 weeks
Levomethadyl, methadone, pimozide
4 weeks
Arsenic trioxide*, Ibogaine
6 weeks
Pentamidine
8 weeks
Astemizole, Probucol, vandetanib
4 months
Amiodarone, chloroquine
1 year
*
Estimated value as pharmacokinetics of arsenic trioxide has not been studied
Other TdP risk Categories 
Patients 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 patient management and the patient has been stable on 
therapy. Close monitoring with ECGs and electrolytes is recommended.
Patients with congenital long QT syndrome (CLQTS) are excluded from this study.
Guidance regardless of TdP risk category
Following study treatment initiation if it is considered essential for patient management to 
give drugs known to prolong QTc interval, regardless of TdP risk category, close 
monitoring with ECGs and electrolytes is recommended.

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Appendix J
Definition of Women of Childbearing Potential and 
Acceptable Contraceptive Methods
Definition of Women of Childbearing Potential 
Women of Childbearing Potential (WoCBP): 
Women between menarche and menopause who have not been permanently or surgically 
sterilized and are capable of procreation.
Women NOT of Childbearing Potential:
Women who are permanently or surgically sterilized or post-menopausal (definitions below):
Permanent sterilization includes hysterectomy and/or bilateral oophorectomy and/or bilateral 
salpingectomy but excludes bilateral tubal occlusion.  Tubal occlusion is considered a highly 
effective method of birth control but does not absolutely exclude possibility of pregnancy.  
(The term occlusion refers to both occluding and ligating techniques that do not physically 
remove the oviducts).
!
Women who have undergone tubal occlusion should be managed on trials as if they are of 
WoCBP (e.g. undergo pregnancy testing etc., as required by the study protocol).
!
Women will be considered post-menopausal if they are amenorrhoeic for 12 months 
without an alternative medical cause. The following age-specific requirements apply:
!
Women under 50 years old will be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatments and with LH and FSH levels in the post-menopausal range.
!
Women over 50 years of age will be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous hormonal 
treatments.
Acceptable contraception methods
Highly effective method of birth control is defined in Note 3 in ICH Guidance M3 
(Nonclinical Safety Studies for the conduct of Human Clinical trials for Pharmaceuticals) as 
one that results in a low failure rate (e.g. less than 1 percent per year) when used consistently 
and correctly.  
Note that women should have been stable on their chosen method of birth control for a 
minimum of 2 weeks before entering the trial.  Generic names and examples of trade names 
are given.  As trade names may vary, investigators should check the generic name of any 
contraception to ensure suitability.  

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Highly effective contraception methods are: 
!
Total sexual abstinence (abstinence must be for the total duration of the trial and the 
follow-up period)
!
Vasectomized sexual partner plus male condom (with participant assurance that partner 
received post-vasectomy confirmation of azoospermia)
!
Tubal occlusion plus male condom
!
Intra-uterine Device (IUD) - provided coils are copper-banded, plus male condom 
!
Intra-uterine system (IUS) Levonorgestrel Intra Uterine System (eg, Mirena), plus male 
condom
!
Medroxyprogesterone injections (Depo-Provera) plus male condom 
!
Etonogestrel implants (eg, Implanon, Norplan) plus male condom
!
Normal and low dose combined oral contraceptive pills, plus male condom
!
Norelgestromin / ethinylestradiol transdermal system plus male condom
!
Intravaginal device (eg ethinylestradiol and etonogestrel ) plus male condom 
!
Cerazette (desogestrel) plus male condom.  Cerazette is currently the only highly 
efficacious progesterone based pill
Unacceptable contraception methods
The following methods are considered not to be highly effective and are therefore not 
acceptable contraceptive methods in AstraZeneca clinical trials:
!
Triphasic combined oral contraceptives (COCs)
!
All progesterone only pills except, Cerazette
!
All barrier methods, if intended to be used alone
!
Non-copper containing IUDs
!
Fertility awareness methods
!
Coitus interruptus

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