A Multicentre, Open-label, Single-arm, Molecular Profiling Study of Patients With EGFR Mutation-positive Locally Advanced or Metastatic NSCLC Treated With Osimertinib
Phase: PHASE2
Conditions: EGFR Mutation Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer
Sponsor: AstraZeneca

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This document contains confidential commercial information, disclosure of which is 
prohibited without providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
Clinical Study Protocol
Drug Substance
AZD9291, Osimertinib
Study Code
D5161C00003
Version
7.0
Date
14 April 2023
A multicentre, open-label, single-arm, molecular profiling study of patients 
with EGFR mutation-positive locally advanced or metastatic NSCLC treated 
with osimertinib
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden

Clinical Study Protocol
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
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Synopsis- Statistical methods and sections 8.1, 9.3: Statistical Considerations and End of 
Study Timelines were revised based on the results of the FLAURA study.
Sections 1.1, 1.2, 1.3 were updated to include the results of the FLAURA study and the 
latest results from the safety data cut-off. The reference to Soria et al 2018 was added.
Figure 1 was amended to include the whole blood sample taken at progression.
Sections 3.1 and 3.2:
Inclusion #2: was modified to reflect the specificity of country regulation for legal age.
Inclusion #5: was modified following AstraZeneca commitment to FDA request to clarify 
the tests to be used to select patients for enrolment in the study.
Inclusion #6 and Exclusion criteria #19: were modified to align with the FLAURA protocol. 
The part about the CNS metastasis was revised and moved to Exclusion criteria #19.
Section 3.6: removed ‘Corneal ulceration’ to reflect the TAGRISSO Core Data Sheet 
(CDS). Added ‘Grade 3 or higher adverse reaction that does not improve to Grade 0-2 after 
withholding for up to 3 weeks’ to be consistent with Section 6.8.
Table 1, Table 2, Sections 5.2.4, 5.2.6.1, 6.8.4:
An extensive ophthalmological assessment prior to the start of treatment with osimertinib is 
no longer required according to the CDS. The effect of osimertinib on eyes is no longer 
under review and therefore the requirement to collect photographs of any eye effects has 
been removed. A general eye examination is performed as part of the Physical Examination.
Assessment of left ventricular function by Echocardiogram or MUGA is no longer required 
in all patients prior to the start of treatment with Osimertinib. Left ventricular function 
assessment is now only required in patients with pre-existing cardiac disease that does not 
meet the criteria for the study exclusion but may worsen on treatment with osimertinib.
Table 2 and Sections 5.3.2, 5.4: the study design has been changed to allow real time 
analysis of the tissue and blood sample taken at the time of progression on osimertinib. An 
additional whole blood sample is required. The analysis will use a Next Generation 
Sequencing (NGS) panel to identify the mechanism of resistance to first-line osimertinib. 
The results of these tests will be provided to the sites to inform the choice of treatment after 
osimertinib.
Section 4.3.1: following phrase “Patients will be followed for the earlier of first subsequent 
anticancer treatment (including surgical) after discontinuing osimertinib or death” removed 
as it is more appropriate in Section 4.3.2 where it is already mentioned.

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inclusion criterion relating to coagulation (and warfarin, a CYP2C9 substrate) was 
originally included based on in vitro results in human hepatocytes which showed a potential 
for increasing the messenger ribonucleic acid (mRNA) of cytochrome P450 (CYP) 3A 
enzymes via pregnane X receptor (PXR) induction. Therefore, all pathways that depend on 
PXR (including CYP2C9) were thought to have potential for induction with a resultant 
impact on warfarin. However, a clinical study with the CYP3A substrate simvastatin 
(Reference Study 14) showed no potential interaction and induction was also minimal. 
Similarly, another PXR substrate (Pgp study; Reference Study 36) also showed minimal 
induction. Other PXR substrates, including CYP2C, are unlikely to have an interaction and 
therefore this inclusion criterion is not required.
Sections 3.1 and 5.3.1: inclusion criterion 7 and mandatory tissue collection details below 
were amended to further define the requirements of sufficient tissue samples for this study.
7. Possibility of obtaining sufficient tissue sample, via a biopsy or surgical resection of the 
primary tumour or metastatic tumour tissue, within the 60 days prior to study entry and at or 
after RECIST 1.1-defined progression. An archival biopsy is acceptable as long as there has 
been no intervening anticancer treatment since the time the biopsy was obtained to 
enrolment in this clinical study and as long as it was within 60 days of study entry. For 
patients who meet the exception to exclusion criterion #11 (Section 3.2), a fresh tissue 
biopsy must be obtained after the completion of chemotherapy and before osimertinib 
treatment. A sufficient tissue sample would consist of formalin-fixed, 
paraffin-embedded tumour tissue blocks, or at least 15 re-cut unstained sections from 
formalin-fixed paraffin-embedded tumour tissue block, presented on slides. Each 
section should be 5 μm thick.
The Investigator will be asked to provide formalin-fixed, paraffin-embedded tumour tissue 
blocks, or a minimum of 10, but when available,at least 15 re-cut unstained sections from 
formalin-fixed paraffin-embedded tumour tissue block, presented on slides. Each section is 
to be 5 μm thick.
Section 3.2: exclusion criterion 11 was updated as patients who have had prior 
chemotherapy will no longer be allowed to participate in this study: 11. Patients who have 
received previous treatment for metastatic or stage IV disease *
* Prior chemotherapy may affect the resistance profile under study; however, patients who 
have received prior chemotherapy may be permitted if the patients have not received more 
than 4 cycles of first line chemotherapy with a limit of 20% of the total enrolment. The site 
must get Sponsor approval before consenting patients who have received prior 
chemotherapy (Section 3.3).
Subsequently, references to the exception removed from exclusion criterion 11 above have 
been removed throughout the protocol (previously included in Sections 3.1, 3.3, 4.1 
and 5.3.1).

Clinical Study Protocol
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Study Code D5161C00003
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Synopsis, Section 8.2:
Recruitment of 150 patients is appropriate to characterise the frequency of tumour genetic 
and proteomic markers at disease progression regardless of their prevalence. The following 
table displays the precision of the estimated proportion, for example, when 50 evaluable 
paired biopsies are available at the time of the primary analysis.
Section 1.1:
Over the past decade, Multiple clinical trials in patients with an activating mutation of the 
EGFR gene have compared different first- or second-generation oral EGFR TKIs. ... RRs 
and median PFS intervals for gefitinib, erlotinib, and afatinib are 55% to 74% and 9 to 
10 months, 58% to 83% and 9 to 13 months, and 58% to 61% and 9 to 11 months, 
respectively...
Osimertinib is approved for:

the adjuvant treatment after complete tumour resection in patients with NSCLC 
whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution 
mutations.

the first-line treatment of patients with locally advanced or metastatic NSCLC whose 
tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

the treatment of patients with locally advanced or metastatic EGFR T790M 
mutation-positive NSCLC, as detected by an FDA approved test, whose disease has 
progressed on or after EGFR-TKI therapy.
…
First-line EGFRm NSCLC: Clinical experience updated to align with the latest safety data 
and standards.
Adjuvant EGFRm NSCLC: Clinical experience updated to align with the latest safety 
data and standards.
Second line or greater, T790M mutation-positive, advanced NSCLC: Clinical 
experience updated to align with the latest safety data and standards.
Adverse Drug Reactions for Osimertinib Monotherapy: Clinical experience updated to 
align with the latest safety data and standards. New ADR of aplastic anaemia.
Section 1.4, Figure 1: The follow-up column in the study design figure was split into 
2 columns, the 28-day Follow-up visit and the period to first subsequent anticancer 
treatment or death.
Section 1.4.1 Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis – (new section added)

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Section 3.2: Text updated to align with the latest safety data and standards. and to add 
COVID-19 exclusion.
15. 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, or active infection (eg, patients receiving treatment for 
infection) including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). 
Screening for chronic conditions is not required), or active uncontrolled HBV 
infection.
─Screening for chronic conditions is not required.
Should patients with HBV infection be included, patients are only eligible if they 
meet all the following criteria:
─Demonstrated absence of HCV co-infection or history of HCV 
co-infection.
─Demonstrated absence of HIV infection.
─Patients with active HBV infection are eligible if they are:

Receiving anti-viral treatment for at least 6 weeks prior to study 
treatment, HBV DNA is suppressed to < 100 IU/mL and 
transaminase levels are below ULN.
─Patients with a resolved or chronic infection HBV are eligible if they are:

Negative for HBsAg and positive for hepatitis B core antibody 
[anti-HBc IgG]. In addition, patients must be receiving anti-viral 
prophylaxis for 2 to 4 weeks prior to study treatment and 6 to 
12 months (TBD by hepatologist) post treatment.
or
─Positive for HBsAg, but for > 6 months have had transaminases levels 
below ULN and HBV DNA levels below < 100 IU/mL (ie, are in an 
inactive carrier state). In addition, patients must be receiving anti-viral 
prophylaxis for 2 to 4 weeks prior to study treatment and 6 to 12 months 
(TBD by hepatologist) post treatment. Refer to Section 3.5.
18. … Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalaemia, hypomagnesaemia, hypocalcaemia, congenital 
long QT syndrome, family history of long QT syndrome or unexplained sudden death 

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under 40 years of age in first degree relatives or any concomitant medication known to 
prolong the QT interval.
Section 3.5: The following restrictions were edited/added to align with the latest safety data 
and standards.
…
2. Male patients should be asked to use barrier contraceptives (ie, by use of condoms) 
during sex with all partners of childbearing potential during the trial and for a washout 
period of 4 months. Female partners (of childbearing potential) of male patients must 
also use a highly effective method of contraception throughout this period. Male 
patients should avoid procreation for 4 months after completion of study treatment. Patients 
should refrain from donating sperm from the start of dosing until 4 months after 
discontinuing study treatment.
3. Once enrolled, all patients must try to avoid concomitant use of medications, herbal 
supplements, and/or ingestion of foods that are known to be potent strong inducers of 
CYP3A4 whenever feasible, but patients may receive any medication that is clinically 
indicated for treatment of AEs. Such drugs must have been discontinued for an appropriate 
period before they enter screening and for a period of 3 weeks after the last dose of 
osimertinib. …
4. … Patients taking concomitant medications whose disposition is dependent upon Breast 
Cancer Resistance Protein (BCRP) and/or P-glycoprotein (P-gp), and which have a 
narrow therapeutic index should be closely monitored for signs of changed tolerability.
…Patients who have received prior treatment with immune-oncology (IO) therapies 
should be closely monitored for an appropriate period of time after the last dose of the 
IO treatment, in accordance with the respective IO label, as immune-mediated adverse 
reactions with the IO therapy may occur at any time during or after discontinuation of 
therapy. The stop date of the prior IO drug therapy should be captured in the eCRF.
5. In patients with resolved or chronic hepatitis B infection (inactive carrier state) or 
active controlled HBV infection on treatment with osimertinib:

Recommend monthly monitoring of ALT/AST, HBV DNA levels and HBsAg (if 
negative at baseline)

Where liver signs and symptoms of viral reactivation appear (HBV DNA levels 
exceeding 10-fold from baseline or ≥100 IU/ml (if baseline HBV DNA levels are 
undetectable) or conversion of HBsAg negative to positive):
o
Expert hepatologist/specialist oversight of the patient is required

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o
Consider interruption or discontinuation of study treatment, based on 
risk-benefit assessment
Section 3.6: … Text updated to align with the latest safety data and standards.
Patients experiencing any of the following AEs will not be permitted to restart study 
treatment:

ILD/pneumonitis
…
Section 3.8: The following text was deleted as survival analysis will not be conducted.
The status of ongoing, withdrawn (from the study), and ‘lost to follow up’ patients at the 
time of the data cut off date for the study analyses should be obtained by the site personnel 
by checking the patient’s notes, hospital records, contacting the patient’s 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. In terminating the study, the Sponsor will 
ensure that adequate consideration is given to the protection of the patients’ interests.
Section 4.1, Table 1: footnote updated:
…
d
To be performed at least every 16 weeks throughout the treatment period. The modality of the 
cardiac function assessments must be consistent within a patient, ie, if echocardiogram is used for 
the screening assessment then echocardiogram should also be used for subsequent scans. To be 
performed only in patients with pre existing cardiac disease that does not meet the criteria for study 
exclusion but may worsen on treatment with osimertinib.
Section 4.1, Table 2: Table was updated to align with the changes in this protocol 
amendment, and footnotes updated as follows:
…
b
Six 4-week cycles followed by 8-week cycles from Cycle 7 onwards to 3.5 years (Day 1277), and 
10-week cycles from 3.5 years to disease progression. Patients who continue to receive osimertinib 
beyond RECIST 1.1-defined progression, if continuing to show clinical benefit to treatment as judged by 
the Investigator, will continue to follow the treatment visit schedule and assessments excluding study 
specific RECIST assessments and plasma samples for ctDNA and blood-borne biomarkers will only be 
obtained at treatment discontinuation.
c
As a minimum, telephone contact should be made with the patient 28 days (window + 7 days) following 
the discontinuation of study drug (last dose of IP).
…

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f
The second mandatory tumour tissue biopsy may be performed any time between Investigator-assessed, 
RECIST 1.1-defined progression and up to 7 days after the discontinuation start of osimertinib. before 
any new systemic anticancer treatment. If a patient discontinues osimertinib before RECIST 1.1-
defined progression, the second biopsy will not be performed.
g
Plasma samples for ctDNA and blood-borne biomarkers will only be obtained at the treatment 
discontinuation visit.
h
If screening assessments have been performed within 14 days prior to starting study treatment, they do 
not have to be repeated on Visit 2 if the patient’s condition has not changed. The assessments are to be 
completed pre-dose on visit day. Laboratory tests may be performed the day prior to study visits.
i
ECG is also to be performed in event of any cardiac AE.
j
To be performed only in patients with pre existing cardiac disease that does not meet the criteria for 
study exclusion but may worsen on treatment with osimertinib at least every 16 weeks throughout the 
treatment period. ...
k
The screening assessment should be performed within 28 days prior to study drug initiation. Subsequent 
assessments are to be performed every 8 weeks (± 7 days) from study enrolment until 3.5 years 
(Day 1277), and then every 10 weeks (± 14 days) until RECIST 1.1-defined progression, even if a 
patient discontinues treatment prior to progression or receives other anticancer treatment...
…
n
At progression, a whole blood sample will be obtained at the same time  within 7 days of when the 
tissue biopsy is performed.
o
The progression biopsy should be done prior to the start of subsequent systemic anticancer 
treatment…
Section 4.3: Follow-up clarified:
1. All patients will be followed up for safety at approximately 28 days.
2. All patients will be followed up for RECIST 1.1-defined progression.
3. All patients will be followed up for subsequent anticancer treatment/death.
Section 4.3.1:
As a minimum, telephone contact should be made with the patient 28 days (± 7 days) 
following the discontinuation of osimertinib (last dose of IP) to collect new AEs and 
follow-up on any ongoing AEs and concomitant medications (including any subsequent 
cancer therapy). anticancer treatment). Refer to Section 6.3.1 for full details on AE 
recordings during follow-up.
Section 4.3.2: Progression Follow-up for RECIST 1.1-defined progression
Section 5.2.1:
Magnesium was added to the list of chemistry tests in Table 3, Laboratory Safety Tests.
Section 5.2.4:
An echocardiogram or multigated acquisition scan (MUGA) to assess LVEF will be 
performed at screening (prior to first dose of osimertinib) only in patients with pre existing 

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cardiac disease that does not meet and at least every 16 weeks throughout the criteria for 
study exclusion but may worsen on treatment with osimertinib. Subsequent assessment 
period. Additional assessments of LVEF should be performed as clinically indicated…
Section 5.3.2: A 7-day window was added between progression biopsy sampling and 
collection of a whole blood sample.
At progression, a whole blood sample will be taken within 7 days of the time the tissue 
biopsy is obtained.
Section 6.5:
A maximum tolerated dose has not been established for osimertinib. In the context of a 
clinical study, An overdose is any dose which exceeds the daily dose that is defined in the 
clinical study protocol.
Section 6.8, Table 4: To align with the latest safety data and standards:
Table 4
Osimertinib Dose Adjustment Information for Adverse Reactions
Target organ
Adverse reaction
Dose modification
Pulmonary
Interstitial lung disease/pneumonitis
Permanently discontinue osimertinib
Cardiac
QTc interval greater than 500 msec on at 
least 2 separate ECGs
Withhold osimertinib until QTc interv
is less than 481 msec or recovery to 
baseline if baseline QTc is more than
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 allo
for situations where causality in 
relation to osimertinib may be 
difficult to determine.)
…
If a toxicity resolves or reverts to ≤ CTCAE Grade 2 within 3 weeks of onset withholding 
osimertinib, treatment with osimertinib may be restarted at the same dose or a lower dose 
using the rules below for dose modifications (Table 5) and with discussion and agreement 
with the AstraZeneca Study Team Physician as needed. There will be no individual 
modifications to dosing schedule in response to toxicity, only potential dose reduction or 
dose interruption.
If the toxicity does not resolve to ≤ CTCAE Grade 2 after 3 weeks of withholding 
osimertinib, then the patient should be withdrawn from the study and observed until 
resolution of the toxicity.

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Section 6.8.2: to align with the latest safety data and standards:
QTc Prolongations
In light of the potential for QT changes associated with osimertinib, electrolyte 
abnormalities (hypokalaemia, hypomagnesaemia, hypocalcaemia) must be corrected 
to be within normal ranges prior to first dose and electrolyte levels monitored during 
study treatment.
Patients with QTc QT interval corrected using Fridericia’s correction (QTcF) prolongation 
to > 500 msec should have study treatment interrupted and regular ECGs performed until 
resolution to < 481 msec, or recovery to baseline, if baseline QTcF is ≥ 481 msec and
then restarted at a reduced dose of 40 mg, or 80mg at the discretion of the Investigator. If 
the toxicity does not resolve to ≤CTCAE Grade 1 within 21 days, the patient will be 
permanently withdrawn from study treatment.
Permanent discontinuation due to toxicity
Patients experiencing interstitial lung disease, QTc prolongation with signs/symptoms of 
serious arrhythmia or Grade 3 or higher adverse reaction that does not improve to Grade 0 
to 2 after withholding for up to 3 weeks will not be permitted to restart study 
treatment.
Section 6.8.3: to align with the latest safety data and standards:
Keratitis
Keratitis was reported in 0.7% (n=6) of the 833 patients treated with osimertinib in the 
AURA studies.  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.
Section 6.8.4: Erythema multiforme and Stevens-Johnson syndrome (new section) to 
align with the latest safety data and standards:
Case reports of Erythema multiforme (EM) and Stevens-Johnson syndrome (SJS) 
have been uncommonly and rarely reported, respectively, in association with 
osimertinib treatment. Before initiating treatment, patients should be advised of signs 
and symptoms of EM and SJS. If signs and symptoms suggestive of EM develop, close 
patient monitoring and drug interruption or discontinuation of osimertinib should be 
considered. If signs and symptoms suggestive of SJS appear, osimertinib should be 
interrupted or discontinued immediately.

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Section 6.8.5 Aplastic anaemia (new section) to align with the latest safety data and 
standards:
Rare reports of aplastic anaemia have been reported in association with osimertinib 
treatment. Some cases had a fatal outcome. Before initiating treatment, patients 
should be advised of signs and symptoms of aplastic anaemia including but not limited 
to persistent fever, bruising, bleeding, pallor. If signs and symptoms suggestive of 
aplastic anaemia develop, close patient monitoring and drug interruption or 
discontinuation of osimertinib should be considered. Osimertinib should be 
discontinued in patients with confirmed aplastic anaemia.
Section 6.8.6: to align with the latest safety data and standards:
Changes in cardiac contractility
Across clinical trials, LVEF decreases greater than or equal to 10% and a drop to less than 
50% occurred in 4.0% (26/655) 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. Echocardiogram/MUGA to assess LVEF should be performed at screening In 
patients with pre existing cardiac disease risk factors and those with conditions that does 
not meet the criteria for study exclusion but may worsen on treatment with osimertinib. 
Subsequent can affect LVEF, cardiac monitoring, including an assessment of LVEF at 
baseline and during treatment, should be performed as clinically indicated. considered.
In patients who develop relevant cardiac signs/symptoms during treatment, cardiac 
monitoring including LVEF assessment should be considered.
Section 7.8: Patients receiving study treatment at the time of study completion (ie, after 
final DCO date) will be switched to commercial supply and/or another study to ensure 
continuation of treatment, may continue to receive osimertinib, if in the opinion of their 
treating physician they are continuing to derive clinical benefit from continued treatment.
Synopsis, Section 8.1: …The primary final analysis will be performed at study end (see 
Section 9.3 for definition of “end of study”). when approximately 50 patients have 
evaluable paired biopsies upon progression.
…The first 100 patients to be enrolled within the first 5 months (ie, from first patient 
inclusion to the timing of the global protocol amendment). This will be followed by a pause 
in recruitment of 3 6 months to account for the issue and approval of the global protocol 
amendment. This will further be followed by 4 months 1 month of recruitment to enrol the 
remaining 50 patients, assuming an exponentially distributed recruitment rate to account for 
the regional differences in approval times and slow uptake of recruitment following the 
protocol amendment.

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This is an exploratory study which may inform other studies in the osimertinib development 
programme and therefore earlier interim analyses may not be reported in a formal CSR.
performed. Furthermore, a later analysis may be performed when more than 50 patients 
have evaluable paired biopsies to understand the profile of patients who have longer times 
to progression.
If a patient progresses in the ELIOS study and then enrols in a subsequent AZ study, 
and if appropriate consent is provided, the biomarker results from a progression 
biopsy (generated in either the other study or ELIOS), may be shared between both 
studies and the data may be analysed as part of the ELIOS study.
Section 8.3.1: Primary analysis set Intention to Treat (PAS ITT)
An extension of The PAS will include all patients with evaluable paired biopsies (i.e. valid 
sequencing results from Foundation Medicine Inc. for both the baseline and progression 
biopsies),, which are defined as follows: the first biopsy taken prior to osimertinib treatment 
and the second biopsy taken at any time between Investigator-assessed, RECIST 1.1-
defined progression and before the start of any new anti cancer therapy. Any patients that 
discontinue osimertinib prior to disease progression e.g. patient decision, adverse event etc. 
will not be considered part of the primary analysis set systemic anticancer treatment. Any 
patients that discontinue osimertinib prior to disease progression eg, patient decision, 
adverse event etc. will not be considered part of the primary analysis set systemic 
anticancer treatment. If the Investigator judges the patient to have progressed but the 
programmatically defined RECIST progression does not occur, the patient will still be 
considered evaluable, as long as an adequate tissue sample is provided at the time of 
progression. This analysis set will be used as a sensitivity for the analysis of the primary 
endpoint.
Section 8.5.4 (deleted): Interim analysis
This is an exploratory study which may inform other studies in the osimertinib development 
program and therefore earlier interim analyses may be performed.
Section 8.5.4:
The analyses associated with the exploratory objective will be reported separately and will 
not form part of the CSR. Any HER2/tissue/plasma analysis may be published outside of 
the CSR.

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Section 9.3:
The estimated date of the first patient enrolled is Q2 2018.
A patient is considered to have completed the study when he/she has progressed or
died.
The end of the study is defined as when the earliest of these scenarios is met:

All enrolled patients complete their participation in the study either through 
disease progression or withdrawal for other reasons.

The study will end in October 2024, as it is estimated that by then there will be 
sufficient data to support study endpoints. If, at this time (October 2024 or at 
another time if AstraZeneca or Regulatory Authorities decide to stop study due to 
any concerns, eg, patient safety), there are ongoing patients who are drawing 
benefit from study treatment, they will be switched to commercial supply and/or 
another study to ensure continuation of treatment, and the study will close using 
the available data for the final analysis. A CSR will be written at this time, 
including all data collected during the study. For any patients who continue in 
progression follow-up, any additional safety data will be collected and summarised 
in the CSR.
…
The study may be terminated at individual centres after the primary analysis has concluded, 
if there are no ongoing patients.
Section 9.4:
ILD-like events (new)
ILD/pneumonitis are to be reported as AEs in the CRF, with additional details 
captured in the "ILDIS" eCRF.
Appendix D: Guidance Regarding Potential Interactions with Concomitant 
Medications
Table D1: Drugs inducing CYP3A4
Contraindicated drugs
Withdrawal period prior to osimertinib start
Carbamazepine, phenobarbital (phenobarbitone),
phenytoin, rifampicin, rifabutin, rifapentine, 
St John’s Wort
3 weeks
Phenobarbitone
5 weeks

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Osimertinib may increase the concentration of sensitive breast cancer resistance protein 
(BCRP) and P-gp substrates (concentration of the sensitive BCRP substrate, rosuvastatin, is
and sensitive P-gp substrate, fexofenadine, are increased).
Table D2: Exposure, pharmacological action and toxicity may be increased by 
osimertinib
Warning of possible interaction
Advice
Rosuvastatin
Drugs are permitted but caution should be exercised and patients
monitored closely for possible drug interactions. Please refer to 
full prescribing information for all drugs prior to 
co-administration with osimertinib.
Sulfasalazine
Doxorubicin
Daunorubicin
Topotecan
Dabigatran
Aliskiren
Digoxin
D 2
Drugs that May prolong QT interval
The drugs listed in this section are taken from information provided by The Arizona Center 
for Education and Research on Therapeutics and The Critical Path Institute, Tucson, 
Arizona and Rockville, Maryland. Ref:  http://www.arizonacert.org/medical pros/drug
lists/drug lists.htm. on the CredibleMeds® website https://www.crediblemeds.org/. The 
website categorises drugs based on the risk of inducing Torsades de Pointes (TdP).
During screening the drugs that patients are currently receiving (prescription and 
non-prescription) should be checked against the ArizonaCert website. In addition, 
drugs intended for use following study treatment initiation should be checked against 
the website.
D 2.1 Drugs with a known risk of Torsades de Pointes
Drugs in this category are known to prolong the QT interval or induce Torsades de 
Pointes and are clearly associated with a known risk of TdP, even when taken as 
recommended.
D 2.1.1Before commencing study treatment
Drugs in the category of known risk of TdP must have been discontinued prior to the 
start of administration of study treatment in accordance with guidance provided in 
D4.

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D 2.1.2During study treatment
It is recommended that drugs in the category of known risk of TdP are not be 
combined co-administered with study treatment (osimertinib.  Recommended withdrawal 
periods following cessation of treatment with ) and for a period of two weeks after 
discontinuing study treatment, however, if it is considered essential for patient 
management to co-administer these agents are provided in the table drugs with study 
treatment (osimertinib), close monitoring of ECGs and electrolytes is recommended.
The list of drugs may not be exhaustive and is subject to change as new information 
becomes available. As such investigators are recommended to search the 
CredibleMeds® website (https://www.crediblemeds.org/) to provide the most up-to-
date information.
Table D3
Drugs Prolonging QT Intervalwith a known risk of TdP
Contraindicated drug Drug name
Withdrawal period prior to 
osimertinib study treatment start b
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
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 c , Ibogaine
6 weeks
Pentamidine
8 weeks
Astemizole, Probucol, Vandetanib
4 months
Amiodarone, Chloroquine
1 year
a
This list should be checked against the full and most current list presented in the CredibleMeds® 
website.
b
Values determined from comprehensive review (internal to AZ) of each compound’s PK half-life 
and determination of the washout period.
c
Estimated value as PK of arsenic trioxide has not been studied.

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follow-up on any ongoing AEs and concomitant medications (including any subsequent 
anticancer treatment).
Synopsis (study design), Section 4.1 (Table 2), and Section 8.3.1: The text “new systemic 
anticancer treatment” and “subsequent systemic anticancer treatment” were changed to 
“new systemic anticancer treatment” and “subsequent systemic anticancer treatment”.
Throughout the document: Minor typographical errors were corrected.
Version 7.0, 14 April 2023
Main changes to the protocol are summarised below:
Synopsis, Section 8.1: The details related to final analysis are updated.
The final analysis will be performed at study end (see Section 9.3 for definition of “end of 
study”), and when approximately 50 patients have evaluable paired biopsies upon 
progression. Assuming a 70% rate of patients having a biopsy at both baseline and 
progression, and with an assumed technical failure rate of 30% of the samples (assume an 
overall failure rate of 51%), then we should expect approximately 50 evaluable paired 
biopsies to be available when approximately 103 of the 150 patients have progressed, which 
would be expected to occur approximately 38 months after the first patient is enrolled.
Section 1.1: Per Investigator Brochure’s annual update, study details were updated.
…
Adjuvant EGFRm NSCLC
…
At the DCO of the DFS analysis (11 April 2022), the DFS HR for HR for patients with 
stage II-IIIA disease was 0.23 (95% CI: 0.18, 0.30), demonstrating a clinically 
meaningful 77% reduction in the risk of disease recurrence or death for patients 
randomised to osimertinib compared with patients randomised to placebo.
Adverse Drug Reactions for Osimertinib Monotherapy
As of 12 November 20221, a total of 52734939 patientsubjects (51554821 NSCLC patients 
and 118 healthy volunteers) have been included in the osimertinib clinical development 
programme (not including those patients enrolled in Named Patient Supply [NPS], Early 
Access Programmes or Real-World Evidence studies). Of these 52734939 patientsubjects, 
30752983 patientsubjects received osimertinib monotherapy (2957865 patients and 118 
healthy volunteers), 1151989 patients received osimertinib in combination with another 
treatment, and 1047967 patients were exposed to comparator treatment (including placebo). 
Of the 1047967 patients exposed to comparator treatment, 16990 patients subsequently 

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crossed over from comparator treatment to osimertinib monotherapy during their respective 
studies. A total of 1129511041 patients have been dosed with osimertinib.
…
Other ADRs associated with administration of osimertinib included interstitial lung disease 
(ILD) or ILD-like adverse reactions (eg, pneumonitis), QTc interval prolongation, keratitis, 
haematological effects, erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic 
epidermal necrolysis (TEN), and aplastic anaemia.
Section 3.2: Text updated to align with the latest safety data and standards.
…
─Demonstrated absence of HIV infection.
….
─Patients with a resolved or chronic infection HBV are eligible if they are:

Negative for HBsAg and positive for hepatitis B core antibody [anti-HBc 
IgG]. In addition, patients must be receiving anti-viral prophylaxis for 2 
to 4 weeks prior to study treatment and 6 to 12 months (TBD by 
hepatologist post treatment.
or

Positive for HBsAg, but for > 6 months have had transaminases levels 
below ULN and HBV DNA levels below < 100 IU/mL (ie, are in an 
inactive carrier state). In addition, patients must be receiving anti-viral 
prophylaxis for 2 to 4 weeks prior to study treatment and 6 to 12 months 
(TBD by hepatologist post treatment. Refer to Section 3.5.
Should patients with HIV infection be included, patients are only eligible if they 
meet ALL of the following criteria:

Undetectable viral RNA load for 6 months

CD4+ count of > 350 cells/µL

No history of AIDS-defining opportunistic infection within the past 12 months

Stable for at least 4 weeks on the same anti-HIV medications.
Section 3.5: to align with the latest safety data and standards, following restrictions were 
added.
6.
Patients should receive HBV anti-viral prophylaxis post treatment as 
determined by their hepatologist.

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7.
In patients with resolved or chronic hepatitis B infection (inactive carrier state) or 
active controlled HBV infection on treatment with osimertinib:
─Recommend monthly monitoring of ALT/AST, HBV DNA levels and HBsAg 
(if negative at baseline)
─Where liver signs and symptoms of viral reactivation appear (HBV DNA 
levels exceeding 10-fold from baseline or ≥100 IU/mL (if baseline HBV 
DNA levels are undetectable) or conversion of HBsAg negative to positive):

Expert hepatologist/specialist oversight of the patient is required

Consider interruption or discontinuation of study treatment, based on 
risk-benefit assessment.
8.
In patients with HIV, viral RNA load and CD4 + cell count should be 
monitored per local SoC (eg, every 3 months).
Section 4.1: Table 1, footnote a and Table 2, footnote p: to align with the latest safety 
data and standards, following was added as a footnote:
“Monthly pregnancy testing and monitoring of WOCBP is recommended, however 
this schedule may be modified to comply with local legislation”.
Section 5.2.1 Laboratory safety assessments, Table 3: to align with the latest safety data 
and standards, addition of laboratory parameter (creatine phosphokinase).
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
..
…
S/P-Magnesium
Creatine phosphokinase
Section 6.8: Table 4: to align with the latest safety data and standards, following details 
were updated:
Table 4
Osimertinib Dose Adjustment Information for Adverse Reactions

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Target organ
Adverse reaction
Dose modification
Cardiac
QTc interval greater than 
500 msec on at least 2 
separate ECGs
Withhold osimertinib until QTc interval is less than 
481 msec or recovery to baseline if baseline QTc is 
more than 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.)
Cutaneous
Stevens-Johnson 
Syndrome and toxic 
epidermal necrolysis 
(TEN)
Permanently discontinue osimertinib
Blood and 
lymphatic 
system
Aplastic anaemia
Permanently discontinue osimertinib
Section 6.8.4: to align with the latest safety data and standards, following details were 
updated:
6.8.4 Erythema multiforme, and Stevens-Johnson syndrome and toxic epidermal 
necrolysis
Case reports of EM and TEN have been uncommonly reported, and SJS have been 
uncommonly and rarely reported, respectively, in association with osimertinib treatment. 
Before initiating treatment, patients should be advised of signs and symptoms of EM, and
SJS and TEN. If signs and symptoms suggestive of EM develop, close patient monitoring 
and drug interruption or discontinuation of osimertinib should be considered. If signs and 
symptoms suggestive of SJS appear, osimertinib should be interrupted. Osimertinib should 
be or discontinued immediately if diagnosis of SJS or TEN is confirmed.
Section 9.3: End of study detail was updated.
…

The study will end by Q2in October20234, as it is estimated that by then there will be 
sufficient data to support study endpoints. If, at this time (Q2October 20234 or at 
another time if AstraZeneca or Regulatory Authorities decide to stop study due to any 
concerns, eg, patient safety), there are ongoing patients who are drawing benefit from 
study treatment, they will be switched to commercial supply and/or another study to 
ensure continuation of treatment, and the study will close using the available data for the 

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final analysis. A CSR will be written at this time, including all data collected during the 
study. 
Section 6.7, Section 7.8, Section 9.3.1, Section 10, Appendix A, Appendix B1: According 
to Late Phase oncology template release note, CSP amendment was updated.
Throughout the document: Minor typographical errors were corrected.

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CLINICAL STUDY PROTOCOL SYNOPSIS
A multicentre, open-label, single-arm, molecular profiling study of patients 
with EGFR mutation-positive locally advanced or metastatic NSCLC 
treated with osimertinib
International Coordinating Investigator
Zofia Piotrowska, MD
Thoracic Oncology
55 Fruit Street
Boston, MA 02114-2696
USA
Study sites and number of patients planned
Approximately 150 patients with epidermal growth factor receptor (EGFR) mutation-positive 
locally advanced or metastatic non-small cell lung cancer will be recruited from multiple 
centres globally.
Phase of development II
Study design
This is a phase II, open-label, single-arm tissue and plasma acquisition study assessing the 
efficacy, safety and underlying resistance mechanisms of osimertinib (80 mg orally, once 
daily) as first-line treatment in patients with locally advanced or metastatic EGFR 
mutation-positive non-small cell lung cancer who are EGFR tyrosine kinase inhibitor 
treatment-naïve and eligible for first-line treatment.
It has been determined that approximately 150 patients need to be recruited to fulfil the 
objectives of the study. EGFR mutation status should be determined based on a tumour biopsy 
or plasma sample by a local laboratory certified by Clinical Laboratory Improvement 
Amendments (United States of America [USA] sites) or an accredited local laboratory (sites 
outside of the USA).

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Secondary Objectives:
Outcome Measures:
To assess the efficacy of osimertinib as first-
line EGFR tyrosine kinase inhibitor therapy for 
patients with EGFR mutation-positive locally 
advanced or metastatic non-small cell lung 
cancer
Progression-free survival, according to RECIST 
1.1 by Investigator assessment, and other selected 
clinical efficacy endpoints including:

Objective response rate

Duration of response

Disease control rate
To assess the efficacy of osimertinib in patient 
subgroups defined by molecular profile, 
including but not limited to:

EGFR Ex19del or L858R mutation

EGFR Ex19del or L858R detectable in 
plasma-derived circulating tumour 
deoxyribonucleic acid
Progression-free survival, according to RECIST 
1.1 by Investigator assessment, and other selected 
clinical efficacy endpoints including:

Objective response rate

Tumour shrinkage/depth of response, defined 
as best change from baseline in target lesion 
tumour size

Time to treatment discontinuation or death

Important patient and disease characteristics
To further assess the efficacy of osimertinib 
post-progression

Time to treatment discontinuation or death

Time to first subsequent therapy or death 
(TFST)
Safety Objective:
Outcome Measures:
To summarise the safety and tolerability 
profile of osimertinib as first-line EGFR 
tyrosine kinase inhibitor therapy for patients 
with EGFR mutation-positive locally advanced 
or metastatic non-small cell lung cancer

Adverse events graded by Common 
Terminology Criteria for Adverse Events 
version 4.0

Clinical chemistry, haematology and 
urinalysis

Vital signs, physical examination, body weight

Electrocardiogram

World Health Organization performance status
Target patient population
Male and female patients aged 18 years and over with locally advanced or metastatic 
pathologically confirmed adenocarcinoma of the lung, not amenable to curative surgery or 
radiotherapy. Patients will have a tumour that harbours one of the EGFR mutations known to 
be associated with EGFR tyrosine kinase inhibitor sensitivity, either alone or in combination 
with other EGFR mutations (EGFR mutation status determined by a local laboratory). Patients 
must be EGFR tyrosine kinase inhibitor treatment-naïve and eligible to receive first-line 
treatment with osimertinib.

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Duration of treatment
Treatment with osimertinib 80 mg once daily will commence following enrolment. A cycle of 
treatment is defined as 28 days of once daily treatment with osimertinib (Cycle 1 to Cycle 6 
inclusive). From Cycle 7 to 3.5 years (Day 1277), a cycle is defined as a 56-day treatment 
period. From 3.5 years to disease progression, a cycle is defined as a 70-day treatment period. 
Patients may continue to receive osimertinib as long as they are continuing to show clinical 
benefit, as judged by the Investigator, and in the absence of discontinuation criteria.
Investigational product, dosage and mode of administration
Osimertinib is an oral, potent, selective, irreversible inhibitor of both EGFR tyrosine kinase 
inhibitor sensitising and resistance mutations in non-small cell lung cancer with a significant 
selectivity margin over wild type EGFR. Osimertinib (80 mg orally, once daily) will be 
administered. Doses may be reduced to 40 mg if needed for the management of toxicity.
Statistical methods
The final analysis will be performed at study end (see Section 9.3 for definition of “end of 
study”), and when approximately 50 patients have evaluable paired biopsies upon progression. 
Assuming a 70% rate of patients having a biopsy at both baseline and progression, and with an 
assumed technical failure rate of 30% of the samples (assume an overall failure rate of 51%), 
then we should expect approximately 50 evaluable paired biopsies to be available when 
approximately 103 of the 150 patients have progressed, which would be expected to occur 
approximately 38 months after the first patient is enrolled. This calculation assumes patients 
are recruited over 12 months, exponentially distributed progression times with a 19-month 
median and a 2-piece recruitment function that assumes an exponentially distributed 
recruitment rate.
This is an exploratory study which may inform other studies in the osimertinib development 
programme and therefore earlier interim analyses may be performed, such interim analyses 
may not be reported in a formal clinical study report (CSR).
Recruitment of 150 patients is appropriate to characterise the frequency of tumour genetic and 
proteomic markers at disease progression regardless of their prevalence. The following table 
displays the precision of the estimated proportion, for example, when 50 evaluable paired 
biopsies are available.
Precision of Estimates of Marker Frequency with 50 Available and Evaluable Paired 
Biopsies
Marker Frequency
95% confidence interval a
10%
(3%, 22%)
30%
(18%, 45%)
50%
(36%, 64%)
a
Exact binomial confidence intervals.

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If a patient progresses in the ELIOS study and then enrols in a subsequent AZ study, and if 
appropriate consent is provided, the biomarker results from a progression biopsy (generated in 
either the other study or ELIOS), may be shared between both studies and the data may be 
analysed as part of the ELIOS study.
The primary data analysis set will include all patients with evaluable paired biopsies. This 
analysis set will be used for the analysis of the primary endpoint. The full analysis set will 
include all patients who receive at least one dose of osimertinib and will be used for all other 
efficacy and safety analyses.
The number of patients with a given tumour genetic and proteomic marker will be divided by 
the number of patients who have evaluable biopsies and have progressed according to the 
Investigator to calculate the proportion with a given marker at progression. Exact binomial 
95% confidence intervals will be calculated.

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TABLE OF CONTENTS
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
CLINICAL STUDY PROTOCOL SYNOPSIS .................................................. 26
TABLE OF CONTENTS................................................................................... 31
1.
INTRODUCTION ............................................................................................. 40
1.1
Background and Rationale for Conducting This Study ....................................... 40
1.2
Rationale for Study Design, Doses and Control Groups...................................... 44
1.3
Benefit/Risk and Ethical Assessment ................................................................. 45
1.4
Study Design...................................................................................................... 45
1.4.1
Study conduct mitigation during study disruptions due to cases of civil 
crisis, natural disaster, or public health crisis...................................................... 47
2
STUDY OBJECTIVES...................................................................................... 48
2.1
Primary Objective .............................................................................................. 48
2.2
Secondary Objectives......................................................................................... 48
2.3
Safety Objective................................................................................................. 49
2.4
Exploratory Objective ........................................................................................ 49
3
PATIENT SELECTION, ENROLMENT, RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL.................................................. 49
3.1
Inclusion Criteria ............................................................................................... 49
3.2
Exclusion Criteria .............................................................................................. 51
3.3
Patient Screening and Enrolment........................................................................ 55
3.4
Procedures for Handling Incorrectly Enrolled Patients ....................................... 55
3.5
Restrictions........................................................................................................ 55
3.6
Discontinuation of Investigational Product......................................................... 57
3.6.1
Procedures for discontinuation of a patient from investigational product ............ 58
3.7
Criteria for Withdrawal...................................................................................... 58
3.7.1
Screen failures ................................................................................................... 58
3.7.2
Withdrawal of informed consent ........................................................................ 59
3.8
Discontinuation of the Study.............................................................................. 59
4
STUDY PLAN AND TIMING OF PROCEDURES........................................... 59
4.1
Screening/Enrolment Period............................................................................... 59

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4.2
Treatment Period................................................................................................ 65
4.2.1
Cycle 1 to 6 inclusive......................................................................................... 65
4.2.2
Cycle 7 and subsequent cycles ........................................................................... 65
4.2.3
Treatment discontinued...................................................................................... 65
4.3
Follow-up Period ............................................................................................... 65
4.3.1
28 days after treatment discontinued .................................................................. 65
4.3.2
Follow-up for RECIST 1.1-defined progression ................................................. 65
5
STUDY ASSESSMENTS.................................................................................. 66
5.1
Efficacy Assessments......................................................................................... 66
5.1.1
Tumour evaluation............................................................................................. 66
5.2
Safety Assessments............................................................................................ 66
5.2.1
Laboratory safety assessments............................................................................ 66
5.2.2
Physical examination ......................................................................................... 67
5.2.3
Electrocardiogram.............................................................................................. 68
5.2.3.1
Resting 12-lead electrocardiogram ..................................................................... 68
5.2.4
Echocardiogram/Multigated acquisition scan ..................................................... 68
5.2.5
Vital signs.......................................................................................................... 68
5.2.6
Other safety assessments.................................................................................... 69
5.2.6.1
Ophthalmologic exam........................................................................................ 69
5.3
Other Assessments............................................................................................. 69
5.3.1
Resistance profiling............................................................................................ 69
5.3.2
Circulating tumour deoxyribonucleic acid and blood-borne biomarkers ............. 70
5.4
Biomarker Analysis............................................................................................ 70
5.4.1
Storage, re-use and destruction of biological samples......................................... 70
5.4.2
Labelling and shipment of biological samples .................................................... 70
5.4.3
Chain of custody of biological samples .............................................................. 70
5.4.4
Withdrawal of informed consent for donated biological samples........................ 71
6
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 71
6.1
Definition of Adverse Events ............................................................................. 71
6.2
Definitions of Serious Adverse Event................................................................. 72
6.3
Recording of Adverse Events............................................................................. 72
6.3.1
Time period for collection of adverse events ...................................................... 72
6.3.2
Follow-up of unresolved adverse events............................................................. 72
6.3.3
Variables............................................................................................................ 73
6.3.4
Causality collection............................................................................................ 74
6.3.5
Adverse events based on signs and symptoms.................................................... 74
6.3.6
Adverse events based on examinations and tests ................................................ 74
6.3.7
Hy’s Law ........................................................................................................... 75
6.3.8
Disease progression............................................................................................ 75
6.3.9
New cancers....................................................................................................... 75
6.3.10
Handling of deaths ............................................................................................. 75

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6.4
Reporting of Serious Adverse Events ................................................................. 75
6.5
Overdose............................................................................................................ 76
6.6
Pregnancy .......................................................................................................... 77
6.6.1
Maternal exposure.............................................................................................. 77
6.6.2
Paternal exposure............................................................................................... 77
6.7
Medication Error, Drug Abuse, and Drug Misuse............................................... 78
6.7.1
Timelines........................................................................................................... 78
6.7.2
Medication Error................................................................................................ 78
6.7.3
Drug Abuse........................................................................................................ 79
6.7.4
Drug Misuse ...................................................................................................... 79
6.8
Management of Investigational Product-Related Toxicities ................................ 80
6.8.1
Interstitial lung disease/pneumonitis-like toxicity............................................... 81
6.8.2
QTc prolongation............................................................................................... 81
6.8.3
Keratitis ............................................................................................................. 82
6.8.4
Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal 
necrolysis........................................................................................................... 82
6.8.5
Aplastic anaemia................................................................................................ 82
6.8.6
Changes in cardiac contractility.......................................................................... 82
7
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 83
7.1
Identity of Investigational Product...................................................................... 83
7.2
Dose and Treatment Regimens........................................................................... 83
7.3
Labelling............................................................................................................ 83
7.4
Storage............................................................................................................... 83
7.5
Compliance........................................................................................................ 84
7.6
Accountability.................................................................................................... 84
7.7
Concomitant and Other Treatments.................................................................... 84
7.7.1
Other concomitant treatment .............................................................................. 84
7.8
Post-study Access to Study Treatment................................................................ 84
8
STATISTICAL ANALYSES BY ASTRAZENECA.......................................... 85
8.1
Statistical Considerations ................................................................................... 85
8.2
Sample Size Estimate......................................................................................... 85
8.3
Definitions of Analysis Sets ............................................................................... 86
8.3.1
Primary analysis set ........................................................................................... 86
8.3.2
Full analysis set.................................................................................................. 86
8.4
Outcome Measures for Analyses ........................................................................ 86
8.4.1
Calculation or derivation of primary endpoint variables ..................................... 86
8.4.2
Calculation or derivation of efficacy variables.................................................... 87

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8.4.3
Calculation or derivation of safety variables....................................................... 88
8.5
Methods for Statistical Analyses ........................................................................ 89
8.5.1
Analysis of the primary variables ....................................................................... 89
8.5.2
Analysis of the secondary variables.................................................................... 89
8.5.3
Subgroup analysis.............................................................................................. 89
8.5.4
Exploratory analysis........................................................................................... 90
9
STUDY AND DATA MANAGEMENT BY ASTRAZENECA......................... 90
9.1
Training of Study Site Staff................................................................................ 90
9.2
Monitoring of the Study..................................................................................... 90
9.2.1
Source data ........................................................................................................ 91
9.2.2
Study agreements............................................................................................... 91
9.2.3
Archiving of study documents............................................................................ 91
9.3
Study Timetable and End of Study..................................................................... 91
9.3.1
End of Study Definition ..................................................................................... 92
9.4
Data Management .............................................................................................. 93
10
ETHICAL AND REGULATORY REQUIREMENTS....................................... 94
10.1
Ethical Conduct of the Study.............................................................................. 94
10.2
Patient Data Protection....................................................................................... 94
10.3
Ethics and Regulatory Review............................................................................ 94
10.4
Informed Consent............................................................................................... 95
10.5
Changes to the Clinical Study Protocol and Informed Consent Form.................. 95
10.6
Audits and Inspections ....................................................................................... 96
11
LIST OF REFERENCES ................................................................................... 97
LIST OF TABLES
Table 1
Screening (Visit 1) Study Schedule .......................................................59
Table 2
Study Schedule – On Study Treatment and Discontinuation ..................61
Table 3
Laboratory Safety Variables..................................................................67
Table 4
Osimertinib Dose Adjustment Information for Adverse Reactions.........80
Table 5
Dose Interventions ................................................................................81
Table 6
Precision of Estimates of Marker Frequency with 50 Available and 
Evaluable Paired Biopsies.....................................................................86
Table E1
Drugs Inducing CYP3A4 .................................................................... 116

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Table E2
Exposure, Pharmacological Action and Toxicity May be Increased 
by Osimertinib .................................................................................... 117
Table E3
Drugs With a Known Risk of TdP a..................................................... 118
LIST OF FIGURES
Figure 1
Study Flow Chart ..................................................................................46
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................98
Appendix B
Additional Safety Information............................................................. 105
Appendix C
International Airline Transportation Association (IATA) 6.2 
Guidance Document............................................................................ 110
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ...................................................................... 111
Appendix E
Guidance Regarding Potential Interactions with Concomitant 
Medications ........................................................................................ 116
Appendix F
Guidelines for Evaluation of Objective Tumour Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid 
Tumours) ............................................................................................ 120
Appendix G
Definition of Women of Childbearing Potential and Highly 
Effective Contraceptive Methods ........................................................ 128
Appendix H
Changes Related to Mitigation of Study Disruptions Due to Cases 
of Civil Crisis, Natural Disaster, or Public Health Crisis...................... 130

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
ADR
Adverse drug reaction
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BCRP
Breast Cancer Resistance Protein
BICR
Blinded Independent Central Review
CDS
Core Data Sheet
CI
Confidence interval
CIOMS
Council for International Organizations of Medical Sciences
cMET
Proto-oncogene encoding hepatocyte growth factor receptor
CNS
Central nervous system
CRO
Contract Research Organisation
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
Circulating tumour deoxyribonucleic acid
CYP
Cytochrome P
DCO
Data cut-off
DCR
Disease control rate
DILI
Drug-induced liver injury
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
DoR
Duration of response
ECG
Electrocardiogram
eCRF
Electronic case report form
EGFR
Epidermal growth factor receptor
EGFRm+
Epidermal growth factor receptor mutation-positive

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Abbreviation or 
special term
Explanation
EM
Erythema multiforme
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
Hb
Haemoglobin
HBV
Hepatitis B virus
HER2
Human epidermal growth factor receptor 2
HIV
Human immunodeficiency virus
HL
Hy’s Law
HR
Hazard ratio
HRCT
High-resolution computed tomography
IATA
International Airline Transportation Association
IB
Investigator brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
ILD
Interstitial lung disease
IMP
Investigational medicinal product
INR
International normalised ratio
International 
Coordinating 
Investigator
If a study is conducted in several countries the International Coordinating 
Investigator is the Investigator coordinating the Investigators and/or 
activities internationally
IO
Immune-oncology
IP
Investigational product, also referred to as ‘study drug’ and ‘study 
treatment’ in this protocol 
IRB
Institutional Review Board, synonymous to Ethics Committee
ITT
Intent to Treat
IUD
Intrauterine Device
IUS
Intrauterine System
IVRS/IWRS
Interactive Voice Response System/Interactive Web Response System
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities

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Abbreviation or 
special term
Explanation
MRI
Magnetic resonance imaging
MUGA
Multigated acquisition scan
NCI
National Cancer Institute
NGS
Next Generation Sequencing
NSCLC
Non-small cell lung cancer
NTL
Non-target lesion
OAE
Other significant adverse event
ORR
Objective response rate
OS
Overall survival
PAS
Primary analysis set
PFS
Progression-free survival
P-gp
P-glycoprotein
PHL
Potential Hy’s Law
PK
Pharmacokinetics
PR
Partial response
PXR
Pregnane X receptor
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected using Fridericia’s correction
RECIST
Response Evaluation Criteria in Solid Tumours 
RR
Response rate
SAE
Serious adverse event 
SAP
Statistical analysis plan
SD
Stable disease
SJS
Stevens-Johnson syndrome
SoC
Standard of Care
T790M
Amino acid substitution at position 790 in EGFR, from a threonine to a 
methionine
TBL
Total bilirubin
TdP
Torsades de Pointes
TFST
Time to first subsequent therapy or death
TKI
Tyrosine kinase inhibitor
TL
Target lesions

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Abbreviation or 
special term
Explanation
TNM
Tumour, Node, and Metastasis Classification of Malignant Tumours
TTD
Time to treatment discontinuation or death
ULN
Upper limit of normal
USA
United States of America
WBDC
Web based data capture
WHO
World Health Organization
WOCBP
Women of childbearing potential

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1.
INTRODUCTION
1.1
Background and Rationale for Conducting This Study
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
Epidermal growth factor receptor (EGFR) inhibition is the standard of care (SoC) for locally 
advanced or metastatic non-small cell lung cancer (NSCLC) in patients with EGFR-activating 
mutations. In approximately 50 to 60% of patients, resistance to EGFR tyrosine kinase 
inhibitor (TKI) agents develops by acquiring a T790M mutation (amino acid substitution at 
position 790 in EGFR, from a threonine to a methionine) (Cross et al 2014, Kuiper et al 2014, 
Li et al 2014, Oxnard et al 2011, Yu et al 2013).
Multiple clinical trials in patients with an activating mutation of the EGFR gene have 
compared different first- or second-generation oral EGFR TKIs. Several studies have 
consistently demonstrated that EGFR TKIs (gefitinib, erlotinib, and afatinib) produce higher 
response rates (RRs), longer progression-free survival (PFS), and improve quality of life 
compared with standard platinum-based doublet chemotherapy in patients with good 
performance status (Grade 0-2) whose tumour harbours an activating (sensitising) EGFR 
mutation. RRs and median PFS intervals for gefitinib, erlotinib, and afatinib are 55% to 74% 
and 9 to 10 months, 58% to 83% and 9 to 13 months, and 58% to 61% and 9 to 11 months, 
respectively (Asami and Atagi 2016). Based on the results of previous prospective studies, 
these EGFR TKIs seem to demonstrate comparable efficacy with regard to RR and PFS in 
patients with locally advanced or metastatic EGFR-mutated NSCLC.
Osimertinib Mechanism of Action
Investigators should be familiar with the current Investigator Brochure (IB).
Osimertinib (AZD9291, TAGRISSO) is an oral, potent, irreversible EGFR-TKI selective for 
EGFR-TKI-sensitising and T790M resistance mutations with a significant selectivity margin 
over wild type EGFR. As a result, osimertinib can effectively block EGFR signalling both in 
EGFR single mutant cells with activating EGFR mutations and in double mutant cells bearing 
both the primary EGFR-activating and secondary resistance T790M mutation. Osimertinib is 
currently under investigation as a treatment option in 1) patients with advanced T790M 
mutation-positive NSCLC who have previously failed an EGFR TKI; 2) patients with 
advanced EGFR-mutated NSCLC who are treatment-naïve; and 3) in combination with novel 
agents for patients with EGFR TKI-resistant NSCLC.
Osimertinib is approved for:

the adjuvant treatment after complete tumour resection in patients with NSCLC whose 
tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

the first-line treatment of patients with locally advanced or metastatic NSCLC whose 
tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

the treatment of patients with locally -advanced or metastatic EGFR T790M mutation-
positive NSCLC whose disease has progressed on or after EGFR TKI therapy.

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Experience with osimertinib in NSCLC
Clinical experience with osimertinib is described in the current version of the IB. Please refer 
to the IB for details of the clinical programme.
In the phase I/II AURA study (D5160C00001), osimertinib was administered to patients with 
locally advanced or metastatic EGFR mutation-positive (EGFRm+) NSCLC 
(Gil-Bazo and Rolfo 2016). Promising efficacy results were observed in 127 patients 
evaluable for response among the 138 patients with T790M mutation-positive disease 
confirmed by central testing who were previously treated with an EGFR TKI: objective 
response rate (ORR) was 61% (95% confidence interval [CI], 52%-70%), and disease control 
rate (DCR; complete response + partial response + stable disease) was 95% 
(95% CI, 90%-98%). In the 138 patients with detectable T790M mutation-positive disease, the 
median PFS based on 30% maturity of data was 9.6 months (95% CI, 8.3-not reached), and 
88% of these patients had an estimated duration of response (DoR) of 6 months or longer 
(Jänne et al 2015).
Promising evidence of efficacy has also been observed in patients with treatment-naïve 
NSCLC treated with osimertinib as the first-line EGFR TKI. Results are available from 
2 phase I expansion cohorts in which patients received osimertinib as first-line treatment in 
the AURA study (n = 60; 30 patients on 80 mg per day and 30 patients on 160 mg per day). 
The median follow-up at the data cut-off (DCO) date of 04 Jan 2016 was 16.6 months. The 
overall RR was 77% (95% CI, 64%-87%), which was amongst the best reported for first-line 
therapy of EGFR-mutated locally advanced or metastatic NSCLC. The overall DCR was 
98% (95% CI: 89%-100%). The maximum DoR was 22.1 months (patient ongoing in 
response at 04 Jan 2016). The median PFS was 19.3 months; data were immature with respect 
to DoR and PFS, but the lower 95% CIs for the median were 12.5 months for DoR and 
13.7 months for PFS. The percentage of patients remaining progression-free at 12 months was 
72% (95% CI: 59%-82%) and 55% (95% CI: 41%-67%) at 18 months. The drug was well 
tolerated with few adverse events (AEs), particularly at the approved 80 mg dose, where just 
10% of patients required dose reduction to manage toxicities. Initial data suggest that patients 
who had disease progression did not have a T790M mutation as the mechanism of resistance, 
suggesting that first-line treatment with osimertinib may be beneficially changing the biology 
of the disease.
First-line EGFRm NSCLC
In a phase III study (FLAURA study; D5160C00007), a total of 673 patients with 
locally-advanced or metastatic EGFRm NSCLC have been dosed with first-line treatment in 
the FLAURA study (in both the Global cohort and the China cohort) (Soria et al 2018).
Of the 556 patients randomised in the Global cohort, 279 received osimertinib 80 mg once 
daily and 277 received the SoC (gefitinib or erlotinib). At data cut-off 1 (DCO1) 
(12 June 2017), the data provided strong evidence for the clinical benefit of osimertinib for the 
first-line treatment of patients with locally advanced or metastatic NSCLC whose tumours 
have EGFR with Ex19Del or L858R activating mutations, with a median Investigator-

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assessed PFS of 18.9 months with osimertinib and 10.2 months with SoC, representing an 8.7-
month improvement for osimertinib compared with SoC (p < 0.0001; hazard ratio [HR] 0.46; 
95% CI 0.37, 0.57).
Data from the FLAURA study also confirmed the superior CNS efficacy results in first-line 
setting that have been reported in later lines of therapy with osimertinib. There was a 
statistically significant (p = 0.014) and clinically meaningful improvement in CNS PFS in the 
osimertinib arm compared with the SoC arm based on CNS Blinded Independent Central 
Review (BICR; HR: 0.48 [95% CI: 0.26, 0.86]), indicating a 52% reduction in the risk of CNS 
disease progression or death in the osimertinib arm compared to the SoC arm.
At DCO2 (25 June 2019), final overall survival (OS) analysis in the global study, 
321/556 patients had died (
). The HR 
for OS was 0.799 (adjusted 95.05% CI: 0.6406, 0.9968), signifying a 20% lower risk of death 
in the osimertinib arm compared with the SoC arm. The difference between treatment arms in 
favour of osimertinib was statistically significant, as the p-value of 0.0462 was below the 
pre-defined level of 0.0495 required at this analysis. Median OS was 38.6 (95% CI: 34.5, 
41.8) months in the osimertinib arm, and 31.8 (95% CI: 26.6, 36.0) months in the SoC arm, a 
difference of 6.8 months. Post-progression outcomes showed a clinically relevant longer time 
from randomisation to TFST or death for patients on osimertinib compared to patients on SoC 
(HR: 0.478 [95% CI: 0.3927, 0.5810]; 2-sided p < 0.0001). There was also a clinically 
relevant longer time to second subsequent therapy for patients on osimertinib compared to 
patients on SoC (HR: 0.687 [95% CI: 0.5610, 0.8424]; 2-sided p = 0.0003).
Adjuvant EGFRm NSCLC
The effectiveness of osimertinib in the adjuvant setting was investigated in the Phase III 
ADAURA study, which investigated the use of osimertinib versus placebo in patients with 
stage IB-IIIA NSCLC with a centrally confirmed common EGFRm mutation (Ex19del and/or 
L858R, either alone or in combination with other EGFR mutations), who had undergone 
complete tumour resection, with or without postoperative adjuvant platinum-based 
chemotherapy. A total of 682 patients were randomised to treatment, of whom 337 osimertinib 
arm patients and 343 placebo arm patients received at least 1 dose of study treatment. At the 
DCO of the primary analysis (17 January 2020), in patients with stage II-IIIA disease, a 
statistically significant and clinically meaningful improvement in DFS for patients randomised 
to receive osimertinib versus placebo was observed (HR: 0.17; 99.06% CI: 0.11, 0.26; 
p < 0.0001). A greater proportion of osimertinib arm patients was alive and disease-free at all 
assessed timepoints compared with those in the placebo arm. At the DCO of the DFS analysis 
(11 April 2022), the DFS HR for HR for patients with stage II-IIIA disease was 0.23 (95% CI: 
0.18, 0.30), demonstrating a clinically meaningful 77% reduction in the risk of disease 
recurrence or death for patients randomised to osimertinib compared with patients randomised 
to placebo.
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Osimertinib 80 mg, oral, once daily has an acceptable safety profile in patients receiving 
treatment for NSCLC, in both the adjuvant and advanced NSCLC treatment settings. In the 
pivotal osimertinib clinical development programme to date (n = 
patients), the majority 
of adverse drug reactions (ADRs) were Common Terminology Criteria for Adverse Events 
(CTCAE) Grade 1 or 2 in severity. The most commonly reported ADRs were diarrhoea (47%) 
and rash (45%), paronychia (33%), dry skin (32%), and stomatitis (24%). Other ADRs 
associated with administration of osimertinib included interstitial lung disease (ILD) or 
ILD-like adverse reactions (eg, pneumonitis), QTc interval prolongation, keratitis, 
haematological effects, erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic 
epidermal necrolysis (TEN), and aplastic anaemia.
Based on the available clinical trial data, cardiac failure is considered to be an important 
potential risk; however, a causal relationship between changes in cardiac contractility and 
osimertinib has not been established. In the placebo-controlled ADAURA study, 1.6% (5/312) 
of patients treated with osimertinib and 1.5% (5/331) of patients treated with placebo 
experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less 
than 50%.
1.2
Rationale for Study Design, Doses and Control Groups
Study D5160C00007 A Phase III, Double-Blind Randomised Study to Assess the efficacy and 
safety of osimertinib versus SoC EGFR TKI as first-line treatment in patients with EGFRm+ 
locally advanced or metastatic NSCLC (FLAURA) has demonstrated a significant benefit for 
osimertinib vs SoC EGFR TKIs with respect to efficacy endpoints. It is hypothesised that 
osimertinib may deliver this clinical benefit in the first-line setting by preventing the most 
common type of EGFR TKI resistance observed in NSCLC patients with acquired EGFR TKI 
resistance (T790M-mediated resistance).
This study is an uncontrolled, single-arm study in patients with locally advanced or metastatic 
EGFRm+ NSCLC. The study will investigate whether the use of osimertinib as first-line 
therapy will result in favourable efficacy due to delayed T790M-mediated resistance. 
Additionally, while it is known that 50% to 60% of patients receiving first- and 
second-generation EGFR TKIs first-line will progress on treatment due T790M-mediated 
resistance, the mechanisms of resistance to osimertinib first-line are not well characterised, 
and this study aims to investigate these further.
The primary objective of this study is to examine and compare the tumour molecular profile at 
or after the point of disease progression with that prior to treatment initiation in patients 
receiving osimertinib as first-line EGFR TKI therapy. To gain a better understanding of 
resistance mechanisms in patients receiving osimertinib treatment, tumour tissue and plasma 
samples will be examined for tumour genetic and non-genetic aberrations that may be 
important in determining response and resistance to treatment. Two mandatory tumour 
biopsies will be taken: the first biopsy before initiating osimertinib treatment and the second 
biopsy at any time between Investigator-assessed, Response Evaluation Criteria in Solid 
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Tumours version 1.1 (RECIST 1.1)-defined progression and before the start of any new 
anticancer treatment, as indicated in the Schedule of Assessments (see Table 2).
The secondary endpoints are those that are appropriate to determine efficacy in this patient 
population and include PFS, ORR, DoR, and DCR.
Once-daily doses of 20, 40, 80, 160 and 240 mg of osimertinib were evaluated in the dose 
escalation phase of the AURA study (D5160C00001). Based on the totality of the safety, 
pharmacokinetic, and preliminary efficacy data, 80 mg once daily was selected as the 
recommended phase II dose. Efficacy of osimertinib 80 mg as first-line treatment in patients 
with EGFRm+ locally advanced or metastatic NSCLC with respect to mPFS has been 
demonstrated in the first analysis of data from the FLAURA study. Please refer to the IB for 
additional details. No dosage adjustment is required due to patient age, body weight, gender, 
ethnicity, or smoking status. All patients will receive 80 mg once daily in this study. If 
patients continue to show clinical benefit to treatment as judged by the Investigator, patients 
may continue to receive osimertinib beyond RECIST 1.1-defined progression. Therefore, 
there is no maximum duration of treatment.
1.3
Benefit/Risk and Ethical Assessment
Please see the current edition of the IB (Sections 5.2 and 5.4) for the most recent summary of 
the risks of osimertinib.
Preclinical data and clinical efficacy and safety data from the FLAURA study 
(D5160C00007) support the hypothesis that osimertinib monotherapy is an effective first-line 
treatment of NSCLC tumours driven via the EGFR pathway.
The safety profile of osimertinib in the first-line setting in the FLAURA study was favourable 
with the majority of toxicities being Grade 1 or 2 EGFR-related AEs, ie, diarrhoea, dry skin 
and paronychia (Soria et al 2018). The safety profile of osimertinib in the first-line setting was 
consistent with the existing safety profile for osimertinib in the second line and later setting. 
All trials of osimertinib, including the present study, exclude patients with clinically 
significant toxicities related to prior treatments and they exclude patients with a history of ILD 
or clinically active ILD as this is an uncommon but well documented EGFR-related toxicity.
It is therefore, reasonable and appropriate to evaluate osimertinib monotherapy as first-line 
treatment in EGFRm+ NSCLC patients, according to the proposed study design.
1.4
Study Design
This is a phase II, open-label, single-arm tissue and plasma acquisition study assessing the 
efficacy and safety of osimertinib (80 mg orally, once daily) as first-line treatment in 
EGFR TKI treatment-naïve patients with locally advanced or metastatic EGFRm + NSCLC, 
and the underlying resistance mechanisms to treatment (Figure 1).

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Figure 1
Study Flow Chart

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1.4.1
Study conduct mitigation during study disruptions due to cases of civil crisis, 
natural disaster, or public health crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis 
(eg, during quarantines and resulting site closures, regional travel restrictions, and 
considerations if site personnel or study patients become infected with SARS-CoV-2 or 
similar pandemic infection) which would prevent the conduct of study-related activities at 
study sites, thereby compromising the study site staff or the patient’s ability to conduct the 
study. The Investigator or designee should contact the study Sponsor to discuss whether the 
mitigation plans below should be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study patients, maintain 
compliance with Good Clinical Practice, and minimise risks to study integrity.
Where allowable by local health authorities, Ethics Committees, healthcare provider 
guidelines (eg, hospital policies) or local government, these changes may include the 
following options:

Obtaining consent/reconsent for the mitigation procedures (note, in the case of 
verbal consent/reconsent, the ICF should be signed at the patient’s next contact with 
the study site).

Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened patients. 
The Investigator should confirm this with the designated Study Physician.

Home or Remote visit: Performed by a site qualified HCP or HCP provided by a 
third-party vendor.

Telemedicine visit: Remote contact with the patients using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices.

At-home investigational product (IP) administration: Performed by a site qualified 
HCP, HCP provided by a third-party vendor, or by the patients or the patient’s 
caregiver, if possible. Additional information related to the visit can be obtained via 
telemedicine.
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
see Appendix H.

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2
STUDY OBJECTIVES
2.1
Primary Objective
Primary Objective:
Outcome Measure:
To examine the tumour genetic and proteomic 
profile at the point of disease progression in 
patients receiving osimertinib as first-line 
EGFR TKI therapy for EGFRm+ locally 
advanced or metastatic NSCLC compared to 
the profile prior to initiation of treatment
Proportion of patients with a given tumour genetic 
and proteomic marker (including, but not limited 
to, EGFR mutations, human epidermal growth 
factor receptor 2 [HER2], and proto-oncogene 
encoding hepatocyte growth factor receptor 
[cMET] expression and/or amplification) at the 
point of disease progression as defined by the 
Investigator; the choice of markers is dependent on 
the profile comparison at the point of disease 
progression and prior to treatment initiation
2.2
Secondary Objectives
Secondary Objectives:
Outcome Measures:
To assess the efficacy of osimertinib as 
first-line EGFR TKI therapy for patients with 
EGFRm+ locally advanced or metastatic 
NSCLC
PFS, according to RECIST 1.1 by Investigator 
assessment, and other selected clinical efficacy 
endpoints including:

ORR

DoR

DCR
To assess the efficacy of osimertinib in patient 
subgroups defined by molecular profile, 
including but not limited to:

EGFR Ex19del or L858R mutation

EGFR Ex19del or L858R detectable in 
plasma-derived circulating tumour 
deoxyribonucleic acid (ctDNA)
PFS, according to RECIST 1.1 by Investigator 
assessment, and other selected clinical efficacy 
endpoints including:

ORR

Tumour shrinkage/depth of response, defined 
as best change from baseline in target lesion 
tumour size

Time to treatment discontinuation or death 
(TTD)

Important patient and disease characteristics
To further assess the efficacy of osimertinib 
post-progression

TTD

Time to first subsequent therapy or death 
(TFST)

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3.
Patients with histological confirmation of locally advanced or metastatic, 
non-squamous NSCLC who are not candidates for local curative treatment.
4.
Patients with M1 stage according to the Tumour, Node, and Metastasis 
Classification of Malignant Tumours (TNM) version 7 including M1a (malignant 
effusion) or M1b (distant metastasis), or locally advanced disease that is not a 
candidate for curative treatment (including patients who progress after 
chemo-radiotherapy in stage III disease).
5.
Patients with an EGFR deletion or mutation known (from tumour biopsy or plasma) 
to be associated with EGFR TKI sensitivity before treatment assessed by a local 
laboratory certified by Clinical Laboratory Improvement Amendments (USA sites) 
or an accredited local laboratory (sites outside of the USA).
6.
Existence of measurable or evaluable disease (as per RECIST 1.1 criteria).
7.
Possibility of obtaining sufficient tissue sample, via a biopsy or surgical resection of 
the primary tumour or metastatic tumour tissue, within the 60 days prior to study 
entry and at or after RECIST 1.1-defined progression. An archival biopsy is 
acceptable as long as there has been no intervening anticancer treatment since the 
time the biopsy was obtained to enrolment in this clinical study and as long as it 
was within 60 days of study entry. A sufficient tissue sample would consist of 
formalin-fixed, paraffin-embedded tumour tissue blocks, or at least 15 re-cut 
unstained sections from formalin-fixed paraffin-embedded tumour tissue block, 
presented on slides. Each section should be 5 μm thick.
8.
WHO performance status 0-1.
9.
Life expectancy ≥ 12 weeks.
10.
Capacity to swallow.
11.
Patients able to complete study and within geographical proximity allowing for 
adequate follow-up.
12.
Resolution of all acute toxic effects of previous anticancer therapy (which can only 
be adjuvant or neoadjuvant) or surgical interventions to Grade 1 according to the 
National Cancer Institute (NCI) CTCAE version 4.0 (except for alopecia or other 
side effects that the Investigator does not consider to be a risk to patient safety).
13.
Female patients must be using highly effective contraceptive measures, and must 
have a negative pregnancy test prior to start of dosing if of childbearing potential or 
must have evidence of non-childbearing potential by fulfilling one of the following 
criteria at screening:

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─Postmenopausal defined as aged 50 years or more and amenorrhoeic for at least 
12 months following cessation of all exogenous hormonal treatments.
─Women under 50 years old would be considered postmenopausal if they have 
been amenorrhoeic for 12 months or more following cessation of exogenous 
hormonal treatments and with luteinising hormone and follicle -stimulating 
hormone levels in the postmenopausal range for the institution.
─Documentation of irreversible surgical sterilisation by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation.
14.
Male patients must be willing to use barrier contraception (see Restrictions, 
Section 3.5).
3.2
Exclusion Criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Locally advanced lung cancer candidate for curative treatment through radical 
surgery and/or radio(chemo)therapy.
2.
Patients diagnosed with another lung cancer subtype, patients with mixed NSCLC 
with predominantly squamous cell cancer, or with any small cell lung cancer 
component.
3.
Patients with an EGFR exon 20 insertion.
4.
Patients with just one measurable or evaluable tumour lesion that has been resected 
or irradiated prior to their enrolment in the study.
5.
Second active neoplasia.
6.
Treatment with an investigational drug within five half-lives of the compound.
7.
Participation in another clinical study with an IP during the last 3 weeks before the 
first day of study treatment.
8.
Patients who have received prior immunotherapies.
9.
Patients who have received prior EGFR treatments for lung cancer.
10.
Patients who have received prior treatment with an EGFR TKI including in the 
adjuvant setting.
11.
Patients who have received previous treatment for metastatic or stage IV disease.

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12.
Prior treatment with cytotoxic chemotherapy for advanced NSCLC 
(neoadjuvant/adjuvant chemotherapy is permitted if at least 6 months have elapsed 
between the end of chemotherapy and the first day of study treatment).
13.
Patients with a history of cancer that has been completely treated, with no evidence 
of malignant disease currently cannot be enrolled in the study if their chemotherapy 
was completed less than 6 months prior and/or have received a bone marrow 
transplant less than 2 years before the first day of study treatment.
14.
Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the 
time of starting study treatment with the exception of alopecia and Grade 2, prior 
platinum-therapy related neuropathy.
15.
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, or active infection (eg, patients receiving 
treatment for infection) including hepatitis C and human immunodeficiency virus 
(HIV), or active uncontrolled Hepatitis B virus (HBV) infection.
─Screening for chronic conditions is not required.
Should patients with HBV infection be included, patients are only eligible if they 
meet all the following criteria:
─Demonstrated absence of HCV co-infection or history of HCV co-infection.
─Demonstrated absence of HIV infection.
─Patients with active HBV infection are eligible if they are:

Receiving anti-viral treatment for at least 6 weeks prior to study treatment, 
HBV DNA is suppressed to < 100 IU/mL and transaminase levels are 
below upper limit of normal (ULN).
─Patients with a resolved or chronic infection HBV are eligible if they are:

Negative for HBsAg and positive for hepatitis B core antibody [anti-HBc 
IgG]. In addition, patients must be receiving anti-viral prophylaxis for 2 to 
4 weeks prior to study treatment.
or

Positive for HBsAg, but for > 6 months have had transaminases levels 
below ULN and HBV DNA levels below < 100 IU/mL (ie, are in an 
inactive carrier state). In addition, patients must be receiving anti-viral 
prophylaxis for 2 to 4 weeks prior to study treatment. Refer to Section 3.5.

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Should patients with HIV infection be included, patients are only eligible if they 
meet ALL of the following criteria:
─Undetectable viral RNA load for 6 months
─CD4+ count of > 350 cells/µL
─No history of AIDS-defining opportunistic infection within the past 12 months
─Stable for at least 4 weeks on the same anti-HIV medications.
16.
Patients who have had a surgical procedure unrelated to the study within 14 days or 
major surgery within 1 month prior to the administration of the study drug; patients 
with a significant traumatic lesion (as judged by the Investigator that would risk 
patient safety) during the 4 weeks prior to starting the administration of the study 
drug; patients who have not recovered from the side effects of any major surgery; or 
patients who might need major surgery during the course of the study.
17.
Past medical history of ILD, drug-induced ILD, radiation pneumonitis which 
required corticosteroid treatment, or any evidence of clinically active ILD.
18.
Any of the following cardiac criteria:
─Mean resting QT interval corrected for heart rate (QTc) > 470 msec, obtained 
from 3 ECGs, using the screening clinic ECG machine-derived QTc value.
─Any clinically important abnormalities in rhythm, conduction or morphology of 
resting ECG, eg, complete left bundle branch block, third-degree heart block, 
and second-degree heart block.
─Any factors that increase the risk of QTc prolongation or risk of arrhythmic 
events such as heart failure, hypokalaemia, hypomagnesaemia, hypocalcaemia, 
congenital long QT syndrome, family history of long QT syndrome or 
unexplained sudden death under 40 years of age in first degree relatives or any 
concomitant medication known to prolong the QT interval.
19.
Spinal cord compression, symptomatic and unstable brain metastases except for 
those patients who have completed definitive therapy and have had a stable 
neurological status for at least 2 weeks after completion of definitive therapy. 
Patients may be on corticosteroids to control brain metastases if they have been on a 
stable dose for 2 weeks (14 days) prior to the start of study treatment and are 
clinically asymptomatic.

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20.
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.
21.
Inadequate bone marrow reserve or organ function as demonstrated by any of the 
following laboratory values:
─Absolute neutrophil count < 1.5 x 109/L.
─Platelet count < 100 x 109/L.
─Haemoglobin (Hb) < 90 g/L.
─Alanine aminotransferase (ALT) > 2.5 times the ULN if no demonstrable liver 
metastases or > 5 times ULN in the presence of liver metastases.
─Aspartate aminotransferase (AST) > 2.5 times ULN if no demonstrable liver 
metastases or > 5 times ULN in the presence of liver metastases.
─Total bilirubin (TBL) > 1.5 times ULN if no liver metastases or >3 times ULN 
in the presence of documented Gilbert’s Syndrome (unconjugated 
hyperbilirubinaemia) or liver metastases.
─Creatinine > 1.5 times ULN concurrent with creatinine clearance < 50 mL/min 
(measured or calculated by Cockcroft and Gault equation); confirmation of 
creatinine clearance is only required when creatinine is > 1.5 times ULN.
22.
Female patients who are breastfeeding.
23.
Patients currently receiving (or unable to stop use prior to receiving the first dose of 
study treatment) medications or herbal supplements known to be potent inducers of 
cytochrome (CYP) 3A4 (at least 3 weeks prior; Appendix E). All patients must try 
to avoid concomitant use of any medications, herbal supplements, and/or ingestion 
of foods with known inducer effects on CYP3A4.
24.
Patient unwilling to undergo a biopsy at the time of disease progression.
25.
History of hypersensitivity to active or inactive excipients of osimertinib or drugs 
with a similar chemical structure or class to osimertinib.
26.
Judgement 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.
27.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site).

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28.
Previous enrolment in the present study.
For procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Patient Screening and Enrolment
Investigators should keep a record, the patient screening log, of patients who entered pre-study 
screening.
The Investigators will:
1.
Determine patient eligibility (see Section 3.1 and Section 3.2).
2.
Obtain signed informed consent from the potential patient or their guardian/legal 
representative before any study specific procedures are performed.
3.
Assign potential patient a unique enrolment number, beginning with ‘E#’ 
(generated in the Interactive Voice Response System/Interactive Web Response 
System [IVRS/IWRS]).
If a patient withdraws from participation in the study, then his/her enrolment code cannot be 
re-used.
3.4
Procedures for Handling Incorrectly Enrolled Patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Patients who are 
enrolled, but subsequently found not to meet all the eligibility criteria must not be initiated on 
treatment, and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is enrolled in error, or incorrectly 
started on treatment, the Investigator should inform the AstraZeneca Study Physician 
immediately, and a discussion should occur between the AstraZeneca Study Physician and the 
Investigator regarding whether to continue or discontinue the patient from treatment. The 
AstraZeneca Study Physician must ensure all decisions are appropriately documented.
3.5
Restrictions
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after:
1.
Females of childbearing potential should use highly effective methods of 
contraception from the time of screening until 6 weeks after discontinuing study 
treatment. Highly effective methods are provided in Appendix G.
2.
Male patients should be asked to use barrier contraceptives (ie, by use of condoms) 
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washout period of 4 months. Female partners (of childbearing potential) of male 
patients must also use a highly effective method of contraception throughout this 
period. Male patients should avoid procreation for 4 months after completion of 
study treatment. Patients should refrain from donating sperm from the start of 
dosing until 4 months after discontinuing study treatment.
3.
Once enrolled, all patients must try to avoid concomitant use of medications, herbal 
supplements, and/or ingestion of foods that are known to be strong inducers of 
CYP3A4 whenever feasible, but patients may receive any medication that is 
clinically indicated for treatment of AEs. Such drugs must have been discontinued 
for an appropriate period before they enter screening and for a period of 3 weeks 
after the last dose of osimertinib. All concomitant medications should be captured 
on the electronic case report form (eCRF). Guidance on medicines to avoid, 
medications that require close monitoring, and on washout periods is provided (see 
Appendix E).
4.
If medically feasible, patients taking regular medication, with the exception of 
potent inducers of CYP3A4 (see above), should be maintained on their regular 
medication throughout the study period. Patients taking concomitant medications 
whose disposition is dependent upon Breast Cancer Resistance Protein (BCRP) 
and/or P-glycoprotein (P-gp), and which have a narrow therapeutic index should be 
closely monitored for signs of changed tolerability as a result of increased exposure 
of the concomitant medication while receiving osimertinib. Guidance on 
medications to avoid, medications that require close monitoring and on washout 
periods is provided (see Appendix E).
Patients taking rosuvastatin should have creatine phosphokinase levels monitored 
(due to BCRP-mediated increase in exposure). If the 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.
Patients who have received prior treatment with immune-oncology (IO) therapies 
should be closely monitored for an appropriate period of time after the last dose of 
the IO treatment, in accordance with the respective IO label, as immune-mediated 
adverse reactions with the IO therapy may occur at any time during or after 
discontinuation of therapy. The stop date of the prior IO drug therapy should be 
captured in the eCRF.
5.
Patients should receive HBV anti-viral prophylaxis post treatment as determined by 
their hepatologist. 
6.
In patients with resolved or chronic hepatitis B infection (inactive carrier state) or 
active controlled HBV infection on treatment with osimertinib:

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─Recommend monthly monitoring of ALT/AST, HBV DNA levels and HBsAg 
(if negative at baseline)
─Where liver signs and symptoms of viral reactivation appear (HBV DNA levels 
exceeding 10-fold from baseline or ≥100 IU/mL (if baseline HBV DNA levels 
are undetectable) or conversion of HBsAg negative to positive):

Expert hepatologist/specialist oversight of the patient is required

Consider interruption or discontinuation of study treatment, based on 
risk-benefit assessment.
7.
In patients with HIV, viral RNA load and CD4 + cell count should be monitored per 
local SoC (eg, every 3 months).
3.6
Discontinuation of Investigational Product
Patients may be discontinued from IP in the following situations:

Patient decision; the patient is at any time free to discontinue treatment, without 
prejudice to further treatment

AE

Severe noncompliance with the Clinical Study Protocol

Pregnancy

Patient incorrectly initiated on study treatment

Objective disease progression and patient is no longer receiving clinical benefit

Lost to follow-up

Patient starts receiving additional anticancer therapy

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Patients experiencing any of the following AEs will not be permitted to restart study 
treatment:

ILD/pneumonitis

QTc interval prolongation with signs/symptoms of serious arrhythmia (see Table 4)

Grade 3 or higher adverse reaction that does not improve to Grade 0 to 2 after 
withholding study treatment for up to 3 weeks
3.6.1
Procedures for discontinuation of a patient from investigational product
At any time, patients are free to discontinue IP or withdraw from the study (ie, IP and 
assessments; see Section 3.7) without prejudice to further treatment. A patient that decides to 
discontinue IP will always be asked about the reason(s) and the presence of any AEs. If 
possible, they will be seen and assessed by an Investigator(s). AEs will be followed up (see 
Section 6); all study drugs should be returned by the patient.
Study procedures related to serious adverse events (SAEs) and anticancer treatment must be 
captured until the patient no longer has RECIST 1.1 assessments (disease progression or 
permanent withdrawal from the study).
If a patient is withdrawn from the study, see Section 3.7.
3.7
Criteria for Withdrawal
3.7.1
Screen failures
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be treated in the study.
These patients should have the reason for study withdrawal recorded as ‘Screen failure’ 
(ie, the potential patient who does not meet one or more criteria required for participation in a 
trial). For those patients, only demography data and reason for discontinuation will be 
recorded. Supporting safety information can be collected in case of a SAE, if applicable.
Patients who initially fail screening due to out of range laboratory values will be allowed to 
repeat the laboratory assessment within the Screening Period, and if the repeat laboratory 
values are compliant with the inclusion/exclusion criteria, the patient may be enrolled into the 
study and receive study treatment. For patients who experience a temporary acute medical 
event that would prohibit enrolment of the patient within the normal duration of the Screening 
Period, discussion of an extension of the Screening Period with the medical monitor may 
occur. Otherwise, patients will not be rescreened and the patient identification number for
screen failures will not be re-used.

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3.7.2
Withdrawal of informed consent
Patients are free to withdraw from the study at any time (IP and assessments) without 
prejudice to further treatment. Withdrawal of consent should be clearly documented in the 
patient notes and in the eCRF.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AEs. The Investigator will follow-up AEs outside of the clinical study.
If a patient withdraws from participation in the study, then his/her enrolment code cannot be 
re-used. Withdrawn patients will not be replaced.
3.8
Discontinuation of the Study
The study may be stopped if, in the judgement of AstraZeneca, trial patients are placed at 
undue risk because of clinically significant findings that:

Meet individual stopping criteria or are otherwise considered significant

Are assessed as causally related to study drug

Are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the eCRF. All reasons for discontinuation of 
treatment must be documented.
4
STUDY PLAN AND TIMING OF PROCEDURES
The Schedule of Assessments for the screening visit is shown in Table 1. On study 
assessments are shown in Table 2.
4.1
Screening/Enrolment Period
At screening, consenting patients are assessed to ensure that they meet eligibility criteria. 
Patients who do not meet these criteria must not be enrolled in the study.
Procedures will be performed according to Table 1 within 28 days prior to Day 1.
The following assessments need to be repeated for patients where > 28 days will have lapsed 
since their last Screening Period to the date of proposed enrolment.
Table 1
Screening (Visit 1) Study Schedule
Day
Day -28 to -1
Informed consent
X

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Day
Day -28 to -1
Assignment of unique enrolment number (IVRS/IWRS)
X
Demography and baseline characteristics
X
Medical and surgical history
X
Inclusion/exclusion criteria
X
Physical examination including weight and eyes 
X
WHO performance status (0-1)
X
Vital signs (includes blood pressure, pulse and temperature), height 
X
Haematology/clinical chemistry
X
ECG
X
Echocardiogram/MUGA d
X
Prior cancer therapies including radiotherapy
X
Urinalysis
X
Pregnancy test a
X
Tumour assessment (CT or MRI according to RECIST 1.1) b
X
AEs (from time of consent)
X
Concomitant medications
X
Tumour tissue c
X
Plasma sample for ctDNA and blood-borne biomarkers
X
a
WOCBP must have a negative urine or serum pregnancy test within 28 days prior to starting treatment and 
a confirmatory test before treatment on Day 1. In the event of suspected pregnancy during the study, the test 
should be repeated and, if positive, the patient discontinued from study treatment immediately. Monthly 
pregnancy testing and monitoring of WOCBP is recommended, however this schedule may be modified to 
comply with local legislation.
b
RECIST assessments will be performed using CT or MRI scans of the chest, abdomen and pelvis and 
should be performed no more than 28 days before the first treatment, and as close as possible to the start of 
study treatment.
c
For central collection and baseline resistance profiling; testing will be conducted at a later date. The first 
mandatory tumour tissue biopsy may be an archival or fresh tissue sample obtained within 60 days of study 
entry. An archival biopsy is acceptable as long as no intervening anticancer treatment occurred since the 
time the biopsy was obtained to enrolment in this study, and as long as it is within 60 days of study entry.
d
To be performed at least every 16 weeks throughout the treatment period up to 3.5 years and then at least 
every 20 weeks for the remainder of the treatment period. The modality of the cardiac function assessments 
must be consistent within a patient, ie, if echocardiogram is used for the screening assessment, then 
echocardiogram should also be used for subsequent scans. 
AE = adverse event; CT = computed tomography; ctDNA = circulating tumour deoxyribonucleic acid; 
ECG = electrocardiogram; IVRS/IWRS = interactive voice response system/interactive web response system; 
MRI = magnetic resonance imaging; MUGA = multigated acquisition scan; RECIST = Response Evaluation 
Criteria in Solid Tumours; WHO = World Health Organization; WoCBP = women of childbearing potential.

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Table 2
Study Schedule – On Study Treatment and Discontinuation
Screen
ing/
Enrol
ment a
Treatment Period
(further treatment cycles as per C7) b
Follow-up Period
Visit Number
1
2
3
4
5
6
7, 8, 9
10+
Treatment
discontinued
28 
days c
Progressio
n follow-
up o
Cycles / Day
C1
C2
C3
C4, 5, 6
C7 to 
3.5 years
3.5 Years to 
Disease 
Progression
D1
D
8
D15
D1
D1
D1
D169-
1277
D1278+
Day
-28 to 
-1
1
8
15
29
57
85, 113, 141
Every 
8 weeks
Every 
10 weeks
Every 
8 weeks 
prior to 
Day 1277/
Every 
10 weeks 
thereafter
Window (Days)
0
± 
2
± 2
± 2
± 7
± 7
± 7
± 14
± 7
+ 7
± 7/± 14
Informed consent
x
IVRS/IWRS
x
Demography and baseline 
characteristics
x
Medical/surgical history
x
Inclusion/exclusion criteria
x
x
Pregnancy test (WOCBP) p
x
x
Tumour tissue sample d
x d
Tumour tissue sample on 
treatment (optional) e
x e
Tumour tissue sample 
upon disease progression f
x f
Plasma sample for ctDNA 
and blood-borne 
biomarkers
x
x 
pre-
dose
x
x
x
x
x
x
x
x b, g

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Screen
ing/
Enrol
ment a
Treatment Period
(further treatment cycles as per C7) b
Follow-up Period
Visit Number
1
2
3
4
5
6
7, 8, 9
10+
Treatment
discontinued
28 
days c
Progressio
n follow-
up o
Cycles / Day
C1
C2
C3
C4, 5, 6
C7 to 
3.5 years
3.5 Years to 
Disease 
Progression
D1
D
8
D15
D1
D1
D1
D169-
1277
D1278+
Day
-28 to 
-1
1
8
15
29
57
85, 113, 141
Every 
8 weeks
Every 
10 weeks
Every 
8 weeks 
prior to 
Day 1277/
Every 
10 weeks 
thereafter
Window (Days)
0
± 
2
± 2
± 2
± 7
± 7
± 7
± 14
± 7
+ 7
± 7/± 14
Whole blood sample at 
progression n
x
Physical examination, 
including weight and eyes h
x
x
x
x
x
x
x
x
Height
x
WHO performance status
x
x
x
x
x
x
x
x
once at 
start of 
subsequent 
anticancer 
treatment
Vital signs
x
x
x
x
x
x
x
x
x
x
Clinical chemistry/ 
Haematology/
Urinalysis h
x
x
x
x
x
x
x
x
x
x
ECG i
x
x
x
x
x
x
x
x
x
x
Echocardiogram/
MUGA (for LVEF) j
(x)
At least every 16 weeks up to 3.5 years on study drug and then at least every 
20 weeks for as long as on study drug
If clinically 
indicated

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d
For baseline resistance profiling; testing will be conducted at a later date. The first mandatory tumour tissue biopsy may be an archival or fresh tissue 
sample obtained within 60 days of study entry. An archival biopsy is acceptable as long as no intervening anticancer treatment occurred since the time 
the biopsy was obtained to enrolment in this study, and as long as it is within 60 days of study entry.
e
The optional on-treatment biopsy may be performed between Day 15 and Day 21 of Cycle 1.
f
The second mandatory tumour tissue biopsy may be performed any time between Investigator-assessed, RECIST 1.1-defined progression and before the 
start of any new anticancer treatment. If a patient discontinues osimertinib before RECIST 1.1-defined progression, the second biopsy will not be 
performed.
g
Plasma samples for ctDNA and blood-borne biomarkers will only be obtained at the treatment discontinuation visit.
h
If screening assessments have been performed within 14 days prior to starting study treatment, they do not have to be repeated on Visit 2 if the patient’s 
condition has not changed. The assessments are to be completed pre-dose on visit day. Laboratory tests may be performed the day prior to study visits.
i
ECG is also to be performed in event of any cardiac AE.
j
To be performed at least every 16 weeks throughout the treatment period up to 3.5 years and then at least every 20 weeks for the remainder of the 
treatment period. The modality of the cardiac function assessments must be consistent within a patient, ie, if echocardiogram is used for the screening 
assessment, then echocardiogram should also be used for subsequent scans. The patients should also be examined using the same machine and operator 
whenever possible, and quantitative measurements should be taken. A 28-day follow-up assessment will be required if an on-treatment assessment was 
abnormal at the time of discontinuation of study therapy, to confirm reversibility of the abnormality.
k
The screening assessment should be performed within 28 days prior to study drug initiation. Subsequent assessments are to be performed every 8 weeks 
(± 7 days) from study enrolment until 3.5 years (Day 1277), and then every 10 weeks (± 14 days) until RECIST 1.1-defined progression, even if a 
patient discontinues treatment prior to progression or receives other anticancer treatment. Tumour assessment will be performed using CT or MRI of the 
chest, abdomen (including liver and adrenal glands) and pelvis. Any other sites where disease is suspected or known at screening must also be imaged.
l
If the first scheduled progression follow-up visit falls before the 28-day follow-up visit, then AEs and concomitant medications will be assessed at this 
visit in addition to the 28-day follow-up visit.
m
In addition to tumour assessments, patients will be followed for the earlier of first subsequent anticancer therapy (including surgical) after discontinuing 
osimertinib or death.
n
At progression, a whole blood sample will be obtained within 7 days of when the tissue biopsy is performed.
o
The progression biopsy should be done prior to the start of subsequent anticancer treatment.
p
Monthly pregnancy testing and monitoring of WOCBP is recommended, however this schedule may be modified to comply with local legislation.
AE = adverse event; C = cycle; CT = computed tomography; ctDNA = circulating tumour deoxyribonucleic acid; D = day; ECG = electrocardiogram; 
IVRS/IWRS = interactive voice response system/interactive web response system; LVEF = left ventricular ejection fraction; MRI = magnetic resonance 
imaging; MUGA = multigated acquisition scan; RECIST = Response Evaluation Criteria in Solid Tumours; WHO = World Health Organization; 
WOCBP = women of childbearing potential.

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4.2
Treatment Period
Estimated treatment duration is 24 to 36 months; however, there is no maximum duration of 
treatment. Patients may continue to receive osimertinib beyond RECIST 1.1-defined 
progression if they continue to show clinical benefit to treatment as judged by the Investigator.
Descriptions of the procedures for this period are included in Table 2.
4.2.1
Cycle 1 to 6 inclusive
The first 6 cycles will be 4 weeks (28 days) each.
4.2.2
Cycle 7 and subsequent cycles
Cycle 7 to 3.5 years (Day 1277) will be 8 weeks (± 7 days) each. After that, cycles will be 
every 10 weeks (± 14 days) until disease progression.
4.2.3
Treatment discontinued
A treatment discontinuation visit will be performed at the time the study drug is permanently 
stopped. Study procedures should be conducted as shown in Table 2.
4.3
Follow-up Period
1.
All patients will be followed up for safety at approximately 28 days.
2.
All patients will be followed up for RECIST 1.1-defined progression.
3.
All patients will be followed up for subsequent anticancer treatment/death.
4.3.1
28 days after treatment discontinued
As a minimum, telephone contact should be made with the patient 28 days (+ 7 days) 
following the discontinuation of osimertinib (last dose of IP) to collect new AEs and 
follow-up on any ongoing AEs and concomitant medications (including any subsequent 
anticancer treatment). Refer to Section 6.3.1 for full details on AE recordings during 
follow-up.
4.3.2
Follow-up for RECIST 1.1-defined progression
Patients who discontinue study drug for reasons other than RECIST 1.1-defined progression 
will continue RECIST assessments every 8 weeks (± 7 days) (relative to study enrolment) up 
to 3.5 years (1277 days) and every 10 weeks (± 14 days) from Day 1278 to objective 
progression.

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In addition to tumour assessments, the following assessments are also required during this 
follow-up period:

First subsequent anticancer therapy (including surgical) after discontinuing 
osimertinib or death

WHO performance status (once at start of first subsequent anticancer therapy)

Concomitant medication and procedures (only in the first scheduled progression 
follow-up visit)

AEs (only in the first scheduled progression follow-up visit)
5
STUDY ASSESSMENTS
A Web Based Data Capture (WBDC) system will be used for data collection and query 
handling. The Investigator will ensure that data are recorded on the eCRFs as specified in the 
Clinical Study Protocol and in accordance with the instructions provided.
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
Investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.
5.1
Efficacy Assessments
5.1.1
Tumour evaluation
Following the screening assessment, subsequent tumour assessments will be conducted every 
8 weeks (± 7 days) from study enrolment until 3.5 years (Day 1277), and then every 10 weeks 
(± 14 days) until RECIST 1.1-defined progression, even if a patient discontinues treatment 
prior to progression or receives other anticancer treatment. Tumour assessment will be 
performed using computed tomography (CT) or magnetic resonance imaging (MRI) of the 
chest, abdomen (including liver and adrenal glands) and pelvis. Any other sites where disease 
is suspected or known at screening must also be imaged. Scans will continue to be submitted 
up to the point of progression as assessed by the Investigator.
5.2
Safety Assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the times indicated in the Study Plan (see Section 4).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.

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The clinical chemistry, haematology and urinalysis will be performed at a local laboratory at 
or near to the Investigator site. Sample tubes and sample sizes may vary depending on 
laboratory method used and routine practice at the site.
The following laboratory variables will be measured:
Table 3
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Hb
S/P-Creatinine
B-Leukocyte count
S/P-Bilirubin, total
B-Leukocyte differential count (absolute count)
S/P-ALP
B-Platelet count
S/P-AST
S/P-ALT
Urinalysis (dipstick)
S/P-Albumin
U-Hb/Erythrocytes/Blood
S/P-Potassium
U-Protein/Albumin
S/P-Calcium, total
U-Glucose
S/P-Sodium
S/P-Magnesium
Creatine phosphokinase
ALP = alkaline phosphatase, ALT = alanine aminotransferase; AST = aspartate aminotransferase; B = blood; 
Hb = haemoglobin; P = plasma; S = serum; U = urine.
At each visit, approximately 6 mL of blood for clinical chemistry and 9 mL for haematology 
will be taken.
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at the 
centre as source data for laboratory variables. For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 6.3.
NB. In case a patient shows an AST or ALT ≥ 3 x ULN or TBL ≥ 2 x ULN, please refer to 
Appendix D for further instructions.
5.2.2
Physical examination
A physical examination will be performed and include an assessment of the following: general 
appearance, skin, head and neck (including ears, eyes, nose, and throat), respiratory, 
cardiovascular, abdomen, lymph nodes, thyroid, musculoskeletal (including spine and 
extremities), and neurological systems.

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5.2.3
Electrocardiogram
5.2.3.1
Resting 12-lead electrocardiogram
Twelve-lead ECG will be performed at the visits indicated in the Study Plan.
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 one ECG recording should be taken. A standardised 
ECG machine should be used and the patient should be examined using the same machine 
throughout the study if possible.
After the paper ECG has been recorded, the Investigator or designated physician will review 
the ECG and may refer to a local cardiologist if appropriate. A copy of the ECG should be 
filed in the patient’s medical records. If an abnormal ECG finding at screening or baseline is 
considered to be clinically significant by the Investigator, it should be reported as a concurrent 
condition. For all ECGs, details of rhythm, ECG intervals and an overall evaluation will be 
recorded.
If there is a clinically significant abnormal ECG finding during the treatment period, this 
should be recorded on the AE eCRF, according to standard AE collection and reporting 
processes. A 28-day follow-up assessment will be required if an on-treatment assessment was 
abnormal at the time of discontinuation of study therapy, to confirm reversibility of the 
abnormality.
5.2.4
Echocardiogram/Multigated acquisition scan
An echocardiogram or multigated acquisition scan (MUGA) to assess LVEF will be 
performed at screening (prior to first dose of osimertinib) and at least every 16 weeks 
throughout the treatment period until patients have reached 3.5 years on the study. Thereafter, 
echocardiogram or MUGA will be performed at least every 20 weeks for the remainder of the 
treatment period. Additional assessments of LVEF should be performed as clinically 
indicated. The modality of the cardiac function assessments must be consistent within a 
patient, ie, if echocardiogram is used for the screening assessment, then echocardiogram 
should also be used for subsequent scans. The patients should also be examined using the 
same machine and operator whenever possible, and quantitative measurements should be 
taken. A 28-day follow-up assessment will be required if an on-treatment assessment was 
abnormal at the time of discontinuation of study therapy, to confirm reversibility of the 
abnormality.
5.2.5
Vital signs
The assessment of vital signs includes blood pressure, pulse, and temperature (see Table 1 and 
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5.2.6
Other safety assessments
5.2.6.1
Ophthalmologic exam
Full ophthalmic assessment, including slit lamp examination, should be performed if a patient 
experiences any visual symptoms (including blurring of vision). Ophthalmology examination 
results should be collected in the eCRF.
Any clinically significant findings, including those confirmed by the ophthalmologist must be 
reported as an AE.
5.3
Other Assessments
5.3.1
Resistance profiling
The samples will be collected and stored in a central laboratory/repository. Further details on 
sample processing, handling, and shipment are provided in the Laboratory Manual.
Mandatory tissue collection
The first mandatory tumour tissue biopsy will be collected at screening for baseline resistance 
profiling. Tumour tissue may be an archival or fresh tissue sample. An archival tissue sample 
is acceptable as long as there has been no intervening anticancer treatment since the biopsy 
was acquired and enrolment into this study, and as long as it is within 60 days of study entry.
The Investigator will be asked to provide formalin-fixed, paraffin-embedded tumour tissue 
blocks, or a at least 15 re-cut unstained sections from formalin-fixed paraffin-embedded 
tumour tissue block, presented on slides. Each section is to be 5 μm thick.
Biopsy samples taken from bone metastasis and cytology samples are unsuitable for testing 
and should not be provided. Samples may be collected from primary or metastatic tumour 
deposits. The mandatory screening tumour biopsy must not be taken from a previously 
irradiated lesion. The biopsy must not be taken from the lesion(s) selected for inclusion 
criterion #6 (unless only one measurable lesion exists, in which case the baseline tumour 
assessment scans are to be done at least 14 days after the screening biopsy).
The second mandatory tumour tissue biopsy will be performed any time between 
Investigator-assessed, RECIST 1.1-defined progression and before the start of any new 
anticancer treatment. If a patient discontinues osimertinib before RECIST 1.1-defined 
progression, the second biopsy will not be performed.
Optional tissue collection
Patients will be asked to consent to provide additional tumour tissue during treatment. The 
biopsy may be performed between Day 15 and Day 21 of Cycle 1.

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The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the AstraZeneca Biobank or its designee (see 
details in the Laboratory Manual) during the entire life cycle.
5.4.4
Withdrawal of informed consent for donated biological samples
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 analysed,
AstraZeneca is not obliged to destroy the results of this research.
The Principal 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 organisation(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 organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
6
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a subject or clinical study 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product.

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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.
6.2
Definitions of Serious Adverse Event
A SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-up) 
that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-subject hospitalisation or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the subject or may require 
medical intervention to prevent one of the outcomes listed above
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol.
6.3
Recording of Adverse Events
6.3.1
Time period for collection of adverse events
AEs will be collected from the time of signature of informed consent throughout the treatment 
period and including the follow-up period. The safety follow-up period is defined as 28 days 
after study drug is discontinued.
SAEs occurring in the safety follow-up period should be reported to AstraZeneca in the usual 
manner (see Section 6.4).
Following discontinuation of study treatment, SAEs considered related to study procedures 
should continue to be collected while patients are followed up for disease progression as 
outlined in Table 2.
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the eCRF. 
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.

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6.3.3
Variables
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 (yes or no)

Action taken with regard to IP

AE caused patient’s withdrawal from study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date Investigator became aware of SAE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Description of AE
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 

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disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2.
6.3.4
Causality collection
The Investigator will assess causal relationship between 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 investigational product?’
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes.’
A guide to the interpretation of the causality question is found in Appendix B.
6.3.5
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/you were last asked?’, or revealed by observation will be collected and recorded in the 
eCRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms. However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately.
6.3.6
Adverse events based on examinations and tests
The results from the protocol-mandated laboratory tests and vital signs will be summarised in 
the CSR. Deterioration as compared to baseline in protocol-mandated parameters should 
therefore only be reported as AEs if they fulfil any of the SAE criteria or are the reason for 
discontinuation of treatment with the IP unless clearly due to disease progression of disease 
under study (see Section 6.3.8).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low Hb value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.

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6.3.7
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 x ULN together with TBL ≥ 2 x ULN may need to be 
reported as SAEs. Please refer to Appendix D for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law (HL).
6.3.8
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP 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.
6.3.9
New cancers
The development of a new cancer should be regarded as an AE and will generally meet at 
least one of the serious criteria. New cancers are those that are not the primary reason for the 
administration of the study treatment and have been identified after the patient’s inclusion in 
this study. They do not include metastases of the original cancer.
6.3.10
Handling of deaths
All deaths that occur during the study, or within the follow-up period after the administration 
of the last dose of IP (28 days post last dose of IP), 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 module, but should not be reported as a SAE during the study.

Where death is not clearly due to disease progression of the disease under study the 
AE causing the death should be reported to the study monitor as an SAE within 
24 hours. The report should contain a comment regarding the co-involvement of 
progression of disease, if appropriate, and should assign a single primary cause of 
death together with any contributory causes.

Deaths with an unknown cause should always be reported as a SAE but every effort 
should be made to establish a cause of death. A post-mortem may be helpful in the 
assessment of the cause of death, and if performed a copy of the post-mortem 
results (with translation of important parts into English) should be reported in an 
expedited fashion to an AstraZeneca representative within the usual timeframes.
6.4
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 eCRF.

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If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 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, ie, immediately but no later than 24 hours of when he or she becomes aware of 
it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site staff reports a 
SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug.
6.5
Overdose
A maximum tolerated dose has not been established for osimertinib. An overdose is any dose 
which exceeds the daily dose that is defined in the clinical study protocol.
Such overdoses should be recorded as follows:

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.

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For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4. 
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca during the 
course of the study and within 6 weeks of the last dose of osimertinib.
6.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study IP should be discontinued 
immediately.
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 in the course of the study or within 6 weeks of the final dose of the 
IP, then the Investigator or other site personnel informs the appropriate AstraZeneca 
representatives within 1 day, ie, immediately, but no later than 24 hours of when he or she 
becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
6.6.2
Paternal exposure
Pregnancy of the patient’s partners is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital abnormality) should if possible be followed up and documented.
To capture information about a pregnancy from the partner of a male patient, the male 
patient’s partner consent must be obtained to collect information related to the pregnancy and 
outcome; the male patient should not be asked to provide this information. A consent form 
specific to this situation must be used. The outcome of any conception occurring from the date 
of the first dose until 4 months after dosing ends should be followed up and documented.

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6.7
Medication Error, Drug Abuse, and Drug Misuse
6.7.1
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 day, ie, 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 event of medication error, drug abuse, or misuse (see Section 6.4) 
and within 30 days for all other events.
6.7.2
Medication Error
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for an AstraZeneca study drug that either causes harm to the patient 
or has the potential to cause harm to the patient.
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 patient.
Medication error includes situations where an error.

Occurred

Was identified and intercepted before the patient received the drug

Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error, eg, medication prepared incorrectly, even if it was not actually 
given to the patient

Drug not administered as indicated, eg, wrong route dose (error greater than +/-
10%), or wrong site of administration

Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as 
a solid tablet

Drug not stored as instructed, eg, kept in the fridge when it should be at room 
temperature

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
Wrong patient received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to patient (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

Patient accidentally missed drug dose(s), eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Patient failed to return unused medication or empty packaging

Errors related to background and rescue medication, or SoC medication in 
open-label studies, even if an AstraZeneca product, patient 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.
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is a SAE associated with 
the medication error (see Section 6.4) and within 30 days for all other medication errors.
6.7.3
Drug Abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of 
AstraZeneca study drug for a perceived reward or desired non-therapeutic effect.
The full definition and examples of drug abuse can be found in Appendix B 1.
6.7.4
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study patient) of AstraZeneca 
study drug for medicinal purposes outside of the authorised product information, or for 
unauthorised AstraZeneca study drug, outside the intended use as specified in the protocol and 
includes deliberate administration of the product by the wrong route.
The full definition and examples of Drug Misuse can be found in Appendix B 1.

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6.8
Management of Investigational Product-Related Toxicities
Dose adjustment for AEs should be in accordance with the following table:
Table 4
Osimertinib Dose Adjustment Information for Adverse Reactions
Target organ
Adverse reaction
Dose modification
Pulmonary 
Interstitial lung disease/pneumonitis
Permanently discontinue osimertinib
Cardiac
QTc interval greater than 500 msec on at 
least 2 separate ECGs
Withhold osimertinib until QTc 
interval is less than 481 msec or 
recovery to baseline if baseline QTc is 
more than 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)
QTc interval prolongation with 
signs/symptoms of serious arrhythmia
Permanently discontinue osimertinib
Cutaneous
Stevens-Johnson Syndrome and toxic 
epidermal necrolysis (TEN)
Permanently discontinue osimertinib
Blood and 
lymphatic 
system
Aplastic anaemia
Permanently discontinue osimertinib
Other
Grade 3 or higher adverse reaction
Withhold osimertinib for up to 
3 weeks
If Grade 3 or higher adverse reaction 
improves to Grade 0-2 after withholding 
of osimertinib for up to 3 weeks
Osimertinib may be restarted at the 
same dose (80 mg) or a lower dose 
(40 mg)
Grade 3 or higher adverse reaction that 
does not improve to Grade 0-2 after 
withholding for up to 3 weeks
Permanently discontinue osimertinib
Note: The intensity of clinical adverse events graded by the NCI CTCAE version 4.0.
ECG = electrocardiogram; CTCAE = Common Terminology Criteria for Adverse Event; NCI = National Cancer 
Institute; QTc = QT interval corrected for heart rate; TEN = toxic epidermal necrolysis.
If a patient experiences a CTCAE Grade 3 or higher adverse reaction, and/or unacceptable 
toxicity, including a dose-limiting toxicity (DLT), not attributable to the disease or 
disease-related processes under investigation, dosing will be interrupted, and supportive 
therapy administered as required in accordance with local practice/guidelines.
If a toxicity resolves or reverts to ≤CTCAE Grade 2 within 3 weeks of withholding 
osimertinib, treatment with osimertinib may be restarted at the same dose or a lower dose 

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using the rules below for dose modifications (Table 5) and with discussion and agreement 
with the AstraZeneca Study Team Physician as needed. There will be no individual 
modifications to dosing schedule in response to toxicity, only potential dose reduction or dose 
interruption.
If the toxicity does not resolve to ≤CTCAE Grade 2 after 3 weeks of withholding osimertinib, 
then the patient should be withdrawn from the study and observed until resolution of the 
toxicity. 
Table 5
Dose Interventions
Intervention
Osimertinib dose
Starting dose
80 mg
Reduced dose – 1 
40 mg
On resolution of toxicity within 3 weeks:
If an AE subsequently requires dose interruption, osimertinib may restart at the same dose or 
the reduced dose, on resolution/improvement of the AE at the discretion of the Investigator.
6.8.1
Interstitial lung disease/pneumonitis-like toxicity
If new or worsening pulmonary symptoms (eg, dyspnoea) or radiological abnormality 
suggestive of ILD is observed, an interruption in study treatment dosing is recommended, and 
the AstraZeneca study team should be informed. It is strongly recommended to perform a full 
diagnostic workup, to exclude alternative causes such as lymphangitic carcinomatosis, 
infection, allergy, cardiogenic oedema or pulmonary haemorrhage. The results of the full 
diagnostic workup (including high-resolution CT [HRCT], blood and sputum culture, 
haematological parameters) will be captured in the CRF. In the presence of confirmatory 
HRCT scans where other causes of respiratory symptoms have been excluded, a diagnosis of 
ILD should be considered and study treatment permanently discontinued.
In the absence of a diagnosis of ILD, study treatment may be restarted following consultation 
with the AstraZeneca Study Team Physician.
6.8.2
QTc prolongation
In light of the potential for QT changes associated with osimertinib, electrolyte abnormalities 
(hypokalaemia, hypomagnesaemia, hypocalcaemia) must be corrected to be within normal 
ranges prior to first dose and electrolyte levels monitored during study treatment.
Patients with QT interval corrected using Fridericia’s correction (QTcF) prolongation to 
> 500 msec should have study treatment interrupted and regular ECGs performed until 
resolution to < 481 msec, or recovery to baseline, if baseline QTcF is ≥ 481 msec and then 
restarted at a reduced dose of 40 mg, or 80mg at the discretion of the Investigator. If the 

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toxicity does not resolve to ≤ CTCAE Grade 1 within 21 days, the patient will be permanently 
withdrawn from study treatment.
6.8.3
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.
6.8.4
Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal 
necrolysis
Case reports of EM and TEN have been uncommonly reported, and SJS have been rarely 
reported, in association with osimertinib treatment. Before initiating 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 osimertinib 
should be considered. If signs and symptoms suggestive of SJS appear, osimertinib should be 
interrupted. Osimertinib should be discontinued immediately if diagnosis of SJS or TEN is 
confirmed.
6.8.5
Aplastic anaemia
Rare reports of aplastic anaemia have been reported in association with osimertinib treatment. 
Some cases had a fatal outcome. Before initiating treatment, patients should be advised of 
signs and symptoms of aplastic anaemia including but not limited to persistent fever, bruising, 
bleeding, pallor. If signs and symptoms suggestive of aplastic anaemia develop, close patient 
monitoring and drug interruption or discontinuation of osimertinib should be considered. 
Osimertinib should be discontinued in patients with confirmed aplastic anaemia.
Permanent discontinuation due to toxicity
Patients experiencing ILD, QTc prolongation with signs/symptoms of serious arrhythmia or 
Grade 3 or higher adverse reaction that does not improve to Grade 0 to 2 after withholding for 
up to 3 weeks will not be permitted to restart study treatment.
6.8.6
Changes in cardiac contractility
Based on the available clinical trial data, a causal relationship between effects on changes in 
cardiac contractility and osimertinib has not been established. In 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.

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7
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of Investigational Product
Investigational product
Dosage form and strength
Manufacturer
Osimertinib
40 mg tablets
80 mg tablets
AstraZeneca
AstraZeneca will supply osimertinib as tablets (35 tablets per bottle) for oral administration as 
a single daily dose of 80 mg or 40 mg. Osimertinib tablets are packed in high-density 
polyethylene bottles with desiccant and child-resistant closures.
Additional information about the IP may be found in the IB.
7.2
Dose and Treatment Regimens
Osimertinib is administered as 80 mg once daily. Osimertinib can be taken without regard to 
food.
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 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 osimertinib, they should not make up 
for this dose, but should take the next scheduled dose.
The dose of 80 mg osimertinib daily can be reduced to 40 mg osimertinib once daily under 
circumstances described in Section 6.8. Further dose reductions are not possible. Once a dose 
has been reduced, it should not be re-escalated at future cycles.
Any change from dosing schedule, dose interruptions or dose reductions should be recorded.
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfil GMP Annex 13 requirements for labelling. Label 
text will be translated into the local language.
7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions. The IP 
label on the bottle specifies the appropriate storage.

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7.5
Compliance
The administration of all study drugs (including IPs) should be recorded in the appropriate 
sections of the eCRF.
7.6
Accountability
The study drug provided for this study will be used only as directed in the Clinical Study 
Protocol.
The study site staff will account for all study drugs dispensed to and returned from the patient.
Study site staff will account for all study drugs received at the site, unused study drugs and for 
appropriate destruction. Certificates of delivery, destruction should be signed.
7.7
Concomitant and Other Treatments
Guidance on medications to avoid, medications that require close monitoring and on washout 
periods is provided in Section 3.5 and Appendix E.
7.7.1
Other concomitant treatment
Other 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 appropriate sections of the eCRF.
7.8
Post-study Access to Study Treatment
Patients receiving study treatment at the time of study completion (ie, after final DCO date) 
will be switched to commercial supply and/or another study to ensure continuation of 
treatment, if in the opinion of their treating physician they are continuing to derive clinical 
benefit from continued treatment. Such patients will continue to be monitored and all safety 
assessments will be performed until study treatment is discontinued. These patients will then 
be followed up for a period of 28 days after the last study treatment dose is administered for 
any new treatment-related SAEs. A CSR addendum will be prepared if any additional safety 
data are collected.
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 

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informed consent, as applicable.
8
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical Considerations
The primary aim of the study is to examine the molecular profile of patients at the point of 
disease progression and to compare it to the profile prior to initiation of treatment in patients 
receiving osimertinib as first-line therapy. A comprehensive statistical analysis plan (SAP) 
will be prepared and finalised prior to the final analysis. All analyses will be performed by 
AstraZeneca or its representatives.
The final analysis will be performed at study end (see Section 9.3 for definition of “end of 
study”), and when approximately 50 patients have evaluable paired biopsies upon progression. 
Assuming a 70% rate of patients having a biopsy at both baseline and progression, and with an 
assumed technical failure rate of 30% of the samples (assume an overall failure rate of 51%), 
then we should expect approximately 50 evaluable paired biopsies to be available when 
approximately 103 of the 150 patients have progressed, which would be expected to occur 
approximately 38 months after the first patient is enrolled.
This calculation assumes patients are recruited over 12 months, exponentially distributed 
progression times with a 19-month median and a 2-piece recruitment function, assuming an 
exponentially distributed recruitment rate.
The first 100 patients to be enrolled within the first 5 months (ie, from first patient inclusion to 
the timing of the global protocol amendment). This will be followed by a pause in recruitment 
of 6 months to account for the issue and approval of the global protocol amendment. This will 
further be followed by 1 month of recruitment to enrol the remaining 50 patients, assuming an 
exponentially distributed recruitment rate to account for the regional differences in approval 
times and slow uptake of recruitment following the protocol amendment.
This is an exploratory study which may inform other studies in the osimertinib development 
programme and therefore earlier interim analyses may be performed, such interim analyses 
may not be reported in a formal CSR.
If a patient progresses in the ELIOS study and then enrols in a subsequent AZ study, and if 
appropriate consent is provided, the biomarker results from a progression biopsy (generated in 
either the other study or ELIOS), may be shared between both studies and the data may be 
analysed as part of the ELIOS study.
8.2
Sample Size Estimate
Recruitment of 150 patients is appropriate to characterise the frequency of genetic and 
proteomic markers at disease progression regardless of their prevalence. The following table 

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displays the precision of the estimated proportion, for example, when 50 evaluable paired 
biopsies are available.
Table 6
Precision of Estimates of Marker Frequency with 50 Available and 
Evaluable Paired Biopsies
Marker Frequency
95% confidence interval a
10%
(3%, 22%)
30%
(18%, 45%)
50%
(36%, 64%)
a
Exact binomial confidence intervals.
8.3
Definitions of Analysis Sets
The primary analysis set (PAS) will include all patients with evaluable paired biopsies. This 
analysis set will be used for the analysis of the primary endpoint. The full analysis set will 
include all patients who receive at least one dose of osimertinib and will be used for all other 
efficacy and safety analyses.
8.3.1
Primary analysis set
The PAS will include all patients with evaluable paired biopsies, which are defined as follows: 
the first biopsy taken prior to osimertinib treatment and the second biopsy taken at any time 
between Investigator-assessed, RECIST 1.1-defined progression and before the start of any 
new anticancer treatment. If the Investigator judges the patient to have progressed but the 
programmatically defined RECIST progression does not occur, the patient will still be 
considered evaluable. This analysis set will be used for the analysis of the primary endpoint.
8.3.2
Full analysis set
The full analysis set will include all patients who receive at least one dose of osimertinib. The 
full analysis set will be used for all efficacy and safety analyses.
8.4
Outcome Measures for Analyses
8.4.1
Calculation or derivation of primary endpoint variables
The primary endpoint is the proportion of patients with a given genetic and proteomic marker 
(including, but not limited to, EGFR mutations, HER2, and cMET expression and/or 
amplification) at the point of disease progression as defined by the Investigator; the choice of 
markers is dependent on the profile comparison at the point of disease progression and prior to 
treatment initiation. The number of patients with a given genetic and proteomic marker will be 
divided by the number of patients who have evaluable biopsies and have progressed according 
to the Investigator to calculate the proportion with a given marker at progression.

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8.4.2
Calculation or derivation of efficacy variables
Investigator RECIST based assessments
From the Investigator’s review of the imaging scans, the RECIST tumour response data will 
be used to determine each patient’s visit response according to RECIST version 1.1. At each 
visit, patients will be programmatically assigned a RECIST 1.1 visit response of complete 
response, partial response, stable disease or progressive disease depending on the status of 
their disease compared with baseline and previous assessments. If a patient has had a tumour 
assessment, which cannot be evaluated, then the patient will be assigned a visit response of 
not evaluable (unless there is evidence of progression in which case the response will be 
assigned as progressive disease).
Please refer to Appendix F for the definitions of complete response, partial response, stable 
disease and progressive disease.
Progression-free Survival
PFS is defined as the time from first dose of osimertinib until the date of RECIST 1.1-defined 
progression or death (by any cause in the absence of progression) regardless of whether the 
patient withdraws from therapy or receives another anticancer therapy prior to progression. 
Patients who have not progressed or died at the time of analysis will be censored at the time of 
the latest date of assessment from their last evaluable RECIST assessment. However, if the 
patient progresses or dies after 2 or more missed visits, the patient will be censored at the time 
of the latest evaluable RECIST assessment. If the patient has no evaluable visits or does not 
have baseline data, they will be censored at day 1 unless they die within 2 visits of baseline.
The PFS time will always be derived based on scan/assessment dates not, visit dates. RECIST 
assessments/scans contributing towards a particular visit may be performed on different dates. 
The following rules will be applied:

Date of progression will be determined based on the earliest of the dates of the 
component that triggered the progression

When censoring a patient for PFS the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment
Objective Response Rate
ORR rate is defined as the number (%) of patients with at least one visit response of complete 
response or partial response that is confirmed at least 4 weeks later. Data obtained up until 
progression, or last evaluable assessment in the absence of progression, will be included in the 
assessment of ORR. However, any complete response or partial response, which occurred 
after a further anticancer therapy was received, will not be included in the numerator for the 
ORR calculation.
In the case where a patient has 2 non-consecutive visit responses of partial response, then, as 
long as the time between the 2 visits of partial response is greater than 4 weeks and there is no 

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progressive disease between the partial response visits, the patient will be defined as a 
responder. Similarly, if a patient has visit responses of complete response, not evaluable, 
complete response then, as long as the time between the 2 visits of complete response is 
greater than 4 weeks, then a best response of complete response will be assigned.
Duration of Response
DoR will be defined as the time from the date of first documented response, (that is 
subsequently confirmed) until date of documented progression or death in the absence of 
disease progression, the end of response should coincide with the date of progression or death 
from any cause used for the PFS endpoint. The time of the initial response will be defined as 
the latest of the dates contributing towards the first visit response of partial response or 
complete response. If the response is not confirmed, it will not be included.
If a patient does not progress following a response, then their DoR will use the PFS censoring 
time.
Disease control rate
DCR is defined as the percentage of patients who have a best overall response of complete 
response or partial response or stable disease.
Time to treatment discontinuation or death
TTD is defined as the time from the date of first dose of osimertinib to the earliest of 
treatment discontinuation or death. Any patient not known to have discontinued treatment or 
not known to have died at the time of the analysis will be censored at the last known time to 
have not discontinued treatment, ie, the last follow-up visit where this was confirmed.
Time to first subsequent therapy or death
The TFST will be defined as the time from the date of first dose of osimertinib to the earlier of 
the date of anticancer therapy start date following study treatment discontinuation, or death. 
Any patient not known to have had a subsequent anticancer treatment 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 anticancer treatment, ie, the last follow-up visit where this was confirmed.
8.4.3
Calculation or derivation of safety variables
Safety and tolerability will be assessed in terms of AEs, deaths, laboratory data, ECG, and 
vital signs. These will be collected for all patients.
Adverse events
AEs (both in terms of Medical Dictionary for Regulatory Activities [MedDRA] preferred 
terms and CTCAE Grade) will be listed individually by patient.
Any AE occurring before treatment with osimertinib will be included in the data listings but 
will not be included in the summary tables of AEs.

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Any AE occurring within 28 days of discontinuation of osimertinib will be included in the AE 
summaries. Any events in this period that occur after a patient has received further therapy for 
cancer (following discontinuation of osimertinib) will be flagged in the data listings.
Other significant adverse events
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and AEs leading to discontinuation. Based on 
the expert’s judgement, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered other significant adverse 
events (OAEs) and reported as such in the CSR. A similar review of laboratory data/vital 
signs (according to vital sign data collected) will be performed for identification of OAEs.
Examples of these could be marked haematological and other laboratory abnormalities, and 
certain events that lead to intervention (other than those already classified as serious), dose 
reduction or significant additional treatment.
8.5
Methods for Statistical Analyses
8.5.1
Analysis of the primary variables
The proportion of patients with a given genetic and proteomic marker at the point of disease 
progression will be calculated and presented alongside the associated exact binomial 95% CIs. 
If a reasonable proportion of patients have a given marker at baseline, the difference in the 
proportion of patients with that marker between progression and baseline, together with its 
95% CI, may also be calculated.
8.5.2
Analysis of the secondary variables
Secondary variables PFS, DoR, TTD, and TFST will be summarised using a Kaplan-Meier 
plot from which the median and event rates from clinically important landmarks such as 1 and 
2 years will be calculated. The standard error of the natural log of survival time will be used to 
calculate CIs. The CI for the median will be calculated by determining the earliest and latest 
survival times whose 95% CIs contain 0.5. If the 95% CI for survival at the largest event time 
contains 0.5 then the upper confidence limit will be described as Not Calculated.
For DoR only those patients who have responded (a confirmed response) will be included.
ORR and DCR will be summarised as the proportion of patients with a response or disease 
control along with the associated exact binomial 95% CIs.
8.5.3
Subgroup analysis
A full list of exploratory subgroup analyses will be defined in the SAP but will include, if 
numbers allow, comparing groups of patients with different patterns of genetic and proteomic 
markers at disease progression according to:

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
PFS according to RECIST 1.1

ORR

Tumour shrinkage, defined as the best change from baseline in target lesion tumour 
size

TTD

Important patient and disease characteristics (eg, prior use of chemotherapy)
8.5.4
Exploratory analysis
The analyses associated with the exploratory objective will be reported separately and will not 
form part of the CSR. Any HER2/tissue/plasma analysis may be published outside of the 
CSR.
9
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of Study Site Staff
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC
system(s) utilised.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.2
Monitoring of the Study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:

Provide information and support to the Investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the Clinical Study Protocol, that 
data are being accurately and timely recorded in the eCRFs, that biological samples 
are handled in accordance with the Laboratory Manual and that study drug 
accountability checks are being performed

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
Perform source data verification (a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating patients. This 
will require direct access to all original records for each patient (eg, clinic charts)

Ensure withdrawal of informed consent to the use of the patient’s biological 
samples is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the patient
The AstraZeneca representative may apply a risk-based monitoring approach during visits: 
source document review (a holistic review of source documents to determine source adequacy, 
overall eligibility, Good Clinical Practice (GCP), protocol compliance, and patient safety 
throughout the study), and source document verification (cross-checking specific variables in 
the source documents against the eCRF to confirm the accuracy of data transcription).
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
9.2.1
Source data
Refer to the Clinical Study Agreement for location of source data.
9.2.2
Study agreements
The Principal Investigator at each/the centre should comply with all the terms, conditions and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement.
9.3
Study Timetable and End of Study
A patient is considered to have completed the study when he/she has progressed or died.
The end of the study is defined as when the earliest of these scenarios is met:

All enrolled patients complete their participation in the study either through disease 
progression or withdrawal for other reasons.

The study will end in by Q2 2023, as it is estimated that by then there will be sufficient 
data to support study endpoints. If, at this time (Q2 2023 or at another time if AstraZeneca 

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or Regulatory Authorities decide to stop study due to any concerns, eg, patient safety), 
there are ongoing patients who are drawing benefit from study treatment, they will be 
switched to commercial supply and/or another study to ensure continuation of treatment, 
and the study will close using the available data for the final analysis. A CSR will be 
written at this time, including all data collected during the study.
For any patients who continue in progression follow-up, any additional safety data will be 
collected and summarised in the CSR.
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow. AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with osimertinib.
The study may be terminated at individual centres if there are no ongoing patients.
9.3.1
End of Study Definition
For the purpose of Clinical Trial Transparency the definition of the end of the study differs 
under Food and Drug Administration (FDA) and European Union (EU) regulatory 
requirements:

European Union requirements define study completion as the last visit of the last patient 
for any protocol related activity.

Food and Drug Administration requirements defines 2 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 – is defined as 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.
The study may be stopped if, in the judgement of AstraZeneca, study patients are placed at 
undue risk because of clinically significant findings.
As this study is event driven, the accrual of the predetermined number of events included in 
the study endpoints will determine the duration of the data collection phase of the study. There 
will be a final DCO, defined by when approximately 50 patients have evaluable paired 
biopsies upon progression. At this time, the clinical database will close to new data.

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Should the study meet the primary endpoint at any of the prescribed interim analyses, 
additional data cuts may be needed per local health authority requirements.
See Section 7.8 for details on patient management following the final DCO, as well as 
following study completion.
9.4
Data Management
Data management will be performed by Parexel according to the Data Management Plan.
The data collected through third-party sources will be obtained and reconciled against study 
data.
AEs and medical/surgical history will be classified according to the terminology of the latest 
version the MedDRA. Medications will be classified according to the WHO Drug Dictionary. 
All coding will be performed by the Medical Coding Team at Parexel.
Data queries will be raised for inconsistent, impossible or missing data. All entries to the study 
database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan. Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.
When all data have been coded, validated, signed and locked, clean file will be declared. Any 
treatment revealing data may thereafter be added and the final database will be locked.
ILD-like events
ILD/pneumonitis are to be reported as AEs in the CRF, with additional details captured in the 
"ILDIS" eCRF.
Serious adverse event reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site.
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory (ies) internal or 
external to AstraZeneca.

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10
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical Conduct of the Study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki as amended at 64th WMA General Assembly, Fortaleza, Brazil, 
October 2013 and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines and are consistent with International Council for 
Harmonisation (ICH)/GCP, applicable laws and regulatory requirements and the AstraZeneca 
policy on Bioethics and Human Biological Samples. For details refer to Appendix A 1.
10.2
Patient Data Protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. For details refer to Appendix A 4.
10.3
Ethics and Regulatory Review
An Ethics Committee/Institutional Review Board (IRB) should approve the final Clinical 
Study Protocol, including the final version of the Informed Consent Form and any other 
written information and/or materials to be provided to the patients. The Investigator will 
ensure the distribution of these documents to the applicable Ethics Committee/IRB, and to the 
study site staff.
The opinion of the Ethics Committee/IRB should be given in writing. The Investigator should 
submit the written approval to AstraZeneca before enrolment of any patient into the study.
The Ethics Committee/IRB should approve all advertising used to recruit patients for the 
study.
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
If required by local regulations, the Clinical Study Protocol should be re-approved by the 
Ethics Committee/IRB annually.
Before enrolment of any patient into the study, the final Clinical Study Protocol, including the 
final version of the Informed Consent Form, is approved by the national regulatory authority 
or a notification to the national regulatory authority is done, according to local regulations.
AstraZeneca or delegate will handle the distribution of any of these documents to the national 
Regulatory Authorities.
AstraZeneca or delegate will provide Regulatory Authorities, Ethics Committees/IRBs and 
Principal Investigators with safety updates/reports according to local requirements.

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Each Principal Investigator is responsible for providing the Ethics Committees/IRBs with 
reports of any serious and unexpected ADRs from any other study conducted with the IP. 
AstraZeneca or delegate will provide this information to the Principal Investigator so that 
he/she can meet these reporting requirements.
10.4
Informed Consent
The Principal Investigator(s) at each centre will:

Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study.

Ensure each patient is notified that they are free to discontinue from the study at any 
time.

Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided.

Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study. Ensure the original, signed Informed 
Consent Form(s) is/are stored in the Investigator’s Study File.

Ensure a copy of the signed Informed Consent Form is given to the patient.

Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the Informed Consent Form that is approved by an Ethics Committee/IRB.
For details, refer to Appendix A 3
10.5
Changes to the Clinical Study Protocol and Informed Consent 
Form
Study procedures will not be changed without the mutual agreement of the International 
Coordinating Investigator and AstraZeneca.
If there are any substantial changes to the Clinical Study Protocol, then these changes will be 
documented in a new version of the study protocol.
The new version of the Clinical Study Protocol is to be approved by the relevant Ethics 
Committee/IRB and if applicable, also the national regulatory authority approval, before 
implementation. Local requirements are to be followed for new versions of Clinical Study 
Protocols.

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AstraZeneca will distribute any new versions of the Clinical Study Protocol to each Principal 
Investigator(s). For distribution to Ethics Committee/IRB see Section 10.3.
If a change to a Clinical Study Protocol requires a change to a centre’s Informed Consent 
Form, AstraZeneca and the centre’s Ethics Committee/IRB are to approve the revised 
Informed Consent Form before the revised form is used.
10.6
Audits and Inspections
Authorised representatives of AstraZeneca, a regulatory authority or an Ethics Committee/IRB 
may perform audits or inspections at the centre, including source data verification. The 
purpose of an audit or inspection is to systematically and independently examine all 
study-related activities and documents, to determine whether these activities were conducted, 
and data were recorded, analysed, and accurately reported according to the Clinical Study 
Protocol, GCP, guidelines of the ICH, and any applicable regulatory requirements. The 
Investigator will contact AstraZeneca immediately if contacted by a regulatory agency about 
an inspection at the centre.

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11
LIST OF REFERENCES
Asami and Atagi 2016
Asami K, Atagi S. Comparing the efficacy of gefitinib, erlotinib, and afatinib in non-small cell 
lung cancer with activating epidermal growth factor receptor (EGFR) mutations. Austin J 
Lung Cancer Res. 2016;1(1):1003.
Cross et al 2014
Cross DAE, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an 
irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung 
cancer. Cancer Discov. 2014;4(9):1046–61.
Gil-Bazo and Rolfo 2016
Gil-Bazo I, Rolfo C. AZD9291 in TKI EGFR resistance in non-small cell lung cancer and the 
new concept of phase I trials. Transl Lung Cancer Res. 2016;5(1):85-8.
Jänne et al 2015
Jänne PA, Yang JC-H, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in 
EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372:1689-99.
Kuiper et al 2014
Kuiper JL, Heideman DAM, Thunnissen E, Paul MA, van Wijk AW, Postmus PE, et al. 
Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients. 
Lung Cancer. 2014;85:19-24.
Li et al 2014
Li W, Ren S, Li J, Li A, Fan L, Li X, et al. T790M mutation is associated with better efficacy 
of treatment beyond progression with EGFR-TKI in advanced NSCLC patients. Lung Cancer. 
2014;84:295-300.
Oxnard et al 2011
Oxnard GR, Arcila ME, Sima CS, Riely GJ, Chmielecki J, Kris MG, et al. Acquired resistance 
to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of 
patients with tumors harboring the T790M mutation. Clin Cancer Res. 2011;17(6):1616–22.
Soria et al 2018
Soria J-C, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee K.H, et 
al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J 
Med 2018; 387: 113-25.
Yu et al 2013
Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor 
specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with 
EGFR-mutant lung cancers. Clin Cancer Res. 2013;19(8):2240–7.

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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 as amended at 64th WMA General Assembly, Fortaleza, 
Brazil, October 2013 and CIOMS International Ethical Guidelines
Applicable ICH GCP Guidelines
Applicable laws and regulations

The protocol, revised protocol, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.

Any revised protocol will require IRB/IEC and applicable Regulatory Authority approval 
before implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study patients.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
Contract Research Organisation (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 Code of Federal Regulations 312.120, 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 AstraZeneca of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a 
study intervention under clinical investigation are met.

AstraZeneca 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. AstraZeneca will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators.

For all studies except those utilising medical devices, Investigator safety reports must be 
prepared for suspected unexpected serious adverse reaction according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary.

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
Adherence to 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 an SAE or other 
specific safety information (eg, summary or listing of SAEs) from AstraZeneca will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
Regulatory Reporting Requirements for Serious Breaches

Prompt notification by the Investigator to AstraZeneca 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 patient or the reliability and robustness of the data generated in the clinical 
study.

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 
they become aware of it.

In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches.
AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and Investigators. If 
EU Clinical Trials Regulation 536/2014 applies, AstraZeneca is required to enter 
details of serious breaches into the EMA 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 AstraZeneca or delegated party, 
through the contacts (email address or telephone number) provided by AstraZeneca.
A 2
Financial Disclosure
Investigators will provide AstraZeneca with sufficient, accurate financial information as 
requested to allow AstraZeneca to submit complete and accurate financial certification or 
disclosure statements to the appropriate Regulatory Authorities. Investigators are responsible 
for providing information on financial interests during the study and for one year after 
completion of the study.

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A 3
Informed Consent Process

The Investigator or their representative will explain the nature of the study to the 
patient or their legally authorised representative and answer all questions regarding 
the study.

Patients must be informed that their participation is voluntary, and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Patients or their legally authorised representative will be required 
to sign a statement of informed consent that meets the requirements of 21 Code of 
Federal Regulations 50, local regulations, ICH guidelines, privacy and data 
protection requirements, where applicable, and the IRB/IEC or study centre.

The medical record must include a statement that written informed consent was 
obtained before the patient was enrolled in the study and the date the written 
consent was obtained. The authorised person obtaining the informed consent must 
also sign the ICF.

If new information requires changes to the ICF, consider if patients must be 
reconsented and if so, this must be to the most current version of the ICF(s) during 
their participation in the study.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional HBS. The Investigator or authorised designee will explain to 
each patient the objectives of the analysis to be done on the samples and any potential future 
use. Patients will be told that they are free to refuse to participate in any optional samples or 
the future use, and may withdraw their consent at any time and for any reason during the 
retention period.
A 4
Data Protection

Patients will be assigned a unique identifier by AstraZeneca. Any patient records or 
datasets that are transferred to 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 their 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 their medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by 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 

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activities and will not make personal data available to anyone (including internal staff) 
who is not authorised or does not have a business need to know the information. 
!
The patient must be informed that in some cases their data may be pseudonymised. The 
General Data Protection Regulation (EU) (GDPR) defines pseudonymisation 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 
organisational measures to ensure that the personal data are not attributed to an identified 
or identifiable natural person.
 
 
 
The patient’s samples will not be used for any purpose other than those described in the study 
protocol.
A 5
Committees Structure
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing 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://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the study results when they are available. The clinical study and/or summary 
of study results may also be available on other websites according to the regulations of 
the countries in which the study is conducted.
A 7
Data Quality Assurance
!
All patient data relating to the study will be recorded on eCRF unless transmitted to 
AstraZeneca or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.
CCI

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
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Quality tolerance limits will be predefined in the state location(s) to identify systematic 
issues that can impact patient safety and/or reliability of study results. These predefined 
parameters will be monitored during the study, and important deviations from the quality 
tolerance limits and remedial actions taken will be summarised in the CSR.

Monitoring details describing strategy, including definition of study-critical data items 
and processes (eg, risk-based initiatives in operations and quality such as Risk 
Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are included in the 
Monitoring Plans.

AstraZeneca 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 Monitoring Plans.

AstraZeneca 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 (eg, 
CROs).
Study monitors will perform ongoing source data verification as per the Monitoring Plans to 
confirm that data entered into the eCRF by authorised site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of 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 local regulations, according to the AstraZeneca GRAD Schedule. No records 
may be destroyed during the retention period without the written approval of 
AstraZeneca. No records may be transferred to another location or party without written 
notification to AstraZeneca.

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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 entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available.

Definition of what constitutes source data and its origin can be found in site specific 
source data agreement and/or monitoring guidelines. All information in original records 
and certified copies of original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study 
are defined as source documents. Source data are contained in source documents (original 
records or certified copies).
A 9
Study and Site Start and Closure

The study start date is the date on which the clinical study will be open for recruitment of 
patients.

The first act of recruitment is the first site open is considered the first act of recruitment 
and will be the study start date.

The AstraZeneca designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of AstraZeneca. Study sites will be closed 
upon study completion. A study site is considered closed when all required documents 
and study supplies have been collected and a study site closure visit has been performed.

The Investigator may initiate study site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.

Reasons for the early closure of a study site by AstraZeneca or the Investigator may 
include but are not limited to:
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, AstraZeneca’s procedures, or GCP guidelines
Inadequate recruitment of patients by the investigator
Discontinuation of further study intervention development

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
If the study is prematurely terminated or suspended, AstraZeneca shall promptly inform 
the Investigators, the IRBs/IECs, the regulatory authorities, and any CRO(s) used in the 
study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the patient and should 
assure appropriate patient therapy and/or follow-up.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to AstraZeneca 
before submission. This allows AstraZeneca to protect proprietary information and to 
provide comments.

AstraZeneca will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, AstraZeneca will generally 
support publication of multicentre 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
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event
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 (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the patient was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study.
Important Medical Event or Medical Intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the patient or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine

Intensive treatment in an emergency room or at-home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse

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A Guide to Interpreting the Causality Question
When making an assessment of causality, consider the following factors when deciding if 
there is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the 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 aetiology 
such as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if, following a review of the relevant data, there is evidence for 
a ‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgement. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.

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B 1
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 AstraZeneca study drug that either causes harm to the patient or has 
the potential to cause harm to the patient. 
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 patient.
Medication error includes situations where an error: 

Occurred

Was identified and intercepted before the patient received the drug

Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the patient

Drug not administered as indicated, eg, wrong route, dose (error greater than +/- 10%), or 
wrong site of administration 

Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed, eg, kept in the refrigerator when it should be at room 
temperature 

Wrong patient received the medication (excluding IVRS/RTSM errors)

Wrong drug administered to patient (excluding IVRS/RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/RTSM - including those which led to one of the 
above listed events that would otherwise have been a medication error 

Patient accidentally missed drug dose(s), eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Patient failed to return unused medication or empty packaging

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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, 
non-therapeutic excessive use of AstraZeneca study drug 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 patient or if the drug abuse regards a person not enrolled in the study 
(such as a relative of the study patient).
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 patient 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 patient) of AstraZeneca study 
drug for medicinal purposes outside of the authorised product information, or for unauthorised 
AstraZeneca study drug, 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 patient or if the drug misuse regards a person not enrolled in the 
study (such as a relative of the study patient).
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

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
Only half the dose is taken because the study patient feels that they were feeling better 
when not taking the whole dose

Someone who is not enrolled in the study intentionally takes the drug.

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Appendix C
International Airline Transportation Association (IATA) 6.2 
Guidance Document
Labelling and Shipment of Biohazard Samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 3
categories. For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations 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, 
HIV types 1 and 2. They are assigned the following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B

Are to be packed in accordance with UN3373 and IATA 650
Exempt – all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations

Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging

Biological samples transported in dry-ice require additional dangerous goods 
specification for the dry ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable

Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used

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Appendix D
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
D 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 6.3.7 of the Clinical Study Protocol.
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 investigational medicinal product 
(IMP).
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.
D 2
Definitions
Potential Hy’s Law
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 x ULN together 
with total bilirubin (TBL) ≥ 2 x ULN at any point during the study following the start of study 
medication irrespective of an increase in alkaline phosphatase (ALP).
Hy’s Law
AST or ALT ≥ 3 x ULN together with TBL ≥ 2 x ULN, where no other reason, other than the 
IMP, 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 timeframe within which the 
elevations in transaminases and TBL must occur.

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D 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 x ULN

AST ≥ 3 x ULN

TBL ≥ 2 x ULN
The Investigator will 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)

Complete the appropriate unscheduled laboratory electronic case report form (eCRF) 
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 D 2 within this appendix for 
definition) by reviewing laboratory reports from all previous visits
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 D 2 within this appendix for 
definition) by reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory eCRF
D 4
Follow-up
D 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

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
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol
D 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 D 6)

Notify the AstraZeneca representative who will then inform the central study team
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study 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 aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician

If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures
D 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP. The AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will 
also be involved in this review together with other subject matter experts as appropriate.
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF

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
If the alternative explanation is an AE/SAE, record the AE /SAE in the eCRF 
accordingly and follow the AstraZeneca standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes

The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply

As there is no alternative explanation for the HL case, a causality assessment of ‘related’ 
should be assigned
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:

Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the SAE report according to the outcome of the 
review amending the reported term if an alternative explanation for the liver 
biochemistry elevations is determined
D 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 
D 4.2 of this appendix
# 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 

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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.
D 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, eg, chronic or progressing malignant disease, severe 
infection or liver disease, or did the patient meet PHL criteria prior to starting study 
treatment and at their first on study treatment visit as described in D 6.
If No: follow the process described in D 4.2 of this appendix
If Yes:
Determine if there has been a significant change in the patient’s condition# compared with 
when PHL criteria were previously met

If there is no significant change no action is required

If there is a significant change follow the process described in D 4.2 of this appendix
# 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.
D 8
References
US FDA 2009
United States Food and Drug Administration (FDA) [internet]. FDA Guidance for Industry; 
Drug-induced Liver Injury: Premarketing Clinical Evaluation; July 2009 [cited 08 Mar 2022]. 
Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory 
Information/Guidances/UCM174090.pdf.

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Appendix E
Guidance Regarding Potential Interactions with Concomitant 
Medications
The use of any natural/herbal products or other “folk remedies” should be discouraged, but 
use of these products, as well as use of all vitamins, nutritional supplements, and all other 
concomitant medications must be recorded in the eCRF.
E 1
Drugs inducing CYP3A4 metabolism that AstraZeneca strongly 
recommends are not combined with osimertinib
Osimertinib is metabolised 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 must not be used during this study for any patient 
receiving osimertinib.
Table E1
Drugs Inducing CYP3A4
Contraindicated drugs
Withdrawal period prior to osimertinib start
Carbamazepine, phenobarbital (phenobarbitone), 
phenytoin, rifampicin, rifabutin, rifapentine, 
St John’s Wort
3 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 judgement 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).

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Table E2
Exposure, Pharmacological Action and Toxicity May be Increased by 
Osimertinib
Warning of possible interaction
Advice
Rosuvastatin
Drugs are permitted but caution should be exercised and 
patients monitored closely for possible drug interactions. Please 
refer to full prescribing information for all drugs prior to 
co-administration with osimertinib.
Sulfasalazine
Doxorubicin
Daunorubicin
Topotecan
Dabigatran
Aliskiren
Digoxin
E 2
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 on the CredibleMeds® website 
https://www.crediblemeds.org/. The website categorises drugs based on the risk of inducing 
Torsades de Pointes (TdP).
During screening the drugs that patients are currently receiving (prescription and 
non-prescription) should be checked against the ArizonaCert website. In addition, drugs 
intended for use following study treatment initiation should be checked against the website.
E 2.1
Drugs with a known risk of Torsades de Pointes
Drugs in this category are known to prolong the QT interval and are clearly associated with a 
known risk of TdP, even when taken as recommended.
E 2.1.1
Before Commencing Study Treatment
Drugs in the category of known risk of TdP must have been discontinued prior to the start of 
administration of study treatment in accordance with guidance provided in Table E3.
E 2.1.2
During Study Treatment
It is recommended that drugs in the category of known risk of TdP are not co-administered 
with study treatment (osimertinib) and for a period of 2 weeks after discontinuing study 
treatment, however, if it is considered essential for patient management to co-administer these 
drugs with study treatment (osimertinib), close monitoring of ECGs and electrolytes is 
recommended.

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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 
CredibleMeds® website (https://www.crediblemeds.org/) to provide the most up-to-date 
information.
Table E3
Drugs With a Known Risk of TdP a
Drug name
Withdrawal period prior to study 
treatment start b
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
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 c , Ibogaine
6 weeks
Pentamidine
8 weeks
Astemizole, Probucol, Vandetanib
4 months
Amiodarone, Chloroquine
1 year
a
This list should be checked against the full and most current list presented in the CredibleMeds® website.
b
Values determined from comprehensive review (internal to AZ) of each compound’s PK half-life and 
determination of the washout period.
c
Estimated value as PK of arsenic trioxide has not been studied.
AZ = AstraZeneca; PK = pharmacokinetics; TdP = Torsades de Pointes.
E 3
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 of ECGs and electrolytes is recommended.
Patients with congenital long QT syndrome are excluded from this study.

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During study treatment and for a period of 2 weeks after discontinuing study treatment, if it is 
considered essential for patient management to co-administer drugs known to prolong QTc 
interval, regardless of TdP risk category, close monitoring of ECGs and electrolytes is 
recommended.

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Appendix F
Guidelines for Evaluation of Objective Tumour Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumours)
F 1
Introduction
This appendix details the implementation of RECIST 1.1 guidelines (Eisenhauer et al 2009) 
for the D5161C00003 study with regards to Investigator assessment of tumour burden 
including protocol-specific requirements for this study.
F 2
Definition of Measurable, Non-Measurable, Target and 
Non-Target Lesions
Only patients with measurable disease at baseline should be included in the study. Measurable 
disease is defined by the presence of at least one measurable lesion which has not been 
previously irradiated and not chosen for biopsy during the Screening Period.
Measurable:
A lesion, not previously irradiated and not chosen for biopsy during the Screening Period, that
can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph 
nodes which must have short axis ≥15 mm) with CT or MRI and which is suitable for accurate 
repeated measurements. If only one measurable lesion exists, it is acceptable to be used (as a 
target lesion) as long as it has not been previously irradiated and baseline tumour assessment 
scans are done at least 14 days after the screening biopsy is performed.
Non-measurable:

All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis at baseline*)

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

Previously irradiated lesions**

Skin lesions assessed by clinical examination

Brain metastasis

Lesions biopsied within the Screening Period (exception: if only one measurable lesion 
exists, it is acceptable to be used [as a target lesion] as long as it has not been previously 
irradiated and baseline tumour assessment scans are done at least 14 days after the 
screening biopsy is performed)

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*Nodes with < 10 mm short axis are considered non-pathological and should not be recorded 
or followed as a non-target lesion (NTL).
**Localised post-radiation changes which affect lesion sizes may occur. Therefore, lesions 
that have been previously irradiated will not be considered measurable and must be selected as 
NTLs at baseline and followed up as part of the NTL assessment.
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 target lesions.
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 
target lesions (TL) at baseline.
Non-target lesions:
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.
F 3
Methods of Assessment
The same method of assessment and the same technique should be used to characterise 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 below and those 
excluded from tumour assessments for this study are highlighted, with the rationale provided.
Table F1
Summary of Methods of Assessment
Target lesions
Non-target lesions
New lesions
CT (preferred)
MRI
CT (preferred)
MRI
Clinical examination
X-ray, Chest x-ray
CT (preferred)
MRI
Clinical examination
X-ray, Chest x-ray
Ultrasound
Bone Scan
FDG-PET

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F 3.1
Computed Tomography or Magnetic Resonance Imaging
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TL selected for response assessment and to assess NTL and identification 
of any new lesions.
In the D5161C00003 study it is recommended that CT examinations of the chest and abdomen 
(including liver and adrenal glands) and pelvis, will be used to assess tumour burden at 
baseline and follow-up visits. CT examination with intravenous contrast media administration 
is the preferred method. MRI should be used where CT is not feasible or is medically 
contraindicated. For brain lesion assessment, MRI is the preferred method although CT is 
acceptable.
F 3.2
Clinical Examination
In the D5161C00003 study, clinical examination will not be used for assessment of TL. 
Clinically detected lesions can be selected as TLs if they are assessed by CT or MRI scans. 
Clinical examination can be used to assess NTL and to identify the presence of new lesions.
F 3.3
X-ray
F 3.3.1
Chest X-ray
In the D5161C00003 study, chest x-ray assessment will not be used for assessment of TL as 
they will be assessed by CT examination or MRI examination. Chest x-ray can, however, be 
used to assess NTL and to identify the presence of new lesions.
F 3.3.2
Plain X-ray
In the D5161C00003 study plain x-ray may be used as a method of assessment for bone NTL 
and to identify the presence of new bone lesions.
F 3.4
Ultrasound
In the D5161C00003 study, ultrasound examination will not be used for assessment of TL and 
NTL as it is not a reproducible method, does not provide an accurate assessment of tumour 
size and it is subjective and operator dependent. Ultrasound examination can, however, be 
used to identify the presence of new lesions. If new clinical symptoms occur and an 
ultrasound is performed, then new lesions should be confirmed by CT or MRI examination.
F 3.5
Endoscopy and Laparoscopy
In the D5161C00003 study, endoscopy and laparoscopy will not be used for tumour 
assessments as they are not validated in the context of tumour assessment.

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F 3.6
Tumour Markers
In the D5161C00003 study tumour markers will not be used for tumour response assessments 
as per RECIST 1.1.
F 3.7
Cytology and Histology
In the D5161C00003 study histology will not be used as part of the tumour response 
assessment as per RECIST 1.1.
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumour has met criteria for response or 
stable disease. In such circumstances, the cytology is necessary to differentiate between 
response / stable disease (an effusion may be a side effect of the treatment) and progressive 
disease (if the neoplastic origin of the fluid is confirmed). Where cytology findings are not 
available, any effusion that significantly worsens (from trace to large) or appearance of 
clinically significant effusion (requiring change in drug therapy) during the study treatment 
will be considered to be progression of NTL, or disease progression due to new lesions.
F 3.8
Isotopic Bone Scan
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
x-ray at baseline should be recorded as NTL and followed by the same method as per baseline 
assessment.
In the D5161C00003 study isotopic bone scans may be used as a method of assessment to 
identify the presence of new bone lesions at follow-up visits. New lesions will be recorded 
where a positive hot-spot that was not present on the baseline bone scan assessment is 
identified on a bone scan performed at any time during the study. The Investigator should 
consider the positive hot-spot to be a significant new site of malignant disease and represent 
true disease progression in order to record the new lesion. Confirmation by CT, MRI, and 
x-ray is recommended where bone scan findings are equivocal.
F 3.9
FDG-PET Scan
In the D5161C00003 study FDG-PET scans may be used as a method for identifying new 
lesions, according with the following algorithm: new lesions will be recorded where there is 
positive FDG uptake* not present on baseline FDG-PET scan or in a location corresponding 
to a new lesion on CT/MRI at the same follow-up visit. If there is no baseline FDG-PET scan 
available, and no evidence of new lesions on CT/MRI scans then follow-up CT/MRI 
assessments should be continued, scheduled as per protocol or clinical indicated, in order to 
confirm new lesions.
*A positive FDG-PET scan lesion should be reported only when an uptake greater than twice 
that of the surrounding tissue is observed.
F 4
Tumour Response Evaluation

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F 4.1
Schedule of Evaluation
Baseline assessments should encompass all areas of known predilection for metastases in the 
disease under evaluation and should additionally investigate areas that may be involved based 
on signs and symptoms of individual patients and should be performed no more than 28 days 
before the start of study treatment (refer to Study Plan and Section 5.1 from the study 
protocol). Follow-up assessments will be performed every 8 weeks (± 7 days) (relative to 
study enrolment) up to 3.5 years (1277 days) and every 10 weeks (± 14 days) from Day 1278 
to progression as defined by RECIST 1.1 even if a patient discontinues treatment prior to 
progression or receives other anticancer treatment. Any other sites at which new disease is 
suspected should also be adequately imaged at follow-up.
If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits. This schedule 
is to be followed in order to minimise any unintentional bias caused by some patients being 
assessed at a different frequency than other patients.
F 4.2
Target Lesions
F 4.2.1
Documentation of Target Lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), representative of all lesions involved should be identified as TL at baseline. 
Target lesions should be selected on the basis of their size (longest diameter for non-nodal 
lesions or short axis for nodal lesions), but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest 
lesion, which can be measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes). All measurements should be recorded in 
millimetres. At baseline the sum of the diameters for all 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 > 5mm, the minimum size of measurable 
disease at baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the longest diameter should be recorded as 
0 mm.

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
If a TL splits into 2 or more parts, then record the sum of the diameters of those 
parts.

If 2 or more TL 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 eg, radiotherapy, embolisation, surgery, during 
the study, the size of the TL should still be provided where possible.
F 4.2.2
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumour visit 
response for TL.
Table F2
Evaluation of Target Lesions
Complete Response (CR)
Disappearance of all target lesions since baseline. Any 
pathological lymph nodes selected as target lesions 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 progressive disease
Progressive Disease (PD)
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5mm
Not Evaluable (NE)
Only relevant if any of the target lesions were not assessed or not 
evaluable or had a lesion intervention at this visit. Note: If the sum 
of diameters meets the PD criteria, PD overrides not evaluable as a 
target lesion response

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F 4.3
Non-target Lesions
F 4.3.1
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.
Table F3
Evaluation of Non-target Lesions
Complete Response (CR)
Disappearance of all non-target lesions 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 non-target lesions. 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 non-target lesions were not 
assessed and, in the Investigator's opinion, they are not able to provide 
an evaluable overall non-target lesion assessment at this visit.
To achieve ‘unequivocal progression’ on the basis of non-target lesions, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target lesions, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status.
F 4.4
New Lesions
Details of any new lesions will also be recorded with the date of assessment. The presence of 
one or more new lesions is assessed as progression.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: ie, not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour.
If a new lesion is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the new lesion has been confirmed. If repeat scans 

Clinical Study Protocol Appendix E
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Study Code D5161C00003
Version 7.0
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confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan.
F 4.5
Symptomatic Deterioration
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy.
Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumour 
assessments where possible until objective disease progression is observed.
F 4.6
Evaluation of Overall Visit Response
The overall visit response will be derived using the algorithm shown in Table F4.
Table F4
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-D 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 = progressive disease, NE = not 
evaluable, NA = not applicable (only relevant if there were no NTLs at baseline).
F 5
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 tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45(2):228-47.

Clinical Study Protocol Appendix G
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
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Appendix G
Definition of Women of Childbearing Potential and Highly 
Effective 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 
sterilised and are capable of procreation.
Women NOT of Childbearing Potential:
Women who are permanently or surgically sterilised or postmenopausal (definitions below):
Permanent sterilisation 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 (eg, undergo pregnancy testing, as required by the study protocol)

Women will be considered postmenopausal 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 postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatments and with luteinising hormone and follicle-stimulating hormone levels in 
the postmenopausal range
─Women 50 years of age or more will be considered postmenopausal if they have 
been amenorrhoeic for 12 months or more following cessation of all exogenous 
hormonal treatments
Highly effective contraception methods
Highly effective method of birth control is defined in Note 3 in International Conference on 
Harmonisation Guidance M3 (Nonclinical Safety Studies for the Conduct of Human Clinical 
Trials for Pharmaceuticals) as one that results in a low failure rate (eg, 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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Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
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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)

Vasectomised sexual partner plus male condom (with patient assurance that partner 
received post-vasectomy confirmation of azoospermia)

Tubal occlusion plus male condom

Intrauterine device (IUD) – provided coils are copper-banded, plus male condom

Intrauterine system (IUS) levonorgestrel IUS (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 / ethinyl oestradiol transdermal system plus male condom

Intravaginal device (eg, ethinyl oestradiol 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

All progesterone-only pills except, Cerazette

All barrier methods, if intended to be used alone

Non-copper containing IUD

Fertility awareness methods

Coitus interruptus

Clinical Study Protocol Appendix G
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Study Code D5161C00003
Version 7.0
Date 14 April 2023
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Appendix H
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
patients become infected with SARS-CoV-2 or similar pandemic infection) during which 
patients may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
notification from the Sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation.
Please note that during civil crisis, natural disaster, or public health crisis, some study 
assessments and procedures may not be conducted due to international or local policies or 
guidelines, hospital or clinic restrictions and other measures implemented to ensure the 
patient’s safety. If in doubt, please contact the AZ Study Physician.
H 1
Reconsent of Study Patients During Study Interruptions
During study interruptions, it may not be possible for the patients to complete study visits and 
assessments on-site and alternative means for carrying out the visits and assessments may be 
necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in the sections below. Local and regional regulations and/or guidelines regarding 
reconsent of study patients should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should 
be signed at the patient’s next contact with the study site). Visiting the study sites for the sole 
purpose of obtaining reconsent should be avoided.
H 2
Rescreening of Patients to Reconfirm Study Eligibility
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened patients. The Investigator should confirm this with the designated Study 
Physician.
In addition, during study disruption there may be a delay between confirming eligibility of a 
patient and either enrolment into the study or commencing of dosing with study intervention. 
If this delay is outside the screening window specified in Table 1 and Table 2, the patient will 
need to be rescreened to reconfirm eligibility before commencing study procedures. This will 
provide another opportunity to rescreen a patient in addition to that detailed in Section 3.7.1. 
The procedures detailed in Table 1 and Table 2 must be undertaken to confirm eligibility 
using the same randomization number as for the patient.
H 3
Home or Remote Visit to Replace On-site Visit (where applicable)

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A qualified HCP from the study site or third-party vendor service will visit the patient’s home 
or other remote location as per local Standard Operating Procedures, as applicable. Supplies 
will be provided for a safe and efficient visit. The qualified HCP will be expected to collect 
information per the CSP.
H 4
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the patient using 
telecommunications technology, including phone calls, virtual or video visits, and mobile 
health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the patients will allow AEs, concomitant medications, and targeted physical 
examinations to be reported and documented.
H 5
Data Capture During Telemedicine Visits
Data collected during telemedicine or home/remote visits will be captured by the qualified 
HCP (or site delegate) from the study site or third-party vendor service in the source 
documents.

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