Clinical trial NCT03239340
Conditions: EGFR Mutation Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer
Keywords: EGFR, NSCLC, Lung Cancer, Biopsy, Molecular Profiling
Sponsor: AstraZeneca
Start date: 2018-05-30; Completion date: 2023-09-19
Enrollment: 154 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A multicentre, open-label, single-arm, molecular profiling study of patients with EGFR mutation-positive locally advanced or metastatic NSCLC treated with osimertinib.

Detailed description:
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. Participants with EGFR mutation-positive non-small cell lung cancer will be required to consent to 2 mandatory tumour biopsies to be considered for enrolment in this study. The first biopsy will be done prior to initiating treatment with osimertinib and the second biopsy will be obtained any time between Investigator assessed, Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1)-defined progression and before the start of any new anticancer treatment. A third optional biopsy may be taken during the course of treatment at the Investigator's discretion if the patient consents and if clinically feasible. Tumour tissue and plasma samples will be collected and examined for genetic and non genetic aberrations that may be important in determining response and resistance to the treatment that participants will receive as a part of their cancer care. Patients should continue on osimertinib until progression or until other treatment discontinuation criteria are met. However, 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. Tumour assessments will be performed at baseline and then every 8 weeks from study enrolment until 3.5 years, and then every 10 weeks until RECIST 1.1-defined. Patients will be followed up for a period of 28 days following discontinuation of osimertinib. 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. Osimertinib is an oral, potent, selective, irreversible inhibitor of both EGFR tyrosine kinase inhibitor sensitizing 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.

Arms: arm 1: An oral, potent, selective, irreversible inhibitor of both EGFR-tyrosine kinase inhibitor sensitizing and resistance mutations in non-small cell lung cancer
Interventions: intervention 1: Osimertinib
Intervention descriptions: intervention 1: Osimertinib is an oral, potent, selective, irreversible inhibitor of both EGFR-tyrosine kinase inhibitor sensitizing and resistance mutations in non-small cell lung cancer with a significant selectivity margin over wild type EGFR.

Protocol documents:
Prot_000.pdf: 
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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).




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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.


Clinical Study Protocol
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
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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


Clinical Study Protocol
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
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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.


Clinical Study Protocol
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Study Code D5161C00003
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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.




Clinical Study Protocol
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
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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 


Clinical Study Protocol
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
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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.


Clinical Study Protocol
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Study Code D5161C00003
Version 7.0
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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


Clinical Study Protocol
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
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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 


Clinical Study Protocol
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTAIL AND PROPRIETARY 
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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.


Clinical Study Protocol
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Study Code D5161C00003
Version 7.0
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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).




Clinical Study Protocol
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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.


Clinical Study Protocol
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Study Code D5161C00003
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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.


Clinical Study Protocol
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Study Code D5161C00003
Version 7.0
Date 14 April 2023
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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.


Clinical Study Protocol
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Study Code D5161C00003
Version 7.0
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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


Clinical Study Protocol
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Study Code D5161C00003
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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


Clinical Study Protocol
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Study Code D5161C00003
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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) 
during sex with all partners of childbearing potential during the trial and for a 


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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 
Table 2).


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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 
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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


Clinical Study Protocol Appendix A
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Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
106 (131)
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.


Clinical Study Protocol Appendix A
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
107 (131)
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


Clinical Study Protocol Appendix A
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
108 (131)
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


Clinical Study Protocol Appendix A
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
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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.


Clinical Study Protocol Appendix B
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
110 (131)
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


Clinical Study Protocol Appendix C
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
111 (131)
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.


Clinical Study Protocol Appendix C
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
112 (131)
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


Clinical Study Protocol Appendix C
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
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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


Clinical Study Protocol Appendix C
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
114 (131)

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 


Clinical Study Protocol Appendix C
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
115 (131)
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.


Clinical Study Protocol Appendix D
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
116 (131)
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).


Clinical Study Protocol Appendix D
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
117 (131)
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.


Clinical Study Protocol Appendix D
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
118 (131)
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.


Clinical Study Protocol Appendix D
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
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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.


Clinical Study Protocol Appendix E
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
120 (131)
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)


Clinical Study Protocol Appendix E
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
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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


Clinical Study Protocol Appendix E
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
122 (131)
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.


Clinical Study Protocol Appendix E
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
123 (131)
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


Clinical Study Protocol Appendix E
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
124 (131)
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.


Clinical Study Protocol Appendix E
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
125 (131)

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


Clinical Study Protocol Appendix E
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
126 (131)
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
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
127 (131)
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
CONFIDENTIAL AND PROPRIETARY
128 (131)
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.


Clinical Study Protocol Appendix G
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
129 (131)
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
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
130 (131)
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)


Clinical Study Protocol Appendix G
Drug Substance AZD9291, Osimertinib
Study Code D5161C00003
Version 7.0
Date 14 April 2023
CONFIDENTIAL AND PROPRIETARY
131 (131)
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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SAP_001.pdf: 
Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date: 27 September 2023
1
Statistical Analysis Plan
Drug Substance
AZD9291, osimertinib
Study Code
D5161C00003
Version
4.0
Date
27 September 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


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
2
A multicentre, open-label, single-arm, molecular profiling study of patients 
with EGFR mutation-positive locally advanced or metastatic NSCLC treated 
with osimertinib
Study Statistician
Date
PPD


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
3
A multicentre, open-label, single-arm, molecular profiling study of patients 
with EGFR mutation-positive locally advanced or metastatic NSCLC treated 
with osimertinib
Global Product Statistician
Date
PPD


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date: 27 September 2023
4
A multicentre, open-label, single-arm, molecular profiling study of patients 
with EGFR mutation-positive locally advanced or metastatic NSCLC treated 
with osimertinib
Parexel Study Statistician
Date
PPD


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date: 27 September 2023
5
TABLE OF CONTENTS                                                                               PAGE
title page
1
Signature of Study Statistician.....................................................................................................2
Signature of Global Product Statistician ......................................................................................3
Signature of Study Statistician.....................................................................................................4
List of abbreviations....................................................................................................................8
Amendment history...................................................................................................................11
1.
STUDY DETAILS ........................................................................................................15
1.1
Study Objectives........................................................................................................15
1.2
Study Design .............................................................................................................16
1.3
Number of Patients ....................................................................................................26
2.
ANALYSIS SETS.........................................................................................................26
2.1
Definition of Analysis Sets ........................................................................................26
2.1.1
Primary analysis set .............................................................................................26
2.1.2
Full analysis set....................................................................................................27
2.2
Protocol deviations ....................................................................................................28
3.
PRIMARY AND SECONDARY VARIABLES ..................................................28
3.1
Efficacy.....................................................................................................................28
3.1.1
Derivation of RECIST visit responses..................................................................28
3.1.1.1 Target lesions ...................................................................................................29
3.1.1.2 Non-target lesions and new lesions ......................................................................34
3.1.1.3 Overall visit response...........................................................................................35
3.2
Efficacy variables ......................................................................................................36
3.2.1
Primary endpoint .................................................................................................36
3.2.2
Secondary endpoints ............................................................................................36
3.2.2.1 Progression-free survival..................................................................................37
3.2.2.2 Objective response rate.....................................................................................38
3.2.2.3 Duration of response.........................................................................................38
3.2.2.4 Disease control rate ..........................................................................................39
3.2.2.5 Time to treatment discontinuation or death (TTD)............................................39
3.2.2.6 Time to first subsequent therapy or death (TFST).............................................39
3.2.2.7 Best percentage change in TL tumour size........................................................39


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
6
3.3
Safety variables .........................................................................................................40
3.3.1
General considerations for safety assessments......................................................40
3.3.2
Handling missing data..........................................................................................42
3.3.2.1 Imputation of partial dates ................................................................................42
3.3.3
Exposure and dose interruptions...........................................................................43
3.3.4
Adverse events.....................................................................................................43
3.3.5
Laboratory variables ............................................................................................44
3.3.6
Vital signs............................................................................................................45
3.3.7
Physical Examinations .........................................................................................46
3.3.8
Electrocardiograms ..............................................................................................46
3.3.9
Left ventricular ejection fraction (LVEF) .............................................................46
3.3.10
Ophthalmological assessments............................................................................46
3.4
Biomarker variables...................................................................................................46
4.
ANALYSIS METHODS......................................................................................47
4.1
General principles......................................................................................................47
4.2
Analysis methods.......................................................................................................48
4.2.1
Patient disposition................................................................................................48
4.2.2
Attrition of biopsy samples ..................................................................................48
4.2.3
Protocol deviations...............................................................................................48
4.2.4
Demographics and other baseline characteristics..................................................49
4.2.5
Medical history....................................................................................................49
4.2.6
Disease history.....................................................................................................49
4.2.7
Concomitant medication ......................................................................................50
4.2.8
Exposure..............................................................................................................50
4.2.9
Primary and Efficacy Endpoints...........................................................................50
4.2.9.1 Proportion of patients with a given marker .......................................................51
4.2.9.2 Progression-free survival..................................................................................51
4.2.9.3 Confirmed objective response rate....................................................................52
4.2.9.4 Duration of response.........................................................................................52
4.2.9.5 Disease control rate ..........................................................................................52
4.2.9.6 Time to treatment discontinuation or death (TTD)............................................52
4.2.9.7 Time to first subsequent therapy or death (TFST).............................................53
4.2.10
Safety..................................................................................................................53


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
7
4.2.10.1 Adverse events .................................................................................................53
4.2.10.2 Laboratory evaluations .....................................................................................53
4.2.10.3 Vital signs ........................................................................................................54
4.2.10.4 Electrocardiograms...........................................................................................54
4.2.11
Exploratory analysis............................................................................................55
4.2.12
Impact on analyses due to COVID-19 pandemic .................................................55
4.3
Subgroup analysis......................................................................................................55
4.3.1
Best change in TL tumour size.............................................................................55
4.4
Summary of mutations by baseline characteristics......................................................55
5.
INTERIM ANALYSIS ........................................................................................56
6.
CHANGES OF ANALYSIS FROM PROTOCOL ...............................................56
7.
REFERENCES ....................................................................................................56


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
8
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse event
AJCC
American Joint Committee on Cancer 
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
ATC
Anatomical therapeutic chemical
CI
Confidence interval
CM
Concomitant medication
cMET
Proto-oncogene encoding hepatocyte growth factor receptor
CR
Complete response
CrCl
Creatinine Clearance
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
Circulating tumour deoxyribonucleic acid
CYP
Cytochrome P450
DCO
Data cut off
DCR
Disease control rate
DoR
Duration of response
ECG
Electrocardiogram
eCRF
Electronic case report form
EGFR
Epidermal growth factor receptor
EGFRm+
Epidermal growth factor receptor mutation-positive
FAS
Full analysis set
FDA
US Food and Drug Administration
FPI
First patient in
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
Hb
Haemoglobin


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
9
Abbreviation or 
special term
Explanation
HER2
Human epidermal growth factor receptor 2
HL
Hy’s Law
IB
Investigator brochure
ICH
International Council for Harmonisation
IMP
Investigational medicinal product
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.  
IP
Investigational product, also referred to as ‘study drug’ and ‘study 
treatment’ in this protocol 
IRB
Institutional Review Board, synonymous to Ethics Committee
IVRS/IWRS
Interactive Voice Response System/Interactive Web Response System
K-M
Kaplan-Meir
LD
Longest Diameter
LVEF
Left ventricular ejection fraction 
M1a
Malignant effusion
M1b
Distant metastasis
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MUGA
Multigated acquisition scan
NA
Not Applicable
NCI
National Cancer Institute
NE
Not Evaluable
NED
No evidence of disease
NSCLC
Non-small cell lung cancer
NTL
Non-target lesion
OAE
Other significant adverse event
ORR
Objective response rate
PAS
Primary analysis set 
PD
Progressive disease
PFS
Progression-free survival
PHL
Potential Hy’s Law


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
10
Abbreviation or 
special term
Explanation
PID
Percentage intended dose
PR
Partial response
PT
Preferred term
QTc
QT interval corrected for heart rate
QTcF
QTc corrected using Fridericia’s correction
RECIST
Response Evaluation Criteria in Solid Tumours 
RR
Response rate
SAE
Serious adverse event 
SAP
Statistical analysis plan
SAS®
A commercially available integrated system of software products, 
commonly used for reporting and analysis of Clinical Studies 
SD
Stable disease
SOC
System organ class
TBL
Total bilirubin
TEAE
Treatment emergent adverse event
TFST
Time to first subsequent therapy or death
TKI
Tyrosine kinase inhibitor
TL
Target lesion
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


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date: 27 September 2023
11
AMENDMENT HISTORY
CATEGORY
Change refers to:
Date
Description of change
In line with 
CSP?
Rationale
N/A
6/6/2019
Initial approved SAP
N/A
N/A
Derivation of primary 
endpoint(s)
1/26/2022
Section 2.1 added new sensitivity analysis 
set, also updated in Section 6.
No (V4.0)
To allow use of more paired biopsies 
in the analyses. 
Derivation of secondary 
endpoint(s)
9/17/2021
Section 3.1.2.2.6 clarified censoring rules.
Yes 
Not described in CSP in this detail
Derivation of secondary 
endpoint(s)
9/17/2021
Section 3.1.2.2.7 Clarified definition of 
best percentage change in TL tumour size.
Yes 
Not described in CSP in this detail
Safety endpoint(s) 
5/13/2021
Section 3.3.1 Table 7 amended Visit 10 
Upper Limit to 196.
Yes 
Not described in CSP in this detail
Safety endpoint(s) 
10/21/2021
Section 3.3.2.1 Added text on imputation 
of missing death dates.
Yes 
Not described in CSP in this detail
Safety endpoint(s) 
5/13/2021
Section 3.3.5 Added corrected calcium 
formula
Yes 
Not described in CSP in this detail
Safety endpoint(s) 
5/13/2021
Throughout, updated physical 
examination analysis as only look at 
whether it was performed or not.
Yes 
Not described in CSP in this detail
Safety endpoint(s) 
5/13/2021
Section 4.2.9.4 Removed descriptive 
statistics section for ECG data. 
Yes 
Not described in CSP in this detail
Data presentation
9/17/2021
Section 3.3.7 Updated where clinically 
significant physical examination findings 
will be recorded.
Yes 


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
12
CATEGORY
Change refers to:
Date
Description of change
In line with 
CSP?
Rationale
Data presentation
9/17/2021
Section 4.3 Clarified mutations will be 
detected in the tumour. Removed 
reference to T790m subgroups, no longer 
presented. 
Yes 
T790m subgroup had very few 
subjects, decided not relevant to 
analyses.  
Other 
5/13/2021
Section 4.2.5 Deleted the repeated 
‘primary tumour’ and ‘Extent of Disease 
Upon Entry to Study (metastatic, locally 
advanced, both)’
Yes 
Not described in CSP in this detail
Other 
5/13/2021
Added new section 4.2.11 on COVID-19 
impact and added to section 4.2.2 for 
COVID-19 related PDs. 
No (V4.0) 
COVID-19 not covered in CSP. To 
be updated in CSP amendment. 
Other 
9/17/2021
Section 4.2.1 Updated to match table 
14.1.1 (added: patients ongoing in the 
study at DCO, and reasons for study 
discontinuation).
Yes 
Not described in CSP in this detail
Other 
02/12/2021
Section 3.4 updated to include 
information about biomarker data for 
patients who move to another study post 
progression.
No (V4.0)
To allow for potentially more paired 
biopsies to be included in the 
analyses. 
Other
15/02/2022
Section 5 updated to include that an 
interim will be performed using the PAS-
ITT analysis set.
Yes
CSP allows for ad hoc interim 
analyses to be performed. 
Derivation of primary 
endpoint(s)
10/17/2022
Removed PAS-ITT analysis set and 
updated PAS description to include 
biopsies up until the next anticancer
therapy. 
Yes 
Updated to match CSP V5.0.


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
13
CATEGORY
Change refers to:
Date
Description of change
In line with 
CSP?
Rationale
Other
10/17/2022
Updated references of primary analysis to 
final analysis and clarification of when 
final analysis will happen. Added 
definition of study end. 
Yes 
Updated to match CSP V5.0.
Other
04/21/2023
Section 1.2 updated definition of study 
end. Added additional paragraph about 
study end based off CSP, and details on 
patient management following the final 
DCO, as well as following study 
completion.
Yes
Updated to match CSP V7.0
Figure 1
04/21/2023
Replaced Figure 1 with most up to date 
version of the figure.
Yes
Updated to match CSP V7.0
Table 1
04/21/2023
Updated to match Table 2 in CSP.
Yes
Updated to match CSP V7.0
Number of patients
04/21/2023
Section 1.3 updated to match Synopsis 
and Section 8.1 in CSP: …’ and when 
approximately 50 patients have evaluable 
paired biopsies upon progression’
Yes
Updated to match CSP V7.0
Primary Analysis set
04/21/2023
Section 2.1.2 definition updated to match 
Section 8.3.1 in CSP
Yes
Updated to match CSP V7.0
Table 8 and Laboratory 
evaluations
04/21/2023
Included Magnesium and creatine 
phosphokinase to list of laboratory safety 
assessments to match section 5.2.1 and 
Table 3 in CSP. 
Yes
Updated to match CSP V7.0
LVEF
04/21/2023
Section 3.3.9 updated to match Section 
5.2.4 in CSP.
Yes
Updated to match CSP V7.0


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
14
CATEGORY
Change refers to:
Date
Description of change
In line with 
CSP?
Rationale
Data presentation
04/21/2023
Section 4.2.2 added to describe attrition 
table of biopsy samples requested by AZ.
No
Added to explore why patients who 
had an evaluable baseline did not 
have a paired progression sample for 
the primary analysis.
Primary endpoint and 
Proportion of patients 
with a given marker 
05/30/2023
Section 4.2.9.1 Added ‘Ambiguous’ 
category to ‘Pathogenic’ and ‘Likely 
Pathogenic’
No
Included because of discrepancy in 
number of alterations (amplification) 
in ESMO/ESMO Asia due to missing 
“ambiguous” amplification call.
Progression-free survival 
censoring
08/30/2023
Section 3.2.2.1 - Added more detail 
regarding 2 missing visits when the 
assessment interval changes from 8-
weekly to 10-weekly.
Yes
Prior SAP  didn’t consider how 
interval change affected 2 missing 
visits.
Safety analysis windows
and baseline 
09/19/2023
Section 3.3.1 - Extended table past 3.5 
years. Clarified safety assessment baseline 
definition
Yes
Prior SAP  didn’t consider visit 
interval change at 3.5 years.
Data presentation
09/19/2023
Section 4.2.2 - Added category to cover 
those patients that progressed yet didn’t 
have a progression biopsy
Yes
To ensure complete categorisation of 
subjects with baseline biopsy.
Data presentation
09/19/2023
Section 4.1 - Specified that laboratory 
parameters will be presented with AZ 
recommended number of decimal places.
Yes
Match AZ presentation of Lab 
parameters
Baseline for RECIST
09/19/2023
Section 3.1.1, 3.2.2.7 - Specified that 
baseline will consider Tumour 
assessments on day of treatment start.
Yes
Added to ensure higher proportion of 
baseline values for subjects.


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date: 27 September 2023
15
1.
STUDY DETAILS
1.1
Study Objectives
Primary:
Primary Objective:
Outcome Measure:
To examine the genetic and proteomic profile 
at the point of disease progression in patients 
receiving osimertinib as first-line Epidermal 
growth factor receptor (EGFR) tyrosine kinase 
inhibitor (TKI) therapy for EGFR mutation-
positive (EGFRm+) locally advanced or 
metastatic non-small cell lung cancer 
(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. 
Secondary:
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.
Progression-free survival (PFS), according to 
RECIST 1.1 by Investigator assessment, and other 
selected clinical efficacy endpoints including:

Objective response rate (ORR)

Duration of response (DoR)

Disease control rate (DCR)
To assess the efficacy of osimertinib in patient 
subgroups defined by molecular profile, 
including but not limited to:

EGFR Ex19del, T790M or L858R 
mutation

EGFR Ex19del, T790M or L858R 
detectable in plasma-derived 
circulating tumour 
deoxyribonucleic acid (ctDNA)
Progression-free survival, according to RECIST 1.1
by Investigator assessment, and other selected 
clinical efficacy endpoints including:

Objective response rate (ORR)

Tumour shrinkage/depth of response, 
defined as best change from baseline in 
target lesion tumour size

Time to treatment discontinuation or 
death (TTD)


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
16

Important patient and disease 
characteristics
To further assess the efficacy of osimertinib 
post progression

Time to treatment discontinuation or 
death (TTD)

Time to first subsequent therapy or death
(TFST)
Safety:
Safety Objectives:
Outcome Measures:
To summarise the safety and tolerability 
profile of osimertinib as first-line EGFR TKI
therapy for patients with EGFRm+ locally 
advanced or metastatic NSCLC

Adverse events graded by Common 
Terminology Criteria for Adverse Events 
(CTCAE) version 4.0

Clinical chemistry, haematology and 
urinalysis

Vital signs, physical examination, body 
weight

Electrocardiogram (ECG)

World Health Organization (WHO)
performance status
1.2
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).
To be eligible, patients must consent to at least 2 mandatory tumour biopsies and have 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 TKI sensitivity, either alone or in combination 
with other EGFR mutations (EGFR mutation status determined by a local laboratory). Patients 
must be EGFR TKI treatment-naïve and eligible to receive first-line treatment with osimertinib.


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
17
Patients may continue to show clinical benefit to treatment as judged by the Investigator and 
continue to receive osimertinib beyond RECIST 1.1-defined progression. Therefore, there is no 
maximum duration of treatment. On-study assessments are also shown in (Table 1).
A final data cut off (DCO) is planned in Q2 2023, or at the end of the study, when it is estimated 
that there will be approximately 50 patients with evaluable biopsies at baseline and progression.


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date: 27 September 2023
18
Figure 1
Study Flow Chart 


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
19
Table 1
Study Schedule – On Study Treatment and Discontinuation 
Screening/
Enrolment 
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
Progression 
follow-up o
Cycles / Day
C1
C2
D1
C3
D1
C4, 
5, 6
D1
C7 to 3.5 
years
D169-
1277
3.5 Years to 
Disease 
ProgressionD1278+
D1
D8
D15
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


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
20
Screening/
Enrolment 
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
Progression 
follow-up o
Cycles / Day
C1
C2
D1
C3
D1
C4, 
5, 6
D1
C7 to 3.5 
years
D169-
1277
3.5 Years to 
Disease 
ProgressionD1278+
D1
D8
D15
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
Pregnancy test 
(WoCBP) p
x
x
Tumour tissue
sample d
x d
Tumour tissue 
sample on 
treatment 
(optional) e
x e


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
21
Screening/
Enrolment 
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
Progression 
follow-up o
Cycles / Day
C1
C2
D1
C3
D1
C4, 
5, 6
D1
C7 to 3.5 
years
D169-
1277
3.5 Years to 
Disease 
ProgressionD1278+
D1
D8
D15
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
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
Whole blood 
sample at 
progression n
x


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
22
Screening/
Enrolment 
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
Progression 
follow-up o
Cycles / Day
C1
C2
D1
C3
D1
C4, 
5, 6
D1
C7 to 3.5 
years
D169-
1277
3.5 Years to 
Disease 
ProgressionD1278+
D1
D8
D15
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
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


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
23
Screening/
Enrolment 
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
Progression 
follow-up o
Cycles / Day
C1
C2
D1
C3
D1
C4, 
5, 6
D1
C7 to 3.5 
years
D169-
1277
3.5 Years to 
Disease 
ProgressionD1278+
D1
D8
D15
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
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
Tumour 
assessments 
(RECIST) k
x
x
C5D1 and every 
8 weeks until 
Day 1277
Every 10 weeks 
until progression
x




Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
25
a
Consent must be taken prior to 28-day screening period. Screening period will start with first study-related assessment.
b
Six 4-week cycles followed by 8-week cycles from Cycle 7 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.
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 
study drug).
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 treatment (including surgical) after discontinuing 
osimertinib or death.
n
At progression, a whole blood sample will be obtained within 7 days of the tissue biopsy being 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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1.3
Number of Patients
It has been determined that approximately 150 patients are appropriate to characterize the 
frequency of tumour genetic and proteomic markers at disease progression regardless of their 
prevalence. Table 2 displays the precision of the estimated frequency of mutation when, for 
example, 50 evaluable paired biopsies are available.
The final analysis will be performed at study end, and when approximately 50 patients have 
evaluable paired biopsies upon progression. Assuming a 70% of 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. 
Table 2
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.
2.
ANALYSIS SETS
2.1
Definition of Analysis Sets 
The primary analysis set (PAS) will be used for the analysis of the primary endpoint. The full 
analysis set (FAS) will be used for all other efficacy and safety analyses.
2.1.1 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 


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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.
2.1.2 Full analysis set 
The (FAS) will include all patients who receive at least one dose of osimertinib. The FAS will be 
used for all efficacy and safety analyses.
Table 3 summarises the population analysis sets for each outcome variable.
Table 3
Summary of outcome variables and analysis populations
Outcome variable
Population
Primary objective
Proportion of patients with a given marker at progression
as defined by the investigator
PAS
Efficacy data
PFS, ORR, DoR, DCR, TTD, TFST
FAS 
Subgroup analysis
PFS, ORR, Best change in TL tumour size, TTD
FAS
Important patient and disease characteristics
FAS, PAS
Demography data
Important patient and disease characteristics
FAS, PAS
Safety data
Exposure
FAS
AEs 
FAS
Laboratory measurements
FAS
Vital signs
Physical examinations
Electrocardiograms (ECGs)
FAS
FAS
FAS
Abbreviations: AEs = Adverse events; DCR = Disease control rate; DoR = Duration of response; ECG =
Electrocardiogram; FAS = Full analysis set; ORR = Objective response rate; PAS = Primary analysis set; PFS
= Progression free survival; TFST = Time to first subsequent therapy or death; TL = Target lesion; TTD = 
Time to treatment discontinuation or death.


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2.2
Protocol deviations
The following general categories will be considered important protocol deviations which will be 
listed and discussed in the clinical study report (CSR) as appropriate for the study:

Informed consent procedure deviation (eg, no informed consent signed prior to any screening 
procedure)

Eligibility criteria deviation (eg, any inclusion criteria not met or exclusion criteria met)

Received prohibited concomitant medications (or unable to stop use prior to receiving the 
first dose of study drug) or herbal supplements known to be potent inducers of cytochrome 
P450 (CYP) 3A4 (at least 3 weeks prior). Please refer to protocol Section 3.5 for those 
medications that are detailed as ‘not to be administered’ or being ‘restricted concomitant 
medications’. These will be used as a guiding principle for the physician review of all 
medications prior to database lock. 

Management of adverse events: Lack of prompt reporting of cases meeting Hy’s law criteria 
and serious adverse events (SAE) not being reported within 24 hours of awareness of the 
event.

Tumour biopsy sample taken from lesion selected for RECIST assessment (unless only one 
lesion exists and the RECIST scans are performed within 14 days of screening biopsy).

No baseline RECIST 1.1 assessment before start of treatment.

RECIST 1.1 assessments not done every 8 weeks (±7 days) in relationship to the date of first 
dose until RECIST 1.1 defined progression.

Screening assessment not performed within 42 days prior to study drug initiation.
If the number of deviations which are considered to have the potential to impact the primary 
analysis is considered important, sensitivity analyses may be performed on subgroups. This will 
be decided during the data review meeting and before the database lock. The final classification 
of protocol deviations will be made prior to database lock. Any other deviations from monitoring 
notes or reports will be reported in an appendix to the CSR. 
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Efficacy
3.1.1 Derivation of RECIST visit responses
For all patients, the RECIST tumour response data will be used to determine each patient’s visit 
response according to RECIST version 1.1. It will also be used to determine if, and when, a 
patient has progressed in accordance with RECIST and their best objective response to study 
drug.


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Baseline radiological tumour assessments are to be performed no more than 28 days before the 
first dose of treatment, and as close as possible to the start of study treatment. Assessments on 
the day of the first dose where neither time nor a nominal pre-dose indicator are captured will be 
considered prior to the first dose if such procedures are required by the protocol to be conducted 
before the first dose. Tumour assessments are then performed every 8 weeks (±1 week)
following the start of study treatment until objective disease progression.
If an unscheduled assessment is performed, and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits. This schedule is 
to be followed to minimise any unintentional bias caused by some patients being assessed at a 
different frequency than other patients.
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 1.1. At each visit, patients 
will be programmatically assigned a RECIST 1.1 visit response of complete response (CR), 
partial response (PR), stable disease (SD) or progressive disease (PD), using the information 
from target lesions (TLs), non-target lesions (NTLs) and new lesions and depending on the status 
of their disease compared with baseline and previous assessments. If a patient has had a tumour 
assessment that cannot be evaluated then the patient will be assigned a visit response of not 
evaluable (NE), (unless there is evidence of progression in which case the response will be 
assigned as PD). 
Please refer to Table 4 for the definitions of CR, PR, SD, and PD. 
RECIST outcomes (ie, PFS, ORR etc.) will be calculated programmatically for the site 
Investigator data (see Section 3.2) from the overall visit responses.
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 irradiated 
and not chosen for biopsy during the screening period.
3.1.1.1 Target lesions
Measurable disease is defined as having at least one measurable (by RECIST 1.1) lesion, that has 
not been previously irradiated, which is ≥ 10 mm in the longest diameter (LD), (except lymph 
nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic 
resonance imaging (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 resected or irradiated and baseline tumour assessment scans are done at least 14 days 
after the screening biopsy is performed.
A patient can have a maximum of 5 measurable lesions recorded at baseline with a maximum of 
two lesions per organ (representative of all lesions involved and suitable for accurate repeated 
measurement) and these are referred to as target lesions (TLs). If more than one baseline scan is 


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recorded, then measurements from the one that is closest and prior to first dose of treatment will 
be used to define the baseline sum of TLs. Target lesions should be selected based on 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. 
All other lesions (or sites of disease) not recorded as TL should be identified as non-target 
lesions (NTLs) at baseline. Measurements are not required for these lesions, but their status 
should be followed at subsequent visits.
Table 4 provides the definitions of the criteria used to determine objective tumour visit response 
for TL.
Table 4
TL visit responses
Visit Responses
Description
CR
Disappearance of all TLs since baseline. Any pathological lymph nodes selected 
as TLs must have a reduction in short axis to <10 mm.
PR
At least a 30% decrease in the sum of the diameters of TLs, taking as reference 
the baseline sum of diameters as long as criteria for PD are not met.
SD
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD.
PD
At least a 20% increase in the sum of the diameters of TLs, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest 
on the study). In addition to the relative increase of at least 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. 
NE
Only relevant if any of the TLs were not assessed or not evaluable or had a 
lesion intervention at this visit.  
Note: If the sum of diameters meets the progressive disease criteria, progressive 
disease overrides not evaluable as a TL response.
NA
No TLs are recorded at baseline.
Abbreviations: CR = Complete response; NA= Not applicable; NE = Not evaluable; PD = Progressive disease; PR = 
Partial response; SD = Stable disease; TL = Target lesion.
Rounding of TL data
For calculation of PD and PR for TLs, percentage changes from baseline and previous minimum 
should be rounded to one decimal place before assigning a TL response.  For example, 19.95% 
should be rounded to 20.0% but 19.94% should be rounded to 19.9%.  


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Missing TL data 
For a visit to be evaluable, all TL measurements should be recorded. However, a visit response 
of PD should still be assigned if any of the following occurred:

A new lesion is recorded.

A NTL visit response of PD is recorded.

The sum of TLs is sufficiently increased to result in a 20% increase, and an absolute increase 
of ≥5 mm, from nadir (defined below) even assuming the non-recorded TLs have 
disappeared.
The nadir (ie, the smallest measurement based on the same set of lesions at baseline and on a 
given visit) can only be taken from assessments where all the TLs had a longest diameter (LD) 
recorded.
Lymph nodes
For lymph nodes, if the size reduces to <10 mm, these are considered non-pathological. 
However, a size will still be measured, and this size should still be used to determine the TL visit 
response as normal. In the special case where all lymph nodes are <10 mm and all other TLs are 
0 mm, then although the sum may be >0 mm, the calculation of TL response should be over-
written as a CR. 
TL visit responses subsequent to CR
A CR response can only be followed by CR, PD or NE. If a CR has occurred, then the following 
rules at the subsequent visits must be applied:

Step 1: If all lesions meet the CR criteria (ie, 0 mm or <10 mm for lymph nodes), the 
response will be set to CR irrespective of whether the criteria for PD of TL is also met for 
lymph node (ie, if a lymph node LD increases by 20% but remains <10 mm).

Step 2: If some lesion measurements are missing but all other lesions meet the CR criteria 
(ie, 0 mm or <10 mm for lymph nodes), the response will be set to NE irrespective of 
whether the criteria for PD is also met when referencing the sum of TL diameters.

Step 3: If not all lesions meet the CR criteria, and the sum of lesions meets the criteria for 
PD, the response will be set to PD.

Step 4: If, after steps 1 through 3, a response can still not be determined, the response will be 
set to remain as CR.


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TL too big to measure
If a TL becomes too big to measure, this should be indicated in the database and an estimated 
size (‘x’) above which it cannot be accurately measured should be recorded. If using a value of x 
in the calculation of TL response would not give an overall visit response of PD, then this will be 
flagged and reviewed by the study team. It is expected that a visit response of PD will remain in 
the vast majority of cases.
TL too small to measure
If a TL becomes too small to measure, then this will be indicated as such on the case report form 
and a value of 5mm will be entered into the database and used in TL calculations. However, a 
smaller value may be used if the radiologist has not indicated ‘too small to measure’ on the case 
report form and has entered a smaller value that can be reliably measured. If a lesion has 
completely disappeared, the longest diameter should be recorded as 0 mm.
Irradiated lesions/lesion intervention
Previously irradiated lesions (ie, lesion irradiated prior to entry into the study) should be 
recorded as NTLs and should not form part of the TL assessment.
Any TL (including lymph nodes) which has had intervention during the study (for example, 
irradiation/palliative surgery/embolization) should be handled in the following way and once a 
lesion has had intervention then it should be treated as having intervention for the remainder of 
the study, noting that an intervention will most likely shrink the size of tumours:

Step 1: The diameters of the TLs (including the lesions that have had intervention) will be 
summed and the calculation will be performed in the usual manner. If the visit response is 
PD this will remain as a valid response category. 

Step 2: If there was no evidence of progression after step 1, treat the lesion diameter (for 
those lesions with intervention) as missing and, if ≤1/3 of the TLs have missing 
measurements, scale up as described in the scaling section below. If the scaling results in a 
visit response of PD then the patient would be assigned a TL response of PD.  

Step 3: If after both steps PD has not been assigned, then, if appropriate (ie, if ≤1/3 of the 
TLs have missing measurements), the scaled sum of diameters as calculated in step 2 should 
be used, and PR or SD then assigned as the visit response. Patients with intervention are 
evaluable for CR as long as all non-intervened lesions are 0 (or <10 mm for lymph nodes) 
and the lesions that have been subject to intervention also has a value of 0 recorded. If 
scaling up is not appropriate due to too few non-missing measurements, then the visit 
response will be set to NE.


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
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At subsequent visits the above steps will be repeated to determine the TL and overall visit 
response. When calculating the previous minimum, lesions with intervention should be treated as 
missing and scaled up (as per step 2 above).
Scaling (applicable only for irradiated lesions/lesion intervention)
If >1/3 of TL measurements are missing (because of intervention) then the TL response will be 
NE, unless the sum of diameters of non-missing TL would result in PD (ie, if using a value of 0 
for missing lesions, the sum of diameters has still increased by 20% or more compared to nadir 
and the sum of TLs has increased by ≥5 mm from nadir).
If ≤1/3 of the TL measurements are missing (because of intervention) then the results will be 
scaled up (based on the sizes at the nadir visit to give an estimated sum of diameters) and this 
will be used in calculations; this is equivalent to comparing the visit sum of diameters of the non-
missing lesions to the nadir sum of diameters excluding the lesions with missing measurements.
Example of scaling
Lesion 5 is missing at the follow-up visit; the nadir TL sum including lesions 1-5 was 74mm.
The sum of lesions 1 to 4 at the follow-up visit is 68 mm. The sum of the corresponding lesions 
at the nadir visit is 62mm.
Scale up as follows to give an estimated TL sum of 81mm:
74
62 × 68 = 81mm
CR will not be allowed as a TL response for visits where there is missing data. Only PR, SD or 
PD (or NE) could be assigned as the TL visit response in these cases. However, for visits with 
1/3 lesion assessments not recorded, the scaled-up sum of TLs diameters will be included when 
defining the nadir value for the assessment of progression.
Lesions that split
If a TL splits into two or more parts, then the LDs of the split lesions should be summed and 
reported as the LD for the lesion that split.
Lesions that merge
If two or more TLs merge, then the LD of the merged lesion should be recorded for one of the 
TL sizes and the other TL size(s) should be recorded as 0 cm.


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Study Code D5161C00003
Version 4.0
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Change in method of assessment of TLs 
CT, MRI and clinical examination are the only methods of assessment that can be used within a 
trial, with CT and MRI being the preferred methods and clinical examination only used in special 
cases. If a change in method of assessment occurs, between CT and MRI this will be considered 
acceptable and no adjustment within the programming is needed.
If a change in method involves clinical examination (eg, CT changes to clinical examination or 
vice versa), any affected lesions should be treated as missing.  
3.1.1.2
Non-target lesions and new lesions
At each visit, an overall assessment of the NTL response should be recorded by the Investigator. 
Table 5 provides the definitions of the criteria used to determine and record overall response for 
NTLs at the investigational site at each visit. Non-target lesion response will be derived based on 
the investigator’s overall assessment of NTLs.
Table 5
NTL visit responses
Visit Responses
Description
CR
Disappearance of all NTLs since baseline. All lymph nodes must be non-
pathological in size (<10 mm short axis).
Non CR/Non PD
Persistence of one or more NTLs (with no evidence of progression).
PD
Unequivocal progression of existing NTLs. Unequivocal progression may 
be due to an important progression in one lesion only or in several lesions. 
In all cases, the progression MUST be clinically significant for the 
physician to consider changing (or stopping) therapy. 
NE
Only relevant when one or some of the NTLs were not assessed and, in the 
Investigator’s opinion, they are not able to provide an evaluable overall 
NTL assessment at this visit.
Note: For patients without TLs at baseline, this is relevant if any of the 
NTLs were not assessed at this visit and the progression criteria have not 
been met.
NA
Only relevant if there are no NTLs at baseline.
Abbreviations: CR = Complete response; NA = Not applicable; NE = Not evaluable; PD = Progressive disease; NTL 
= Non-target lesion.
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, the 
overall tumour burden has increased sufficiently to merit a determination of progression. A 
modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify for 
unequivocal progression status.


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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 as 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 
confirm there is a new lesion, then the progression date should be declared using the date of the 
initial scan.
New lesions will be identified via a Yes/No tick box. The absence and presence of new lesions at 
each visit should be listed alongside the TL and NTL visit responses.
A new lesion indicates progression, so the overall visit response will be PD irrespective of the 
TL and NTL response.
If the question ‘Any new lesions since baseline’ has not been answered with Yes or No and the 
new lesion details are blank, this is not evidence that no new lesions are present and should be 
treated as NE in the derivation of overall visit response.
Symptomatic progression is not a descriptor for progression of NTLs or TLs: it is a reason for 
stopping study therapy and will not be included in any assessment of NTLs or TLs.
Patients with ‘symptomatic progression’ 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.
3.1.1.3
Overall visit response
Table 6 defines how the previously defined TL and NTL visit responses will be combined with 
new lesion information to give an overall visit response.
Table 6
Overall visit response
Target lesions
Non-target lesions
New lesions
Overall visit 
response
CR
CR (or NA)
No (or NE)
CR
CR
Non CR/Non PD or NE
No (or NE)
PR


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PR
Non PD or NE or NA
No (or NE)
PR
SD
Non PD or NE or NA
No (or NE)
SD
PD
Any
Any
PD
Any
PD
Any
PD
Any
Any
Yes
PD
NE
Non PD or NE or NA
No (or NE)
NE
NA
CR
No (or NE)
CR
NA
Non CR/Non PD 
No (or NE)
SD
NA
NE
No (or NE)
NE
NA
NA
No (or NE)
NED
Abbreviations: CR = Complete response; NA = Not applicable (only relevant if there were no NTLs at baseline); NE 
= Not evaluable; NED = No evidence of disease; NTL = Non-target lesion; PD = Progressive disease; PR = 
Partial response; SD = Stable disease.
3.2
Efficacy variables
3.2.1 Primary endpoint
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 RECIST 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 paired biopsies and have 
progressed according to the Investigator to calculate the proportion with a given marker at 
progression. New markers will be defined (for an individual patient) to be those present at 
progression that were not present at baseline.  Only markers defined as ‘Pathogenic’, ‘Likely 
pathogenic’ or ‘Ambiguous’ by the analysing lab will be tabulated.
3.2.2 Secondary endpoints
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 1.1. At each visit, patients 
will be programmatically assigned a RECIST 1.1 visit response of CR, PR, SD or PD depending 
on the status of their disease compared with baseline and previous assessments. If a 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).


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3.2.2.1 Progression-free survival
PFS is defined as the time from the 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. PFS 
is calculated in months as follows:  
𝑃𝐹𝑆
= 𝑑𝑎𝑡𝑒𝑜𝑓𝑜𝑏𝑗𝑒𝑐𝑡𝑖𝑣𝑒𝑑𝑖𝑠𝑒𝑎𝑠𝑒𝑝𝑟𝑜𝑔𝑟𝑒𝑠𝑠𝑖𝑜𝑛𝑜𝑟𝑐𝑒𝑛𝑠𝑜𝑟𝑖𝑛𝑔−𝑑𝑎𝑡𝑒𝑜𝑓𝑓𝑖𝑟𝑠𝑡𝑑𝑜𝑠𝑒𝑜𝑓𝑜𝑠𝑖𝑚𝑒𝑟𝑡𝑖𝑛𝑖𝑏+ 1
30.4375
Patients who have not progressed or died at the date of analysis will be censored at the time of 
the latest date of assessment from their last evaluable RECIST 1.1 assessment.
However, if the patient progresses or dies after two or more missed visits (126 days), the patient 
will be censored at the time of the latest evaluable RECIST 1.1 assessment.  
Given the scheduled visit assessment scheme (i.e., eight-weekly for the first 3.5 years [D1277] 
then ten-weekly thereafter) the definition of 2 missed visits will change. Due to a delay in 
enacting CSP version 5.0 there was some variability in when patients transitioned to 10-weekly 
visit. However, we will apply the following rules to all patients.
1. If the previous RECIST 1.1 assessment is baseline, then two missing visits will equate to 
17 weeks since the previous RECIST 1.1 assessment, allowing for a late visit (i.e., 2 x 8 
weeks + 1 week for a late assessment = 17 weeks [119 days]).
2. If the previous RECIST 1.1 assessment is post baseline and ≤ study day 1169, then two 
missing visits will equate to 18 weeks since the previous RECIST 1.1 assessment, allowing 
for early and late visits (i.e., 2 x 8 weeks + 1 week for an early assessment + 1 week for a 
late assessment = 18 weeks [126 days]).
3. If the previous RECIST 1.1 assessment study day is > 1169 and ≤ 1225, then the two missed 
visits occur over the period when the scheduled frequency of RECIST 1.1 assessments 
changes from eight-weekly to ten-weekly, then this will equate to 21 weeks (i.e., take the 
average of 8 and 10 weeks which gives 9 weeks and then apply same rationale, hence 2 x 9 
weeks + 1 week for an early assessment + 2 week for a late assessment = 21 weeks [147 
days]).
4. If the previous RECIST 1.1 assessment study day is > 1225 (when the scheduling changes 
to ten-weekly assessments), two missing visits will equate to 24 weeks (i.e., 2 x 10 weeks 
+ 2 week for an early assessment + 2 week for a late assessment = 24 weeks [168 days]).
If the patient has no evaluable post-baseline visits or does not have baseline data, they will be 
censored at Day 1 unless they die within two visits of baseline (16 weeks plus 1 week allowing 
for a late assessment within the visit window). 


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The PFS time will always be derived based on scan/assessment dates not visit dates.
RECIST 1.1 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 RECIST 
assessment/scan dates contributing to a particular overall visit assessment.
Overall visit assessments will be determined for each assessment (scheduled or unscheduled) and 
will contribute to the derivation of PFS. 
Objective progression is defined as at least a 20% increase in the sum of the diameters of the 
target lesions (compared to previous minimum sum) and an absolute increase of >5 mm, or an 
overall non-target lesion assessment of progression or a new lesion.
3.2.2.2 Objective response rate
ORR is defined as the percentage of patients with a confirmed investigator-assessed response of 
CR or PR and will be based on all treated patients with measurable lesions at baseline. 
A confirmed response of CR/PR means that a response of CR/PR is recorded at 1 visit and 
confirmed by repeat imaging no less than 4 weeks after the visit when the response was first 
observed with no evidence of progression between the initial and CR/PR confirmation visit. Data 
obtained up until progression, or last evaluable assessment in the absence of progression, will be 
included in the assessment of ORR. Patients who discontinue treatment without progression, 
receive a subsequent anticancer therapy (note that for this analysis radiotherapy is not considered a 
subsequent anticancer therapy) and then respond will not be included as responders in the ORR (ie,
both visits contributing to a response must be prior to subsequent therapy for the patient to be 
considered as a responder).
In the case where a patient has 2 non-consecutive visit responses of PR, then, as long as the time 
between the 2 visits of PR is greater than 4 weeks and there is no PD between the PR visits, the 
patient will be defined as a responder. Similarly, if a patient has visit responses of CR, NE, CR, 
then, as long as the time between the 2 visits of CR is greater than 4 weeks, then a best response 
of CR will be assigned.
3.2.2.3 Duration of response
Duration of response (DoR) will be defined as the time from the date of first documented 
response (which is subsequently confirmed) until date of documented progression or death in the 
absence of disease progression (ie, date of PFS event or censoring – date of first response + 1). 
The end of response should coincide with the date of progression or death from any cause used 


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Study Code D5161C00003
Version 4.0
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for the PFS endpoint. The time of the initial response will be defined as the latest of the dates 
contributing towards the first visit that was CR or PR that was subsequently confirmed. If a 
patient does not progress following a response, then their DoR will use the PFS censoring time.
3.2.2.4 Disease control rate
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 at ≥8 weeks. Patients must 
have lesions (either TLs or NTLs) recorded at baseline to be included in the denominator. The 8-
week time point will allow for a visit window and be defined as on or after study day 49
(allowing for the visit window). 
3.2.2.5 Time to treatment discontinuation or death (TTD)
Time to study treatment discontinuation or death (TTD) is defined as the time from first dose of 
osimertinib to the earlier of the date of study treatment discontinuation or death (ie, date of study 
treatment discontinuation/death or censoring – first dose of osimertinib + 1). 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.
3.2.2.6 Time to first subsequent therapy or death (TFST)
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 therapy or not known to have died at the time of the 
analysis will be censored at the earlier of their last known to be alive date or study termination 
date.
3.2.2.7 Best percentage change in TL tumour size 
The percentage change from baseline in TL tumour size will be calculated every 8 weeks. This is 
based on RECIST TL measurements taken at baseline. Tumour size is the sum of the longest 
diameters of the TLs. TLs are measurable tumour lesions. Baseline is defined as in Section 3.1.1.
The percentage change in TL tumour size is calculated by 
𝑇𝐿𝑡𝑢𝑚𝑜𝑢𝑟𝑠𝑖𝑧𝑒−𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒𝑇𝐿𝑡𝑢𝑚𝑜𝑢𝑟𝑠𝑖𝑧𝑒
𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒𝑇𝐿𝑡𝑢𝑚𝑜𝑢𝑟𝑠𝑖𝑧𝑒
× 100%.
The best percentage change in TL size is the maximum reduction from baseline or the minimum 
increase from baseline in the absence of a reduction over the course of the study and will include 
all assessments prior to the earliest of death in the absence of progression, any evidence of 


Statistical Analysis Plan
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Version 4.0
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progression, the start of subsequent anticancer therapy. A negative change denotes a reduction in 
target lesion size. 
3.3
Safety variables
Safety and tolerability will be assessed in terms of AEs, SAEs, AEs leading to discontinuation, 
laboratory data (including clinical chemistry, haematology and urinalysis), vital signs, physical 
examinations, ECGs and World Health Organization (WHO) performance status.
3.3.1 General considerations for safety assessments
Time windows will need defining for any presentations that summarise values by visit (Table 7).
The following conventions should also apply:

The time windows should be exhaustive so that data recorded at any time point has the 
potential to be summarised. Inclusion within the time window should be based on the actual 
date and not the intended date of the visit.  

All unscheduled visit data should have the potential to be included in the summaries.  

The window for the visits following baseline will be constructed in such a way that the upper 
limit of the interval falls halfway between the two visits (the lower limit of the first 
post-baseline visit will be Day 2). If an even number of days exists between two consecutive 
visits, then the upper limit will be taken as the midpoint value minus one day.

For summaries showing the maximum or minimum values, the maximum/minimum value 
recorded on treatment will be used (regardless of where it falls in an interval).

Listings should display all values contributing to a time point for a patient.

For visit-based summaries, if there is more than one value per patient within a time window 
then the value closest to the planned study day should be summarised, or the earlier in the 
event the values are equidistant from the planned study day. The listings should highlight the 
value for that patient that went into the summary table, wherever feasible.

For summaries at a patient level, all values should be included, regardless of whether they 
appear in a corresponding visit-based summary, when deriving a patient level statistic such as 
a maximum.

Baseline will be defined as the last non-missing measurement prior to dosing with study 
treatment. Where safety data are summarised over time, study day will be calculated in 
relation to date of first study treatment. For safety endpoints the last observation before the 
first dose of IP will be considered the baseline measurement unless otherwise specified. 
Assessments on the day of the first dose where neither time nor a nominal pre-dose indicator 
are captured will be considered prior to the first dose if such procedures are required by the 
protocol to be conducted before the first dose.

Missing safety data will generally not be imputed. However, safety assessment values of the 
form of “<x” (ie, below the lower limit of quantification) or >x (ie, above the upper limit of 
quantification) will be imputed as “x” in the calculation of summary statistics but displayed 
as “<x” or “>x” in the listings.


Statistical Analysis Plan
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Study Code D5161C00003
Version 4.0
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Table 7
Visit number and corresponding study day
CRF visit
Target day
Actual assessment day
Analysed visit
Visit 1
D-28
D-28 - D-1
Screening
Visit 2
D1
D1
Day 1
Visit 3
D8
D2-D11
Week 1
Visit 4
D15
D12-D21
Week 2
Visit 5
D29
D22-D42
Week 4
Visit 6
D57
D43-D70
Week 8
Visit 7
D85
D71-D98
Week 12
Visit 8
D113
D99-D126
Week 16
Visit 9
D141
D127-D154
Week 20
Visit 10
D169
D155-D196
Week 24
Visit 11
D225
D197-D252
Week 32
Visit 12
D281
D253-D308
Week 40
Visit 13
D337
D309-D364
Week 48
Visit 14
D393
D365-D420
Week 56
Visit 15
D449
D421-D476
Week 64
Visit 16
D505
D477-D532
Week 72
Visit 17
D561
D533-D588
Week 80
Visit 18
D617
D589-D644
Week 88
Visit 19
D673
D645-D700
Week 96
Visit 20
D729
D701-D756
Week 104
Visit 21
D785
D757-D812
Week 112
Visit 22
D841
D813-D868
Week 120
Visit 23
D897
D869-D924
Week 128
Visit 24
D953
D925-D980
Week 136
Visit 25
D1009
D981-D1036
Week 144
Visit 26
D1065
D1037-D1092
Week 152
Visit 27
D1121
D1093-D1148
Week 160
Visit 28
D1177
D1149-D1204
Week 168
Visit 29
D1233
D1205-D1267
Week 176
Visit 30
D1303
D1268-D1337
Week 186
Visit 31
D1373
D1338-D1407
Week 196
Visit 32
D1443
D1408-D1477
Week 206
Visit 33
D1513
D1478-D1547
Week 216
Visit 34
D1583
D1548-D1617
Week 226
Visit 35
D1653
D1618-D1687
Week 236
Visit 36
D1723
D1688-D1757
Week 246
Visit 37
D1793
D1758-D1827
Week 256
Visit 38
D1863
D1828-D1897
Week 266


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Study Code D5161C00003
Version 4.0
Date 27 September 2023
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CRF visit
Target day
Actual assessment day
Analysed visit
Visit 39
D1933
D1898-D1967
Week 276
Visit 40
D2003
D1968-D2037
Week 286
Visit 41
D2073
D2038-D2107
Week 296
Visit 42
D2143
D2108-D2177
Week 306
Visit 43
D2213
D2178-D2247
Week 316
Visit 44
D2283
D2248-D2317
Week 326
Visit 45
D2353
D2318-D2387
Week 336
3.3.2 Handling missing data
In general, other than for partial dates, missing data will not be imputed and will be treated as 
missing with the exceptions specified for certain efficacy variables.
3.3.2.1 Imputation of partial dates
Concomitant medication and adverse events start dates

If year is missing (or completely missing), do not impute.

If (year is present and month and day are missing) or (year and day are present and month is 
missing), impute as January 1st.

If year and month are present and day is missing, impute day as first day of the month.
Concomitant medication and adverse events end dates

If year is missing (or completely missing), do not impute.

If (year is present and month and day are missing) or (year and day are present and month is 
missing), impute as December 31st, unless this is after the date of death in which case date of 
death will be used instead.

If year and month are present and day is missing, impute day as last day of the month, unless 
this is after the date of death in which case date of death will be used instead.
In addition, for AEs and CMs if, for a partial start date, the start date could (when also 
considering the end date) potentially be on the first study medication date, the start date will be 
imputed with the first study medication date to assume a “worst case” scenario; eg, AE from 
UNK-Feb-2014 to 23-Mar-2014 with first study medication date 21-Feb-2014, then the AE start 
date will be imputed to 21-Feb-2014.
If a patient is known to have died where only a partial death date is available then the date of 
death will be imputed as the latest of the last date known to be alive +1 from the database and the 
death date using the available information provided:

For Missing day only – using the 1st of the month 


Statistical Analysis Plan
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Study Code D5161C00003
Version 4.0
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
For Missing day and Month – using the 1st of January
If there is evidence of death but the date is entirely missing, it will be treated as missing, ie,
censored at the last known alive date.
3.3.3 Exposure and dose interruptions 
Osimertinib will be taken once daily and exposure will be defined as follows:
Total (or intended) exposure of study treatment (days)

Total (or intended) exposure = min(last dose date where dose > 0mg, date of death, date of 
DCO) – first dose date + 1
Actual exposure of study treatment (days)
Actual exposure = intended exposure – total duration of dose interruptions, where intended 
exposure will be calculated as above and a dose interruption is defined as any length of time 
where the patient has not taken any of the planned daily dose. The actual exposure calculation 
makes no adjustment for any dose reductions that may have occurred.
Missed and forgotten doses should be recorded on the EX module as a drug interruption with the 
reason recorded as “Subject forgot to take dose”. These missed or forgotten doses will not be 
included as dose interruptions in the summary tables but the information will appear in the listing 
for dosing. However, these missed and forgotten doses will be considered in the derivation of 
actual exposure.
If a patient permanently discontinues study treatment during a dose interruption, then the date of 
last administration of study medication recorded on DOSDISC will be used in the programming.
Safety Follow-up
Total safety follow-up will be calculated as follows:

Total Safety Follow-up = min([last dose date + 28 days], date of withdrawal of consent, date 
of death, date of DCO) – first dose date +1
3.3.4 Adverse events
AEs and SAEs will be collected from the date of informed consent, throughout the treatment 
period and including the 28-day follow-up period after the last dose of treatment. Events will be 
defined as treatment emergent if they start or worsen (by Investigator report of a change in 
intensity) during the treatment period as defined in the protocol (date of first dose to 28 days post 


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Version 4.0
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last dose, inclusive). The latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA) will be used to code the AEs. AEs will be graded according to the latest version of 
the National Cancer Institute Common Terminology Criteria for AEs (CTCAE).
3.3.5 Laboratory variables
Laboratory data will be collected throughout the study, from screening to treatment 
discontinuation as per the study plan described in the protocol. These include blood and urine 
samples for determination of clinical chemistry, haematology and urinalysis. For the definition of 
baseline and the derivation of post baseline visit values considering visit windows and how to 
handle multiple records, derivation rules as described in Section 3.3.1 will be used. 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 the visit day.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  
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 the 
laboratory method used and routine practice at the site. The laboratory variables defined in Table
8 will be measured. 
Table 8
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Hb
S/P-Creatinine
B-Leucocyte 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


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
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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.
Change from baseline in clinical chemistry, haematology and urinalysis variables will be 
calculated for each post-dose visit on treatment. Common toxicity criteria (CTC) grades will be 
defined at each visit according to the CTC grade criteria using local or project ranges as required, 
after conversion of lab result to corresponding project-wide preferred units.  
Absolute values will be compared to the project reference range and classified as low (below 
range), normal (within range or on limits of range) and high (above range). As applicable, values 
will be converted to standard units and will be graded using CTCAE version referenced in the 
Clinical Study Protocol. Corrected calcium(x) records will be programmatically derived, using
below formula, and appended to the lab dataset for grading.
𝐶𝑜𝑟𝑟𝑒𝑐𝑡𝑒𝑑𝑐𝑎𝑙𝑐𝑖𝑢𝑚(𝑚𝑚𝑜𝑙/𝐿) = 𝑇𝑜𝑡𝑎𝑙𝑐𝑎𝑙𝑐𝑖𝑢𝑚(𝑚𝑚𝑜𝑙/𝐿) + ([40 – 𝑎𝑙𝑏𝑢𝑚𝑖𝑛(𝐺/𝐿)] 𝑥0.02)
The maximum (or minimum) on-treatment value (depending on the direction of an adverse 
effect) will be defined for each laboratory parameter as the maximum (or minimum) post-dose 
value up until treatment discontinuation.
Local reference ranges will be used for the primary interpretation of laboratory data at the local 
laboratory. Project reference ranges will be used throughout for reporting purposes. The 
denominator used in laboratory summaries of CTC grades will only include evaluable patients, in 
other words those who had sufficient data to have the possibility of an abnormality.
For example:

If a CTC criterion involves a change from baseline, evaluable patients would have both a 
baseline and at least 1 post-dose value recorded.

If a CTC criterion does not consider changes from baseline, to be evaluable the patient needs 
only to have 1 post dose-value recorded.
3.3.6 Vital signs
Vital signs data (blood pressure, pulse and temperature) will be obtained at every visit up until 
treatment discontinuation and will be used for reporting. Change from baseline in vital signs 
variables will be calculated for each post-dose visit on treatment. For derivation of post-baseline 


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Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
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visit values, considering visit window, and to handle multiple records, derivation rules as 
described in Section 3.3.1 will be used. 
3.3.7 Physical Examinations
Physical examination data (indication whether data were collected or not) will be obtained at the 
start of each cycle (including screening) up until treatment discontinuation. Clinically significant 
findings at screening will be recorded in surgical or medical history. Any new or aggravated 
clinically relevant abnormal medical finding at a physical examination will be reported as an AE.
3.3.8 Electrocardiograms
Electrocardiogram (ECG) data (details of rhythm, ECG intervals and an overall evaluation) will 
be obtained at every visit until treatment discontinuation. If there is an abnormal on-treatment 
assessment at the time of treatment discontinuation then a 28-day follow-up assessment will be 
required to confirm reversibility of the abnormality. 
3.3.9 Left ventricular ejection fraction (LVEF)
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. 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.
3.3.10
Ophthalmological assessments
Full ophthalmic assessment, including slit lamp examination, will 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. 
3.4
Biomarker variables
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 




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Study Code D5161C00003
Version 4.0
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The final analysis timepoint, at study end, and when approximately 50 patients have evaluable 
paired biopsies upon progression, will include production of all the tables, listings and figures,
which will be specified and finalised in a separate TLF shell document before database lock. 
4.2
Analysis methods
4.2.1 Patient disposition
The total number of patients screened (including screening failures), enrolled (ie, patients with 
informed consent), patients who received any study drug and patients who did not receive any 
study drug, patients ongoing treatment at DCO, patients ongoing in the study at DCO, patients 
who completed treatment, patients who discontinued treatment and the reason for 
discontinuation, and patients who discontinued the study and the reason for discontinuation will 
be summarised.
The number and percentage of patients included in the analysis populations and the number of 
patients recruited by country and centre will be also presented.
4.2.2 Attrition of biopsy samples
To explore why patients who had an evaluable baseline did not have a paired progression sample 
for the primary analysis, the total number of patients that had a baseline biopsy, the number of 
patients that had a baseline biopsy that was not evaluable, and the number of patients that had an 
evaluable baseline biopsy will be summarised. The number of patients that had not progressed at 
DCO, withdrew from the study prior to progression, died prior to progression, did not have a 
biopsy after progression, had a progression biopsy that was not evaluable, or had an evaluable 
progression biopsy will be further summarised for patients that had an evaluable baseline biopsy.
4.2.3 Protocol deviations
All identified important protocol deviations will be listed and summarised for the FAS. All 
protocol deviations will be defined by the study team and identified and classified as important 
or not important before database lock. All important protocol deviations confirmed to be due to 
Coronavirus Disease 2019 (COVID-19) will be summarised.  


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Study Code D5161C00003
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4.2.4 Demographics and other baseline characteristics 
Demographic and baseline subject characteristics will be listed and summarised for the FAS and 
the PAS and defined subgroups by mutation status. Standard descriptive statistics will be 
presented for the continuous variables of:

Age (years)

Weight (kg)

Height (cm)

Body mass index (kg/m2), calculated as:
6789:;
:789:;<

Nicotine consumption (number of pack years)
The total counts and percentages of patients will be presented for the categorical variables of:

Age group (years) (grouped as <50, ≥50-<65, ≥65-<75, ≥75)

Sex

Race

Ethnic group

Smoking status.

WHO performance status (0/1)

EGFR mutation type (Ex19del, L858R)
4.2.5 Medical history
Relevant medical history (past and current) and relevant surgical history will be coded using the 
most recent version of MedDRA.
All medical history will be summarised (number and percentage of patients) for the FAS by 
system organ class (SOC) and preferred term (PT).
4.2.6 Disease history
The following disease characteristics will be summarized for all patients in the FAS (unless 
specified otherwise), the PAS and defined subgroups by mutation status:

Disease characteristics at baseline (time from original diagnosis, primary tumour location, 
histology type, regional lymph nodes, distant metastases, stage/ American Joint Committee 
on Cancer [AJCC] stage).

Extent of disease upon entry to study (metastatic/locally advanced, site of metastatic disease).

Previous cancer therapy (Neo-adjuvant, adjuvant chemotherapy, any previous radiotherapy, 
any previous surgery).


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
EGFR mutation status

Site of local/metastatic disease

Brain metastases and Visceral metastases

Baseline TL size (mean and categories: <40, 40-79, 80-119, ≥120mm)

Histology type
4.2.7 Concomitant medication
Prior and concomitant medications are defined as follows:

Prior medications are medications taken prior to or during screening with a stop date prior to 
the first dose of study drug

Concomitant medications are medications with or without a stop date on or after the date of 
first dose of study drug (and could have started prior to or during treatment).
Concomitant medication will be summarised using frequency tables by Anatomical therapeutic 
chemical (ATC) classification code (based on World Health Organisation (WHO) classification).
4.2.8 Exposure
The following summaries will be produced for the FAS and the PAS:

Total exposure to study treatment, 

Actual exposure to study treatment 

Number of and reasons for dose interruptions 

Number of and reasons for dose reductions 

Time on study – defined as the time in days from the start date of treatment to the date of last 
study assessment or the date of withdrawal.
4.2.9 Primary and Efficacy Endpoints
Table 9 presents the formal statistical analyses to be conducted for the primary and efficacy 
endpoints. 
Table 9
Formal analyses 
Endpoints analysed 
Notes
Proportion of patients with a given genetic and 
proteomic marker at the point of disease progression 
as defined by the Investigator
Primary analysis
PFS
Secondary analysis
Objective response rate


Statistical Analysis Plan
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Version 4.0
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Duration of response
Disease control rate
Subgroup analyses
PFS
Objective response rate
Best change in TL tumour size
Time to treatment discontinuation or death 
Time to treatment discontinuation or death
Time to first subsequent therapy or death
4.2.9.1 Proportion of patients with a given marker 
The proportion of patients with a given genetic and proteomic marker at the point of disease 
progression (as defined by the investigator) will be calculated and presented alongside the 
associated exact binomial 95% Clopper-Pearson (exact) confidence intervals (CIs).  
If a reasonable proportion (at least 20%) 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% adjusted Wald CI, may also be calculated.
The primary analysis table will include the frequency and proportion of new pathogenic, likely 
pathogenic or ambiguous mutations and will be split by gene name and variant-type. Other tables 
will follow the same layout but will look at pathogenic, likely pathogenic or ambiguous 
mutations at baseline and all pathogenic mutations at disease progression. New markers will be 
defined (for an individual patient) to be those present at progression that were not present at 
baseline. Only markers defined as ‘Pathogenic’, ‘Likely pathogenic’ or ‘Ambiguous’ by the 
analysing lab will be tabulated.
4.2.9.2 Progression-free survival
PFS will be analysed using Kaplan-Meier (K-M) methodology from which the median and its 
95% CI will be provided, together with event rates at clinically important landmarks (ie, at 6, 12, 
18 and 24 months).
The treatment status at progression of patients at the time of analysis will be summarised. This 
will include the number (%) of patients who were on treatment at the time of progression, the 
number (%) of patients who discontinued study drug prior to progression, the number (%) of 
patients who have not progressed and were on treatment or discontinued treatment. This will also 
provide the distribution of the number of days prior to progression for the patients who have 
discontinued treatment.


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
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Additional supportive summaries
Summary statistics will be given for the number of days from censoring to DCO for all censored 
patients, see Section 3.2.2.1.
Additional summaries will be produced for the following points:

The duration of follow-up will be summarised using median time from the treatment start 
date to the censoring date (date last known to have not progressed) in censored (not 
progressed) patients only.

The number and percentage of patients who are censored due to two or more consecutive 
missed RECIST assessments.

New lesions (ie, sites of new lesions).
4.2.9.3 Confirmed objective response rate
Objective response rate will be summarised as the proportion of patients with a response (ie,
CR/PR indicating a response of CR/PR being recorded at 1 visit and confirmed by repeat 
imaging no less than 4 weeks later with no evidence of progression between the initial and 
CR/PR confirmation visit), along with the associated exact binomial 95% CI using the Clopper-
Pearson method. Patients in the FAS must have evidence of disease at baseline to be included in 
the denominator.
4.2.9.4 Duration of response
Duration of response will be analysed using K-M methodology from which the median and 95% 
CI will be produced with event rates at clinically important landmarks as explained in Section 
4.2.9.2. Only patients who have responded (a confirmed response) will be included in the
analysis. 
4.2.9.5 Disease control rate
Disease control rate will be summarised as the proportion of patients with disease control (ie, an 
overall response of PR/CR or SD at ≥ 8 weeks), along with the associated exact binomial 95% CI
using the Clopper-Pearson method. Patients in the FAS must have evidence of disease at baseline 
to be included in the denominator.
4.2.9.6 Time to treatment discontinuation or death (TTD)
TTD will be analysed using K-M methodology from which the median and 95% CI will be 
produced with event rates at clinically important landmarks as explained in Section 4.2.9.2. 


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
53
4.2.9.7 Time to first subsequent therapy or death (TFST)
TFST will be analysed using K-M methodology from which the median and 95% CI will be 
produced with event rates at clinically important landmarks as explained in Section 4.2.9.2. 
4.2.10
Safety
The following sections describe the planned safety summaries for AEs, SAEs, deaths, laboratory 
parameters, vital signs, physical examinations and ECGs.
4.2.10.1
Adverse events
Only TEAEs, ie, AEs developing or worsening in severity (from baseline severity) on or after the 
first day of osimertinib administration up to and including 28 days after the last dose of 
osimertinib (defined as the treatment period) will be summarised.
Any AE occurring before the first dose of osimertinib and AEs occurring 28 days after last dose 
will be listed only and not included in the summaries. 
Any AEs that occur after a patient has received further therapy for cancer (following 
discontinuation of osimertinib) will be flagged in the data listings. Any AEs that occur after a 
patient has received further therapy for cancer within 28 days after discontinuing osimertinib are 
included in the summaries. 
The number of patients experiencing each AE will be summarised by the MedDRA system organ 
class, MedDRA preferred term and worst CTCAE grade. The number and percentage of patients 
with AEs in different categories (ie, causally related, maximum reported intensity, CTCAE grade 
≥3) will be summarised, and events in each category will be further summarised by MedDRA 
system organ class and preferred term. Events will be displayed by international SOC order and 
alphabetical PT. Subjects who report the same AE several times will only appear once in that 
row.
SAEs and deaths will be summarised.
4.2.10.2
Laboratory evaluations
Laboratory data obtained up until treatment discontinuation will be included in the summary 
tables. Absolute values and change from baseline for all continuous haematology, clinical 
chemistry and urinalysis laboratory parameters will be summarised for each visit.


Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
54
Shift tables for change in grade from baseline by treatment group will be produced.  The 
laboratory parameters for which CTC grade shift outputs will be produced are:

Haematology: basophils, eosinophils, haemoglobin, B-leukocyte differential count (absolute 
count), lymphocytes, monocytes, neutrophils and platelets. 

Clinical chemistry: alanine aminotransferase (ALT), albumin, alkaline phosphatase, aspartate 
aminotransferase (AST), bilirubin (total), calcium, creatinine, potassium, and sodium.

Urinalysis:erythrocytes, glucose and protein.
Hy's law
The following summaries will include the number (%) of patients who have:

Elevated ALT, AST, and total bilirubin during the study

AST or ALT ≥3x ULN and total bilirubin ≥2 × ULN during the study (potential Hy’s 
law): the onset date of ALT or AST elevation should be prior to or on the same date of 
total bilirubin elevation.
Liver biochemistry test results over time for patients with elevated ALT or AST (ie, ≥3 × ULN) 
and elevated total bilirubin (ie, ≥ 2 × ULN) at any time will be plotted.  
Individual patient data where ALT or AST plus total bilirubin are elevated at any time will be 
listed (ie, ALT and/or AST ≥3 × ULN and total bilirubin ≥2 × ULN, at any time).
4.2.10.3
Vital signs
Vital sign data obtained up until the 28-day safety follow-up visit will be included in the 
summary tables and will be summarised using descriptive statistics (mean, median, standard 
deviation, minimum, maximum and number of patients). As detailed in Section 3.3.6, changes 
from baseline will also be summarised. 
4.2.10.4
Electrocardiograms
ECG data obtained up until the 28-day safety follow-up visit will be included in the summary 
tables. The following parameters will be summarised by visit:

QTc Interval Fredericia >470 ms (Yes, No)

Overall Evaluation (Normal, Abnormal) 

Clinical significance (Yes, No) 




Statistical Analysis Plan
Drug Substance AZD9291, osimertinib
Study Code D5161C00003
Version 4.0
Date 27 September 2023
56

Gender (Male / Female)

Race (Asian / Non-Asian)

Age at screening (<65 / ≥ 65)

Smoking history (Smoker / Non-Smoker)

Baseline WHO Performance Status (0 / 1)
5.
INTERIM ANALYSIS
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.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
Version 7.0 of the protocol was used when writing the statistical analysis plan. 
7.
REFERENCES
Bonnett et al. 2012
Bonett, Douglas G., and Robert M. Price. "Adjusted Wald confidence interval for a difference of 
binomial proportions based on paired data." Journal of Educational and Behavioral Statistics 
37.4 (2012): 479-488.
Fagerland et al. 2014
Fagerland, Morten W., Stian Lydersen, and Petter Laake. "Recommended tests and confidence 
intervals for paired binomial proportions." Statistics in medicine 33.16 (2014): 2850-2875.
Rodriguez et al. 2016
Rodriguez de Gil, P., et al. “SAS Macros CORR_P and TANGO: Interval Estimation for the 
Difference Between Correlated Proportions in Dependent Samples.” Conference paper. October 
2016. 
Stone et al. 2016
Stone A, Smith P, Bannister W, Lloyd A. Oncology Statistical Guidance Document v3. August 
2016.


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