Clinical trial NCT03853551
Conditions: Non Small Cell Lung Cancer (NSCLC)
Keywords: Non small cell lung cancer (NSCLC)
Sponsor: AstraZeneca
Start date: 2019-04-18; Completion date: 2020-04-15
Enrollment: 60 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a prospective, single-arm, multicenter, phase-IV study investigating the safety of osimertinib in Indian adult patients.

Detailed description:
This is a prospective, single-arm, multicenter, phase-IV trial investigating the safety of osimertinib in Indian adult patients with locally advanced or metastatic EGFR-T790M mutation-positive NSCLC.

Prior to data collection, all patients must sign an informed consent form (ICF) allowing data collection and source data verification in accordance with local requirements and sponsor policy.

Patients with metastatic EGFR T790M mutation-positive NSCLC, who are eligible to osimertinib treatment as per locally approved prescribing information and ratified by an independent clinical judgment of treating physician will be evaluated for the inclusion into the current phase-IV study based on eligibility criteria. EGFR T790M positivity on plasma or tissue biopsy on PCR-based platform will be considered appropriate test. EGFR T790M must be performed after progressive disease on last line of therapy (on or after EGFR TKI therapy). In order to enroll approximately 60 patients, it is expected that approximately 70 patients will be screened.

Arms: arm 1: Single arm
Interventions: intervention 1: Osimertinib
Intervention descriptions: intervention 1: Osimertinib is an oral, potent, selective, irreversible inhibitor of both epidermal growth factor receptor - Tyrosine kinase inhibitors (EGFR-TKI) sensitizing and resistance mutations in nonsmall cell lung cancer (NSCLC) with a significant selectivity margin over wild-type EGFR.

Protocol documents:
Prot_000.pdf: 
 
P a g e  | 1 
 
 
 
 
 
 
 
 
This submission document contains confidential commercial information, disclosure of 
which is prohibited without providing advance notice to AstraZeneca and opportunity to 
object. 
This Clinical Study Protocol has been patient 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 
OSIMERTINIB 
Study Code 
D5161C00005 
Version 
1.0 
Date 
06 November 2017 
A prospective, multicenter, Phase-IV clinical trial to assess safety of 
TAGRISSOTM (Osimertinib) in Indian adult patients with metastatic 
epidermal growth factor receptor (EGFR) T790M mutation-positive 
nonsmall cell lung cancer (NSCLC) 
Sponsor:  
AstraZeneca Pharma India Limited 
Block N1, 12th Floor, Manyata Embassy Business Park 
Rechenahalli, Outer Ring Road, Bangalore-560045. 


Clinical Study Protocol 
Drug Substance OSIMERTINIB  
Study Code D5161C00005 
Version 1.0 
Date 06 November 2017 
2 (40) 
VERSION HISTORY 
Version 1.0, 06 November 2017 
Initial creation 


Clinical Study Protocol 
Drug Substance OSIMERTINIB  
Study Code D5161C00005 
Version 1.0 
Date 06 November 2017 
3 (40) 
PROTOCOL SYNOPSIS 
A prospective, multicenter, Phase-IV clinical trial to assess safety of 
TAGRISSOTM (Osimertinib) in Indian adult patients with locally advanced 
or metastatic epidermal growth factor receptor (EGFR) T790M mutation-
positive non-small-cell lung cancer (NSCLC) 
 
Study site(s) and number of patients planned 
No. of total screened patients: Approximately 70 
No. of total enrolled patients: Approximately 60 
No. of study sites: 10 
Total planned Study period 
 
Estimated date of first patient in 
01-April-2018 
Estimated date of last patient in 
30-December-2018 
Estimated date of last patient last visit 
30-June-2019 
Estimated date of data base lock 
31-July-2019 
BACKGROUND & RATIONALE 
Lung cancer is the leading cause of cancer related mortality world-wide and amongst males in India. 
About 85% of lung cancers are non-small cell lung cancers (NSCLC) and the most common form of 
NSCLC is Adenocarcinoma (Howlader N et al. 2016). Mutations in the Epidermal growth factor 
receptor (EGFR) tyrosine kinase are observed in approximately 10-15% of NSCLC 
adenocarcinomas in the Caucasians (Nguyen, Neal, and Wakelee 2014). Studies from India report a 
much higher frequency of EGFR mutations 23% to 44% (Noronha et al. 2016). Patients harbouring 
activating EGFR mutation often respond well when treated with Tyrosine kinase inhibitors (TKIs).  
Resistance mutations confer resistance to EGFR TKIs in NSCLC tumors and can be de novo or 
acquired. T790M is one such mutation associated with resistance to TKI inhibitors like gefitinib and 
Erlotinib. Clinical data suggests that T790M mutation is found in <5% - 11% of TKI-naïve patients 
(Primary T790M mutation) and about 50% of TKI resistant patients (acquired resistance to T790M 
mutation) (Sequist et al. 2011; Yu et al. 2013; Camidge, Pao, and Sequist 2014).  
Findings from 2 Phase II clinical trials (AURA extension and AURA2) evaluating safety and efficacy 
of osimertinib indicated an objective response rate (ORR) of 66.1% (95% confidence interval [CI] 
61.2, 70.7%) among patients (n = 398) with a T790M mutation (Goss et al. 2016; Chen et al. 2017), 
suggesting that this drug will help address an unmet need in this patient population setting. The phase 
III clinical trial AURA3, presented in World Conference on Lung Cancer on December 2016 and 
published on February 2017 (Mok et al. 2017), compared the treatment with osimertinib 80 mg orally 
once a day to intravenous pemetrexed (500 mg per square meter of body-surface area) plus either 
carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 
weeks for up to six cycles (maintenance pemetrexed was allowed). 419 patients with T790M-positive 
advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy 
were randomized (in a 2:1 ratio; 279 and 140 patients, respectively). The median duration of 
progression-free survival was significantly longer with osimertinib than with platinum therapy plus 
pemetrexed (10.1 months versus 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 
to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% 
CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for 
objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). 


Clinical Study Protocol 
Drug Substance OSIMERTINIB  
Study Code D5161C00005 
Version 1.0 
Date 06 November 2017 
4 (40) 
Osimertinib, a third-generation EGFR-TKI has been approved in the USA, Canada, Mexico, 
European Union, Switzerland, Israel, Japan, Brazil, China, and South Korea for the treatment of 
patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC. 
The USA-based National Comprehensive Cancer Network (NCCN) guidelines included osimertinib 
as one of the recommended treatment options following first-line therapy with erlotinib, afatinib or 
gefitinib (“NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)- Non-Small Cell 
Lung Cancer (Version 8.2017)” 2017).  
51st patient expert committee (SEC) of oncology and hematology on 21-Mar-2017 has given positive 
recommendations for approval of osimertinib for “the treatment of patients with metastatic epidermal 
growth factor receptor (EGFR) T790M mutation-positive nonsmall cell lung cancer (NSCLC), as 
detected by an appropriate test, who have progressed on or after EGFR TKI therapy” with a condition 
to conduct phase IV clinical trial as per the requirements of Indian Good Clinical Practices (GCP) 
and schedule Y of Drugs and Cosmetics Rules, 1945. 
As per recommendation, current phase-IV study is planned with the aim to assess the safety of 
osimertinib in Indian patients as a post-marketing requirement. The data obtained from the present 
study will help to understand the safety profile of osimertinib in Indian patients with EGFR-T790M 
mutation-positive NSCLC and add to the limited burden of safety data on osimertinib currently 
available. 
OBJECTIVES 
Primary Objective: 
Primary Outcome Measure: 
To assess the safety of osimertinib 
among T790M positive NSCLC 
patients of India 
Number, frequency and proportion of patients with adverse 
events (AEs), serious adverse events (SAEs) and AEs of special 
interest (AESI) including interstitial lung disease/pneumonitis-
like events, and on-study deaths. 
STUDY DESIGN 
This is a prospective, single-arm, multicenter, phase-IV trial investigating the safety of osimertinib 
in Indian adult patients with locally advanced or metastatic EGFR-T790M mutation-positive 
NSCLC. Investigator will be trained on the locally approved prescribing information before the 
enrolment of the first patient at their site to ensure compliant and proper dosing of the study drug. 
Patients will be monitored throughout the study period for AEs of osimertinib.  
The decision of patients to participate in this study must not, in any way, impact upon the standard 
of care that they are receiving or any benefits to which they are otherwise entitled. Prior to data 
collection, all patients must sign an informed consent form (ICF) allowing data collection and source 
data verification in accordance with local requirements and sponsor policy.  
Patients with metastatic EGFR T790M mutation-positive NSCLC, who are eligible to osimertinib 
treatment as per locally approved prescribing information and ratified by an independent clinical 
judgment of treating physician will be evaluated for the inclusion into the current phase-IV study 
based on eligibility criteria. EGFR T790M positivity on plasma or tissue biopsy on PCR-based 
platform will be considered appropriate test. EGFR T790M must be performed after progressive 
disease on last line of therapy (on or after EGFR TKI therapy). In order to enroll approximately 60 
patients, it is expected that approximately 70 patients will be screened. 
Patient participation will include a Screening/Enrolment Phase, a Treatment Phase, and a Follow-up 
Phase. The Screening Phase will be up to 7 days prior to Cycle 1, Day 1. The Treatment Phase will 
extend from Cycle 1, Day 1 to Cycle 6, Day 21; or until study drug discontinuation due to either 
disease progression or unacceptable toxicity; or other reasons whichever occurs first, as listed in 
Section 3.9. Each cycle of treatment is defined as 21 days of once daily osimertinib treatment. The 
Follow-up Phase will begin once a patient discontinues study drug or on completion of Treatment 


Clinical Study Protocol 
Drug Substance OSIMERTINIB  
Study Code D5161C00005 
Version 1.0 
Date 06 November 2017 
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Phase, and will continue until 28 days after last dose, death, loss to follow up, consent withdrawal 
for study participation, or study end, whichever occurs first (see Section 3.9, 3.10, 3.11). 
Osimertinib will be provided free of cost by the sponsor to clinical trial patient in the Treatment 
Phase. The sponsor shall provide the laboratory investigations for safety evaluation including 
hematology, biochemistry and ECG as mentioned in the Time and Event Schedule to monitor the 
safety throughout the study period.  
SCREENING PHASE (VISIT 0) 
Patients, or their legally acceptable representative, will provide written informed consent before any 
trial-specific procedures are performed. During the Screening Phase, eligibility criteria will be 
reviewed and a complete clinical evaluation will be performed as specified in the Time and Event 
Schedule. Screening procedures will be performed within 7 days before Cycle 1, Day 1. All baseline 
disease characteristics will be captured based evaluation performed as a part of routine clinical 
practice. The Screening laboratory tests, if any, must be completed within 7 days before Cycle 1, 
Day 1. 
TREATMENT PHASE 
The Treatment Phase will extend from Cycle 1, Day 1 to Cycle 6, Day 21; or until study drug 
discontinuation due to either disease progression or unacceptable toxicity; or other reasons 
whichever occurs first, as listed in Section 3.9. Details of the procedures performed during the 
Treatment Phase are outlined in the Time and Events Schedules. Patients will be closely monitored 
for adverse events and other safety evaluations including laboratory investigations, concomitant 
medications. If disease progression is diagnosed before Cycle 6, Day 21, then the patient will 
discontinue study drug with completion of the End-of-Treatment Visits on the day of progression, 
and will enter the Follow-up Phase. 
END-OF–TREATMENT VISIT (EOT) 
An End-of-Treatment Visit is to be scheduled on Cycle 6, Day 21 of the study drug administration. 
In a case where patient discontinues the study treatment for any reason listed in Section 3.9 before 
Cycle 6, Day 21, last visit of the patient will be considered as End-of-treatment visit. Every effort 
should be made to conduct the telephonic End-of-Study Visit before the patient starts subsequent 
treatment. 
FOLLOW UP PHASE (END-OF-STUDY) 
A telephonic follow-up will be conducted 28 days after the EOT Visit. This will be considered as 
End-of-study visit.  
The observation period including the Enrolment Visit and telephonic end-of-study visit will be up to 
a maximum duration of approximately 23 weeks for each patient. 
PATIENT POPULATION 
Key eligibility criteria include the patients of either sex who are ≥18 years of age with metastatic 
EGFR T790M mutation-positive NSCLC, as detected by an appropriate test, who have progressed 
on or after EGFR TKI therapy by an independent clinical judgment of treating physician based on 
locally approved prescribing information. Patient with either the history of hypersensitivity to 
excipients of the study drug or to drugs with a similar chemical structure or class to the study drug 
OR with pregnant and/or lactating women OR patients participating in any current or future 
interventional trial will not be enrolled in the current study. 
DURATION OF TREATMENT 
The Treatment Phase will extend from Cycle 1, Day 1 to Cycle 6, Day 21; or until study drug 
discontinuation due to either disease progression or unacceptable toxicity; or other reasons 
whichever occurs first, as listed in Section 3.9. 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.  


Clinical Study Protocol 
Drug Substance OSIMERTINIB  
Study Code D5161C00005 
Version 1.0 
Date 06 November 2017 
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POST STUDY ACCESS TO STUDY TREATMENT 
Patients receiving osimertinib at the time of study completion (i.e. after completion of treatment 
phase) may continue to receive osimertinib, if in the opinion of their treating physician they are 
continuing to derive clinical benefit from continued treatment or have not progressed clinically. They 
will be provided osimertinib treatment as per recommendation from treating physician on ethical 
basis. Post-trial access to osimertinib will be provided from local commercial supply though local 
distribution channel. Such patients will not be monitored after EOS visit.  
STUDY DRUG, DOSAGE AND MODE OF ADMINISTRATION 
Osimertinib is an oral, potent, selective, irreversible inhibitor of both EGFR-TKI sensitizing and 
resistance mutations in NSCLC with a significant selectivity margin over wild-type EGFR. 
osimertinib will be administered orally as one 80 mg tablet once a day. A cycle of treatment is 
defined as 21 days of once daily osimertinib treatment. Dose modification will be done as per locally 
approved prescribing information with the use of 40 mg tablet strength if required. 
SAFETY EVALUATIONS 
Safety evaluations will include adverse event monitoring, physical examinations, ECG monitoring, 
clinical laboratory parameters (hematology and biochemistry), vital sign measurements, and WHO 
performance status and death as observed by the investigator. Based on the previous human 
experience with osimertinib, in vitro studies, and animal toxicological findings, interstitial lung 
disease (ILD), QTc interval prolongation, cardiomyopathy and keratitis will be closely monitored. 
Any of the safety monitoring assessments may be performed more frequently, and adverse events 
should be evaluated by the investigator according to the standard practice if clinically indicated. 
Statistical methods 
SAMPLE SIZE JUSTIFICATION 
The primary objective of the trial is to describe the safety profile of osimertinib in routine clinical 
practice and add to the limited burden of safety data on osimertinib currently available as assessed 
by the incidence of adverse events (AEs) (Serious and Non-serious AEs) observed during trial. 
Considering the epidemiology of metastatic NSCLC- adenocarcinoma subtype which are positive 
for EGFR sensitizing mutation and have progressed after EGFR-TKI based treatment in first line 
setting and prevalence of T790M-mutation after such progression, a sample size of 60 patients is 
expected to provide the following exact two sided 95% confidence interval for a list of percentages 
of patients reporting at least one AE (Julious and Campbell 2012). 
Observed rate expressed as % 
(number of patients reporting at least one 
AE*) 
Lower Limit of CI 
(%) 
Upper Limit of CI 
(%) 
0% 
0 
6.0 
1% 
0 
7.8 
2% 
0.1 
9.5 
5% 
1.0 
13.9 
10% 
3.8 
20.5 
20% 
10.8 
32.3 
30% 
18.8 
43.2 
40% 
27.6 
53.5 
50% 
36.8 
63.2 
*the symptom could be any of the expected AE, unexpected AE or SAE. The calculation is based on the link 
between binomial and beta distributions. 
Hypothesis 
No formal hypothesis testing will be conducted.  


Clinical Study Protocol 
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Study Code D5161C00005 
Version 1.0 
Date 06 November 2017 
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Statistical Analysis 
Data will be summarized using descriptive statistics. Continuous variables will be summarized using 
the number of observations, mean, SD, coefficient of variation, median, and range as appropriate. 
Categorical values will be summarized using the number of observations and percentages as 
appropriate. Shift tables will be provided to determine the change in reported outcomes from 
baseline. 
The safety analysis population will include all patients who sign the ICF and receive at least one 
dose of osimertinib. 
Adverse Events (both in terms of 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. 
Any AE occurring within 28 days of discontinuation of study drug (ie, the last dose 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. 
 
 


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Study Code D5161C00005 
Version 1.0 
Date 06 November 2017 
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TIME AND EVENTS SCHEDULE 
Table 1. Time and Event Schedule 
Study Phase 
Screening 
Phase(a) 
Treatment Phase 
Follow-up 
Phase 
Cycle 
Cycles 1-6 
EOT 
EOS 
Visit No. 
1 
2-7 (Day 1 of each cycle) 
8 
 
Study Days 
-6 to 0 
1-109 (21 day per cycle) 
131 
28 days post-
EOT 
Screening/Enrolment visit 
Informed consent(b) 
Patients must sign the informed consent form before any study-specific 
procedures are performed. 
Eligibility Criteria 
X 
 
 
 
Demographics/ Review medical 
history 
X 
 
 
 
WHO Performance Status 
X 
X 
X 
 
General Physical examination 
X 
Symptom-directed physical examination only 
 
Concomitant medication 
recording 
Continuous from time of ICF until 28 days after last osimertinib dose in 
treatment phase. 
Study Drug Administration 
Osimertinib dosing 
 
The recommended dose is 80 mg osimertinib 
once a day until disease progression or 
unacceptable toxicity. Each cycle is of 21 
days. 
 
Disease Evaluations (Disease characteristics will be performed as per routine clinical practice) 
Baseline Disease 
Characteristics 
X 
 
 
 
Safety Evaluations 
Physical examination 
X 
Symptom-directed physical examination only 
 
Vital parameters 
X 
X 
X 
 
Adverse event monitoring 
Continuous from time of ICF until 28 days after last study osimertinib dose 
12-lead ECG 
X 
X 
X 
 
Hematology & Biochemistry 
X 
X 
X 
 
Footnotes:  
a. 
The Screening Phase begins when the first Screening procedure is conducted. Screening tests should be 
performed within 7 days of Cycle 1 Day 1 except for disease evaluations (performed as routine clinical 
practice). 
b. 
Must be signed before first study-related activity. 
 


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Study Code D5161C00005 
Version 1.0 
Date 06 November 2017 
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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ......................................................................................................... 1 
VERSION HISTORY ........................................................................................... 2 
PROTOCOL SYNOPSIS ...................................................................................... 3 
TIME AND EVENTS SCHEDULE ..................................................................... 8 
TABLE OF CONTENTS ...................................................................................... 9 
1. 
Introduction ......................................................................................... 13 
1.1 
Background and rationale for conducting this study ............................ 13 
1.2 
Rationale for study design, doses and control groups ........................... 14 
1.3 
Benefit/risk and ethical assessment....................................................... 14 
1.4 
Study Design ......................................................................................... 14 
2. 
Study Objectives .................................................................................. 14 
3. 
Patient Selection, Enrolment, Randomisation, Restrictions, 
Discontinuation and Withdrawal ...................................................... 15 
3.1 
Inclusion criteria ................................................................................... 15 
3.2 
Exclusion criteria .................................................................................. 15 
3.3 
Patient enrolment and randomization ................................................... 15 
3.4 
Procedures for handling incorrectly enrolled or patients ...................... 16 
3.5 
Methods for assigning treatment groups ............................................... 16 
3.6 
Methods for ensuring blinding .............................................................. 16 
3.7 
Methods for unblinding ......................................................................... 16 
3.8 
Restrictions ........................................................................................... 16 
3.9 
Discontinuation from study treatment .................................................. 17 
3.9.1 
Procedures for discontinuation of a patient from study drug ................ 18 
3.10 
Criteria for withdrawal .......................................................................... 18 
3.10.1 
Withdrawal of the informed consent ..................................................... 18 
3.11 
Discontinuation of the study ................................................................. 18 
4. 
Study Plan and Timing of Procedures .............................................. 19 
5. 
Study Assessments .............................................................................. 20 
5.1 
Safety assessments ................................................................................ 21 
5.1.1 
Laboratory safety assessments .............................................................. 21 
5.1.2 
Physical examination ............................................................................ 21 
5.1.3 
12-Lead ECG ........................................................................................ 21 
6. 
Safety Reporting and Medical Management .................................... 21 


Clinical Study Protocol 
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Study Code D5161C00005 
Version 1.0 
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6.1 
Definition of adverse events ................................................................. 21 
6.2 
Definitions of serious adverse event ..................................................... 22 
6.3 
Recording of adverse events ................................................................. 24 
6.3.1 
Time period for collection of adverse events ........................................ 24 
6.3.2 
Follow-up of unresolved adverse events ............................................... 24 
6.3.3 
Variables ............................................................................................... 24 
6.3.4 
Causality collection ............................................................................... 25 
6.3.5 
Adverse events based on signs and symptoms...................................... 25 
6.3.6 
Adverse events based on examinations and tests .................................. 25 
6.3.7 
Disease progression .............................................................................. 26 
6.3.8 
New cancers .......................................................................................... 26 
6.4 
Reporting of serious adverse events...................................................... 26 
6.5 
Overdose ............................................................................................... 26 
6.6 
Pregnancy .............................................................................................. 27 
6.6.1 
Maternal exposure ................................................................................. 27 
6.6.2 
Paternal exposure .................................................................................. 27 
6.7 
Management of study drug related toxicities ........................................ 28 
7. 
Study Drug and Other Treatments ................................................... 29 
7.1 
Concomitant and other treatments ........................................................ 30 
7.2 
Post Study Access to Study Treatment ................................................. 30 
8. 
Statistical Analyses by AstraZeneca .................................................. 31 
8.1 
Statistical considerations ....................................................................... 31 
8.2 
Sample size estimate ............................................................................. 31 
8.3 
Description of outcome variables in relation to objectives ................... 31 
8.4 
Definitions of analysis sets ................................................................... 31 
8.4.1 
Safety analysis set ................................................................................. 31 
8.5 
Methods for statistical analyses ............................................................ 32 
8.5.1 
Analysis of the primary variable (s) ...................................................... 32 
9. 
Study and Data Management by AstraZeneca ................................ 33 
9.1 
Training of study site personnel ............................................................ 33 
9.2 
Monitoring of the study ........................................................................ 33 
9.2.1 
Source data ............................................................................................ 33 
9.2.2 
Study agreements .................................................................................. 33 
9.2.3 
Archiving of study documents .............................................................. 34 
9.3 
Data management by delegate of AstraZeneca ..................................... 34 
10. 
Ethical and Regulatory Requirements .............................................. 35 
10.1 
Ethical conduct of the study .................................................................. 35 
10.2 
Patient data protection ........................................................................... 35 
10.3 
Ethics and regulatory review................................................................. 35 


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10.4 
Informed consent .................................................................................. 35 
10.5 
Changes to the protocol and informed consent form ............................ 36 
10.6 
Audits and inspections .......................................................................... 37 
11. 
List of References ................................................................................ 38 
APPENDIX A ADDITIONAL SAFETY INFORMATION .......................... 39 
 
LIST OF TABLES 
Table 1. Time and Event Schedule .......................................................................... 8 
Table 2. Laboratory Safety Variables .................................................................... 21 
Table 3. OSIMERTINIB dose adjustment information for adverse reactions ...... 28 
 
LIST OF FIGURES 
Figure 1. Schematic Overview of the Study .......................................................... 20 
 
LIST OF APPENDICES 
Appendix A 
Additional Safety Information ................................................. 38 
 


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Version 1.0 
Date 06 November 2017 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
AE  
Adverse event  
BCRP  
Breast Cancer Resistance Protein  
CI  
Confidence Interval  
CRF  
Case Report Form (electronic/paper)  
CTCAE  
Common Terminology Criteria for Adverse Event  
ECG  
Electrocardiogram  
EGFR  
Epidermal Growth Factor Receptor  
EGFRm  
EGFR Mutation positive; EGFR Sensitizing Mutation positive  
GCP  
Good Clinical Practice  
ICF  
Informed Consent Form  
ICH  
International Conference on Harmonisation  
ILD  
Interstitial Lung Disease  
INR  
International Normalized Ratio  
IWRS  
Interactive Web Response System  
MedDRA  
Medical Dictionary for Regulatory Activities  
MFDS  
Ministry of Food and Drug Safety  
NSCLC  
Non-Small Cell Lung Cancer  
ORR  
Objective response rate  
PFS  
Progression Free Survival  
PT  
Preferred Term  
QT  
Interval on the electrocardiogram representing the duration of 
depolarization and repolarization of the heart  
QTc  
The QT interval corrected for heart rate  
QTcF  
QT interval corrected per Fredericia’s formula  
SAE  
Serious adverse event  
SAP  
Statistical analysis plan  
T790M  
An amino acid substitution at position 790 in EGFR, from a Threonine 
(T) to a Methionine (M). Presence of T790M  
TKI  
Tyrosine Kinase Inhibitor  
WBDC  
Web based data capture  


Clinical Study Protocol 
Drug Substance OSIMERTINIB  
Study Code D5161C00005 
Version 1.0 
Date 06 November 2017 
13 (40) 
1. 
Introduction 
1.1 
Background and rationale for conducting this study 
Lung cancer is the leading cause of cancer related mortality world-wide and amongst males 
in India. About 85% of lung cancers are non-small cell lung cancers (NSCLC) and the most 
common form of NSCLC is Adenocarcinoma (Howlader N et al. 2016). Mutations in the 
Epidermal growth factor receptor (EGFR) tyrosine kinase are observed in approximately 10-
15% of NSCLC adenocarcinomas in the Caucasians. Studies from India report a much 
higher frequency of EGFR mutations 23% to 44% (Noronha et al. 2016). Patients harbouring 
activating EGFR mutation often respond well when treated with Tyrosine kinase inhibitors 
(TKIs).  
Resistance mutations confer resistance to EGFR TKIs in NSCLC tumors and can be de novo 
or acquired. T790M is one such mutation associated with resistance to TKI inhibitors like 
gefitinib and Erlotinib. Clinical data suggests that T790M mutation is found in <5% - 11% 
of TKI-naïve patients (Primary T790M mutation) and about 50% of TKI resistant patients 
(acquired resistance to T790M mutation) (Sequist et al. 2011; Yu et al. 2013; Camidge, Pao, 
and Sequist 2014).  
Findings from 2 Phase II clinical trials (AURA extension and AURA2) evaluating safety 
and efficacy of osimertinib indicated an objective response rate (ORR) of 66.1% (95% 
confidence interval [CI] 61.2, 70.7%) among patients (n = 398) with a T790M mutation 
(Goss et al. 2016; Jänne et al. 2015), suggesting that this drug will help address an unmet 
need in this patient population setting. The phase III clinical trial AURA3, presented in 
World Conference on Lung Cancer on December 2016 and published on February 2017 
(Mok et al. 2017), compared the treatment with osimertinib 80 mg orally once a day to 
intravenous pemetrexed (500 mg per square meter of body-surface area) plus either 
carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) 
every 3 weeks for up to six cycles (maintenance pemetrexed was allowed). 419 patients with 
T790M-positive advanced non-small-cell lung cancer, who had disease progression after 
first-line EGFR-TKI therapy were randomized (in a 2:1 ratio; 279 and 140 patients, 
respectively). The median duration of progression-free survival was significantly longer 
with osimertinib than with platinum therapy plus pemetrexed (10.1 months versus 4.4 
months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The 
objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) 
than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for 
objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). 
Osimertinib, a third-generation EGFR-TKI has been approved in the USA, Canada, Mexico, 
European Union, Switzerland, Israel, Japan, Brazil, China, and South Korea for the 
treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive 
NSCLC. 
The USA-based National Comprehensive Cancer Network (NCCN) guidelines included 
osimertinib as one of the recommended treatment options following first-line therapy with 
erlotinib, afatinib or gefitinib (“NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines®)- Non-Small Cell Lung Cancer (Version 8.2017)” 2017).  
51st patient expert committee (SEC) of oncology and hematology on 21-Mar-2017 has given 
positive recommendations for approval of osimertinib for “the treatment of patients with 


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metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive nonsmall 
cell lung cancer (NSCLC), as detected by an appropriate test, who have progressed on or 
after EGFR TKI therapy” with a condition to conduct phase IV clinical trial as per the 
requirements of Indian Good Clinical Practices (GCP) and schedule Y of Drugs and 
Cosmetics Rules, 1945. 
As per recommendation, current phase-IV study is planned with the aim to assess the safety 
of osimertinib in Indian patients as a post-marketing requirement. The data obtained from 
the present study will help to understand the safety profile of osimertinib in Indian patients 
with EGFR-T790M mutation-positive NSCLC. 
1.2 
Rationale for study design, doses and control groups 
51st patient expert committee (SEC) of oncology and hematology on 21-Mar-2017 has given 
positive recommendations for approval of osimertinib for “the treatment of patients with 
metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive nonsmall 
cell lung cancer (NSCLC), as detected by an appropriate test, who have progressed on or 
after EGFR TKI therapy” with a condition to conduct phase IV clinical trial as per the 
requirements of Indian Good Clinical Practices (GCP) and schedule Y of Drugs and 
Cosmetics Rules, 1945. 
As per recommendation, current phase-IV study is planned with the aim to assess the safety 
of osimertinib in Indian patients as a post-marketing requirement. The data obtained from 
the present study will help to understand the safety profile of osimertinib in Indian patients 
with EGFR-T790M mutation-positive NSCLC and add to the limited burden of safety data 
on osimertinib currently available. 
1.3 
Benefit/risk and ethical assessment 
Not applicable. 
1.4 
Study Design  
This is a prospective, single-arm, multicenter, phase-IV trial investigating the safety of 
osimertinib in Indian adult patients with metastatic EGFR-T790M mutation-positive 
NSCLC. Investigator will be trained on the locally approved prescribing information before 
the enrolment of the first patient at their site to ensure compliant and proper dosing of the 
study drug. Patients will be monitored throughout the study period for AEs of osimertinib. 
2. 
Study Objectives 
Primary Objective: 
Primary Outcome Measure: 
To assess the safety of 
osimertinib among T790M 
positive NSCLC patients of 
India 
• Number, frequency and proportion of patients with 
adverse events (AEs), serious adverse events (SAEs) 
and AEs of special interest (AESI) including 
interstitial lung disease/pneumonitis-like events, and 
on-study deaths. 


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3. 
Patient Selection, Enrolment, Randomisation, Restrictions, 
Discontinuation and Withdrawal  
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for 
this study.  Under no circumstances can there be exceptions to this rule. 
3.1 
Inclusion criteria 
Each potential patient must satisfy all of the following criteria to be enrolled in the study. 
1 
Patient of either sex and ≥18 years of age 
2 
Patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by 
an appropriate test, who have progressed on or after EGFR TKI therapy by an 
independent clinical judgment of treating physician based on locally approved 
prescribing information 
3 
Each patient (or their legally acceptable representative) must sign an informed 
consent form (ICF) indicating that he or she understands the purpose of and 
procedures required for the study and are willing to participate in the study. 
Patients must be willing and able to adhere to the prohibitions and restrictions 
specified in this protocol, as referenced in the informed consent form (ICF). 
3.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1 
Patient with either the history of hypersensitivity to excipients of the study drug or 
to drugs with a similar chemical structure or class to the study drug. 
2 
Pregnant and/or lactating women 
3 
Patients participating in any current or future interventional trial will not be 
enrolled in the current study 
Procedures for withdrawal of incorrectly enrolled patients see section 3.4. 
3.3 
Patient enrolment and randomization 
• 
Approximately 70 patients meeting all inclusion and none of the exclusion criteria will 
be screened for the study to enroll 60 patients in the current study. 
• 
Patients will be in open label treatment. 
• 
Patients who discontinue the study will not be replaced. 
• 
The E-code is the only patient identification number to be used in CSRs and high level 
documents. 
• 
Investigator(s) should keep a record, the patient screening log, of patients who entered 
pre-study screening. 
• 
The Investigator(s) will: 
o Obtain signed informed consent from the potential patient before any study 
specific procedures are performed. 
o Assign potential patient a unique enrolment number code. 
o Determine patient eligibility. 
o Enroll only eligible patients. If a patient withdraws from participation in the 
study, then his/her enrolment code cannot be reused. 


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3.4 
Procedures for handling incorrectly enrolled or 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 
Methods for assigning treatment groups 
Not applicable- This is a single arm study. 
3.6 
Methods for ensuring blinding 
Not applicable – This is an open-label study. 
3.7 
Methods for unblinding  
Not applicable – This is an open label study. 
3.8 
Restrictions 
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after: 
1 
Females of child-bearing potential should use reliable methods of contraception 
from the time of screening until 6 weeks after discontinuing study treatment. 
Acceptable 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 participant assurance that partner received post-
vasectomy confirmation of azoospermia); tubal occlusion plus male condom; intra-
uterine device (IUD) - provided coils are copper-banded, plus male condom; intra-
uterine system (IUS) levonorgestrel intra-uterine system, plus male condom; 
medroxyprogesterone injections plus male condom; etonogestrel implants plus 
male condom; normal and low dose combined oral contraceptive pills, plus male 
condom; norelgestromin / ethinylestradiol transdermal system plus male condom; 
intravaginal device (eg ethinylestradiol and etonogestrel ) plus male condom; 
desogestrel plus male condom.  
2 
Male patients should be asked to use barrier contraceptives (i.e., by use of 
condoms) during sex with all partners during the trial and for a washout period of 4 
months. Male patients should avoid procreation for 4 months after completion of 
trial 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 inducers of 
CYP3A4 whenever feasible, but patients may receive any medication that is 


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clinically indicated for treatment of adverse events. Such drugs must have been 
discontinued for an appropriate period before they enter screening and for a period 
of 3 months after the last dose of TAGRISSO. All concomitant medications should 
be captured on the eCRF. 
4 
If medically feasible, patients taking regular medication, with the exception of 
potent inducers of CYP3A4 (see above), should be maintained on it throughout the 
study period. Patients taking concomitant medications whose disposition is 
dependent upon BCRP and which have a narrow therapeutic index should be 
closely monitored for signs of changed tolerability as a result of increased exposure 
of the concomitant medication whilst receiving TAGRISSO. 
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. 
3.9 
Discontinuation from study treatment 
If a subject's study treatment must be discontinued, this will not result in automatic 
withdrawal of the subject from the study. If a subject discontinues study treatment for any 
reason before the end of the treatment phase, end-of-treatment assessments should be 
obtained and scheduled follow-up phase assessments should continued as specified in the 
Time and Events Schedule. 
Patients may be discontinued from the study drug treatment in the following situations: 
• 
The subject experiences disease progression (as per participating physician's 
assessment) 
• 
Adverse Event (including laboratory abnormality or intercurrent illness) which, in the 
opinion of the investigator, indicates that continued participation in the study is not in 
the best interest of the patient 
• 
The subject (or the subject’s legally acceptable representative) withdraws consent for 
administration of study drug 
• 
The subject received concurrent (non-protocol) anti-cancer treatment for NSCLC 
• 
ILD/Pneumonitis 
• 
Corneal ulcerations 
• 
QTc interval prolongation with signs/symptoms of serious arrhythmia 
• 
Pregnancy 
• 
Any adverse event deemed to be related to osimertinib that requires a dose hold of more 
than 21 days will result in permanent discontinuation of osimertinib. 
• 
Grade 3 or higher adverse reaction that does not improve to Grade 0-2 after withholding 
for up to 3 weeks 
The primary reason for discontinuation of study treatment is to be recorded in the eCRF. 


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3.9.1 
Procedures for discontinuation of a patient from study drug  
At any time, patients are free to discontinue study drug or withdraw from the study (i.e., 
study drug and assessments), without prejudice to further treatment. A patient that decides 
to discontinue study drug will always be asked about the reason(s) and the presence of any 
adverse events.  If possible, they will be seen and assessed by an Investigator(s). Adverse 
events will be followed up (See Section 6) and all study drugs should be returned by the 
patient. 
Enrolled patients who discontinue the study prematurely should immediately stop taking 
study drug and complete the procedures described for End of Treatment Visit, as soon as 
possible but not later than 7 days after discontinuation of study drug.  
If a patient is withdrawn from study, see Section3.9, 3.10, 3.11. 
3.10 
Criteria for withdrawal  
3.10.1 
Withdrawal of the informed consent 
Patients are free to withdraw from the study at any time (study drug and assessments), 
without prejudice to further treatment. 
Reasons for withdrawal from the study:  
• 
Eligibility criteria not fulfilled  
• 
Death  
• 
Withdrawal of consent. 
• 
Lost to follow up (unsuccessful contact with patient despite every effort made by 
investigator)  
Patients who withdraw consent for further participation in the study will not receive any 
further study drug or further study observation. Note that the patient may be offered 
additional tests to withdraw safely.  
A patient who withdraws consent will always be asked about the reason(s) and the presence 
of any adverse events (AE).  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 reused. Withdrawn patients will not be replaced.  
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed, such that there is insufficient information to determine the 
patient’s status at that time. Patients who refuse continuing participation in the study, 
including telephone contact, should be documented as “withdrawal of consent” rather than 
“lost to follow-up.”  Investigators should document attempts to re-establish contact with 
missing patients throughout the study period.  If contact with a missing patient is 
re-established, the patient should not be considered lost to follow-up and any evaluations 
should resume according to the protocol.  
3.11 
Discontinuation of the study 
The study may be stopped if, in the judgment of AstraZeneca, study patients are placed at 
undue risk because of clinically significant findings that: 
• 
meet individual stopping criteria or are otherwise considered significant  


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• 
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 CRF. All reasons for discontinuation 
of treatment must be documented. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests. 
4. 
Study Plan and Timing of Procedures  
Study is planned to be conducted according to plan described in Table 1.  
The decision of patients to participate in this study must not, in any way, impact upon the 
standard of care that they are receiving or any benefits to which they are otherwise entitled. 
Prior to data collection, all patients must sign an informed consent form (ICF) allowing data 
collection and source data verification in accordance with local requirements and sponsor 
policy.  
Patients with metastatic EGFR T790M mutation-positive NSCLC, who are eligible to 
osimertinib treatment as per locally approved prescribing information and ratified by an 
independent clinical judgment of treating physician will be evaluated for the inclusion into 
the current phase-IV study based on eligibility criteria. EGFR T790M positivity on plasma 
or tissue biopsy on PCR-based platform will be considered appropriate test. EGFR T790M 
must be performed after progressive disease on last line of therapy (on or after EGFR TKI 
therapy). In order to enrol approximately 60 patients, it is expected that approximately 70 
patients will be screened. 
Patient participation will include a Screening/Enrolment Phase, a Treatment Phase, and a 
Follow-up Phase. The Screening Phase will be up to 7 days prior to Cycle 1, Day 1. The 
Treatment Phase will extend from Cycle 1, Day 1 to Cycle 6, Day 21; or until study drug 
discontinuation due to either disease progression or unacceptable toxicity; or other reasons 
whichever occurs first, as listed in Section 3.9. Each cycle of treatment is defined as 21 days 
of once daily osimertinib treatment. The Follow-up Phase will begin once a patient 
discontinues study drug or on completion of Treatment Phase, and will continue until 28 
days after last dose, death, loss to follow up, consent withdrawal for study participation, or 
study end, whichever occurs first (see Section 3.9, 3.10, 3.11). 
Osimertinib will be provided free of cost by the sponsor to clinical trial patient in the 
Treatment Phase. The sponsor shall provide the laboratory investigations for safety 
evaluation including hematology, biochemistry and ECG as mentioned in the Time and 
Event Schedule to monitor the safety throughout the study period.  


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Figure 1. Schematic Overview of the Study 
 
28 days±7 days
Follow-up (Telephonic)
Screening / Enrolment Phase (Day -6 to 0)
(n=60 patients)
Tretment Phase (Cycle 1 , Day 1 to Cycle 6, Day 21)
End-of-Treatment Visit (Cycle 6, Day 21 or day of disconinuation if 
early)
 
SCREENING PHASE (VISIT 0) 
Patients, or their legally acceptable representative, will provide written informed consent 
before any trial-specific procedures are performed. During the Screening Phase, eligibility 
criteria will be reviewed and a complete clinical evaluation will be performed as specified 
in the Time and Event Schedule. Screening procedures will be performed within 7 days 
before Cycle 1, Day 1. All baseline disease characteristics will be captured based evaluation 
performed as a part of routine clinical practice. The Screening laboratory tests, if any, must 
be completed within 7 days before Cycle 1, Day 1. 
TREATMENT PHASE 
The Treatment Phase will extend from Cycle 1, Day 1 to Cycle 6, Day 21; or until study 
drug discontinuation due to either disease progression or unacceptable toxicity; or other 
reasons whichever occurs first, as listed in Section 3.9. Details of the procedures performed 
during the Treatment Phase are outlined in the Time and Events Schedules. Patients will be 
closely monitored for adverse events and other safety evaluations including laboratory 
investigations, concomitant medications. If disease progression is diagnosed before Cycle 
6, Day 21, then the patient will discontinue study drug with completion of the End-of-
Treatment Visits on the day of progression, and will enter the Follow-up Phase. 
END-OF–TREATMENT VISIT (EOT) 
An End-of-Treatment Visit is to be scheduled on Cycle 6, Day 21 of the study drug 
administration. In a case where patient discontinues the study treatment for any reason listed 
in Section 3.9 before Cycle 6, Day 21, last visit of the patient will be considered as End-of-
treatment visit. Every effort should be made to conduct the telephonic End-of-Study Visit 
before the patient starts subsequent treatment. 
FOLLOW UP PHASE (END-OF-STUDY) 
A telephonic follow-up will be conducted 28 days after the EOT Visit. This will be 
considered as End-of-study visit.  
The observation period including the Enrolment Visit and telephonic end-of-study visit will 
be up to a maximum duration of approximately 23 weeks for each patient. 
5. 
Study Assessments 
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. 


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5.1 
Safety assessments 
5.1.1 
Laboratory safety assessments 
Blood sample for laboratory measurement will be performed at local laboratory. 
Table 2. Laboratory Safety Variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
B-Haemoglobin (Hb) 
S/P-Creatinine 
B-Leukocyte count 
S/P-Bilirubin, total 
B-Leukocyte differential count (absolute count) 
S/P-Alkaline phosphatise (ALP) 
B-Platelet count 
S/P-Aspartate transaminase (AST) 
 
S/P-Alanine transaminase (ALT) 
 
S/P-Albumin 
 
S/P-Potassium 
 
S/P-Calcium, total 
 
S/P-Sodium 
S/P-Creatine kinase (CK) 
5.1.2 
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, musculo-skeletal (including spine and 
extremities) and neurological systems. 
5.1.3 
12-Lead ECG 
A 12-lead ECG will be taken (supine position, standard ECG with a recommended paper 
speed of 50 mm/second covering at least 6 sequential beats) after the patient has been lying 
down resting for at least 5 minutes. The ECG will be evaluated by the investigator and 
entered as “Normal” or “Abnormal” in the eCRF. If the ECG is evaluated as “Abnormal” 
the abnormality should be further specified. 
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 and is responsible for reporting all SAEs and other 
AEs. 
6.1 
Definition of adverse events 
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical 
product, whether or not considered causally related to the product.  An undesirable medical 
condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) 
or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).  In 
clinical studies, an AE can include an undesirable medical condition occurring at any time, 
including run-in or washout periods, even if no study treatment has been administered. 


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The term AE is used to include both serious and non-serious AEs. 
6.2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (ie screening, treatment, 
follow-up), that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
• 
Is a congenital abnormality or birth defects 
• 
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
For further guidance on the definition of a SAE, see Camidge, D. Ross, William Pao, and Lecia 
V. Sequist. 2014. “Acquired Resistance to TKIs in Solid Tumours: Learning from Lung 
Cancer.” 
Nature 
Reviews 
Clinical 
Oncology 
11 
(8): 
473–81. 
doi:10.1038/nrclinonc.2014.104. 
Chen, Chien-Wei, Chin-Wei Kuo, Yi-Lin Chen, Chung-Liang Ho, Wu-Chou Su, and Chien-Chung 
Lin. 2017. “Successful AZD9291 Therapy in Advanced Non–Small Cell Lung Cancer after 
Failure 
of 
HM61713.” 
Journal 
of 
Thoracic 
Oncology 
12 
(6): 
e72–74. 
doi:10.1016/j.jtho.2017.02.005. 
Goss, Glenwood, Chun-Ming Tsai, Frances A Shepherd, Lyudmila Bazhenova, Jong Seok Lee, Gee-
Chen Chang, Lucio Crino, et al. 2016. “Osimertinib for Pretreated EGFR Thr790Met-
Positive Advanced Non-Small-Cell Lung Cancer (AURA2): A Multicentre, Open-Label, 
Single-Arm, Phase 2 Study.” The Lancet Oncology 17 (12): 1643–52. doi:10.1016/S1470-
2045(16)30508-3. 
Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Kosary CL, Yu M, et al. 2016. “SEER 
Cancer Statistics Review, 1975-2014 (Based on November 2016 SEER Data Submission, 
Posted to the SEER Web Site, April 2017).” Bethesda, MD: National Cancer Institute. 
https://seer.cancer.gov/csr/1975_2014/. 
Jänne, Pasi A., James Chih-Hsin Yang, Dong-Wan Kim, David Planchard, Yuichiro Ohe, Suresh S. 
Ramalingam, Myung-Ju Ahn, et al. 2015. “AZD9291 in EGFR Inhibitor–Resistant Non–
Small-Cell Lung Cancer.” New England Journal of Medicine 372 (18): 1689–99. 
doi:10.1056/NEJMoa1411817. 
Julious, Steven A., and Michael J. Campbell. 2012. “Tutorial in Biostatistics: Sample Sizes for 
Parallel Group Clinical Trials with Binary Data.” Statistics in Medicine 31 (24): 2904–36. 
doi:10.1002/sim.5381. 
Mok, Tony S., Yi-Long Wu, Myung-Ju Ahn, Marina C. Garassino, Hye R. Kim, Suresh S. 
Ramalingam, Frances A. Shepherd, et al. 2017. “Osimertinib or Platinum–Pemetrexed in 
EGFR T790M–Positive Lung Cancer.” New England Journal of Medicine 376 (7): 629–40. 
doi:10.1056/NEJMoa1612674. 
“NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)- Non-Small Cell Lung 
Cancer 
(Version 
8.2017).” 
2017. 
National 
Comprehensive 
Cancer 
Network. 
https://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf. 
Nguyen, Kim-Son H, Joel W Neal, and Heather Wakelee. 2014. “Review of the Current Targeted 
Therapies for Non-Small-Cell Lung Cancer.” World Journal of Clinical Oncology 5 (4): 
576–87. doi:10.5306/wjco.v5.i4.576. 


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Noronha, Vanita, Rakesh Pinninti, Vijay M. Patil, Amit Joshi, and Kumar Prabhash. 2016. “Lung 
Cancer in the Indian Subcontinent.” South Asian Journal of Cancer 5 (3): 95. 
doi:10.4103/2278-330X.187571. 
Sequist, Lecia V., Belinda A. Waltman, Dora Dias-Santagata, Subba Digumarthy, Alexa B. Turke, 
Panos Fidias, Kristin Bergethon, et al. 2011. “Genotypic and Histological Evolution of Lung 
Cancers Acquiring Resistance to EGFR Inhibitors.” Science Translational Medicine 3 (75): 
75ra26-75ra26. doi:10.1126/scitranslmed.3002003. 
Yu, H. A., M. E. Arcila, N. Rekhtman, C. S. Sima, M. F. Zakowski, W. Pao, M. G. Kris, V. A. 
Miller, M. Ladanyi, and G. J. Riely. 2013. “Analysis of Tumor Specimens at the Time of 
Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung 
Cancers.” Clinical Cancer Research 19 (8): 2240–47. doi:10.1158/1078-0432.CCR-12-
2246. 
 
 


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Appendix A to the Clinical Study Protocol. 
6.3 
Recording of adverse events 
6.3.1 
Time period for collection of adverse events 
Adverse Events will be collected from patient actually taking the study drug throughout the 
entire treatment period and during the follow-up period until the end of the study. SAEs will 
be collected from the time at which informed consent is obtained until the end of the study. 
6.3.2 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the patient’s last AE assessment in the study are followed 
up by the Investigator for as long as medically indicated, but without further recording in 
the eCRF. AstraZeneca retains the right to request additional information for any patient 
with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
6.3.3 
Variables  
The following variables will be collect for each AE; 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
Maximum intensity 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the study drug (yes or no) 
• 
Action taken with regard to study drug 
• 
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 serious AE 
• 
AE is serious due to 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to Study procedure(s) 
• 
Causality assessment in relation to Other medication 
• 
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 


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shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2. 
Maximum intensity refers to the complete course of the AE.  The patient (parents/legal 
guardians) will be asked to assess the maximum intensity of the reported AEs according to 
the following scale: 
• 
Mild (awareness of sign or symptom, but easily tolerated) 
• 
Moderate (discomfort sufficient to cause interference with normal activities) 
• 
Severe (incapacitating, with inability to perform normal activities). 
6.3.4 
Causality collection 
The Investigator will assess causal relationship between Study drug and each Adverse Event, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable 
possibility that the event may have been caused by the study drug?’ 
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 A. 
ADDITIONAL SAFETY INFORMATION to the Clinical Study Protocol. 
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 personnel: ‘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. The question will be put to each patient (or parent/legal guardian) in 
local language from Visit 2 to the last follow-up telephone contact.  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 protocol mandated laboratory tests, vital signs and other safety assessments 
will be summarized in the CSR. Deterioration as compared to baseline in these parameters 
will therefore only be reported as AEs if they fulfil any of the SAE criteria or are the reason 
for discontinuation of treatment with the study drug.  
If deterioration in a laboratory value, vital sign or other safety assessment is associated with 
clinical signs and symptoms, the sign or symptom will be reported as an AE and the 
associated laboratory result or other finding will be considered as additional information. In 
the absence of clinical signs and symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).  
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 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable 
to the disease for which the investigational product is being studied.  It may be an increase 
in the severity of the disease under study and/or increases in the symptoms of the disease.  
The development of new, or progression of existing metastasis to the primary cancer under 
study should be considered as disease progression and not an AE.  Events that are 
unequivocally due to disease progression should not be reported as AEs during the 
study. 
6.3.8 
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. 
6.4 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the study drug, 
or to the study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one 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 adverse events where important or relevant information is 
missing, active follow-up is undertaken immediately.  Investigators or other site personnel 
inform AstraZeneca representatives of any follow-up information on a previously reported 
SAE within one calendar day ie immediately but no later than 24 hours of when he or she 
becomes aware of it. 
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed.  
The reference document for definition of expectedness/listedness is the Product Information 
for the osimertinib Overdose. 
6.5 
Overdose 
The risks associated with over dosage of osimertinib are considered to be small. 
In phase I/II clinical trials a limited number of patients were treated with osimertinib daily 
doses of up to 240 mg without dose limiting toxicities. In these studies, patients who were 
treated with osimertinib daily doses of 160 mg and 240 mg experienced an increase in the 
frequency and severity of a number of typical EGFR TKI-induced AEs (primarily diarrhoea 
and skin rash) compared to the 80 mg dose. There is limited experience with accidental 
overdoses in humans. All cases were isolated incidents of patients taking an additional daily 
dose of osimertinib in error, without any resulting clinical consequences. There is no specific 


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treatment in the event of osimertinib overdose. In case of suspected overdose, osimertinib 
should be withheld and symptomatic treatment initiated. 
• 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module. 
• 
An overdose without associated symptoms is only reported on the Overdose CRF 
module. 
If an overdose on an AstraZeneca study drug occurs in the course of the study, 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. 
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 occurring  during the course of the study and 
within 6 weeks of the last dose of TAGRISSO should be reported to Astrazeneca.  
6.6.1 
Maternal exposure 
If a patient becomes pregnant during the course of the study, study drug should be 
discontinued immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product 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 subject 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 
investigational product, then the Investigator or other site personnel informs the appropriate 
AstraZeneca representatives within 1day i.e., immediately but no later than 24 hours of when 
he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 
or 5 calendar days for SAEs (see Section X) 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 subject’s partners is not considered to be an adverse event. 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. 


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To capture information about a pregnancy from the partner of a male subject, the male 
subject’s partner consent must be obtained to collect information related to the pregnancy 
and outcome; the male subject 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. 
6.7 
Management of study drug related toxicities  
If a patient experiences a CTCAE grade 3 and/or unacceptable toxicity 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 onset, treatment with 
study drug may be restarted at the same dose (80 mg) or a lower dose (40 mg) using the 
rules below for dose modifications (Table 3) 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, then the patient should be 
withdrawn from the study and observed until resolution of the toxicity. 
Table 3. OSIMERTINIB dose adjustment information for adverse reactions 
Target 
organ 
Adverse reactiona 
Dose modification 
Pulmonary  ILD/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 greater than 
or equal to 481 msec, then restart at a 
reduced dose (40 mg) 
QTc interval prolongation with 
signs/symptoms 
of 
serious 
arrhythmia 
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  
a Note: The intensity of clinical adverse events graded by the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 


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ECGs: Electrocardiograms; QTc: QT interval corrected for heart rate 
On resolution of toxicity within 3 weeks: 
• 
If an AE subsequently requires dose interruption, study drug may restart at the same 
dose or the reduced dose, on resolution/improvement of the AE at the discretion of the 
Investigator. 
ILD/Pneumonitis-like toxicity  
If new or worsening pulmonary symptoms (e.g., dyspnoea) or radiological abnormality 
suggestive of interstitial lung disease 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 edema, or pulmonary 
hemorrhage. The results of the full diagnostic workup (including high-resolution computed 
tomography, blood and sputum culture, haematological parameters) will be recorded in the 
CRF by the investigator. In the presence of confirmatory HRCT scans where other causes 
of respiratory symptoms have been excluded, a diagnosis of interstitial lung disease (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. 
QTc prolongation  
Patients with 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. If the toxicity does not 
resolve to ≤grade 1 within 21 days the patient will be permanently withdrawn from study 
treatment. 
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. 
Changes in cardiac contractility  
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. 
Patients experiencing corneal ulceration, Interstitial Lung Disease (ILD) or QTc 
prolongation with signs/symptoms of serious arrythmia will not be permitted to restart study 
treatment. 
For the details, please refer to the local prescribing information. 
7. 
Study Drug and Other Treatments 
Osimertinib is an oral, potent, selective, irreversible inhibitor of both EGFR-TKI sensitising 
and resistance mutations in NSCLC with a significant selectivity margin over wild-type 
EGFR. osimertinib will be administered orally as one 80 mg tablet once a day. A cycle of 


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treatment is defined as 21 days of once daily osimertinib treatment. Dose modification will 
be done as per locally approved prescribing information with the use of 40 mg tablet strength 
if required. 
The study drug  
Dosage form and strength  
Osimertinib  
40 mg Tablets  
80 mg Tablets  
The tablets can be taken with or without food and should be swallowed whole with water. 
The tablet should not be crushed, split or chewed. 
If the patient is unable to swallow the tablet, it may first be dispersed in 50 mL of non-
carbonated water. The tablet should be dropped in the water, without crushing, stirred until 
dispersed and immediately swallowed. An additional 100mL of water should be added to 
ensure that no residue remains and then immediately swallowed. 
Doses should be taken approximately 24 hours apart at the same time point each day. Doses 
should not be missed. If a patient misses a scheduled dose, within a window of 12 hours, it 
is acceptable to take the dose. If it is more than 12 hours after the scheduled dose time, the 
missed dose must not be taken, and patients must be instructed to take the next dose at the 
next scheduled time. If a patient vomits after taking their study drug treatment, they must 
not make up for this dose, but must take the next scheduled dose. 
Any change from dosing schedule, dose interruptions, or dose reductions must be recorded 
in the CRF. 
The study drug will be administered according to the prescribing information of the 
approved label by the investigator.  
7.1 
Concomitant and other treatments  
As this study will be performed under clinical practice, the investigator may prescribe any 
other concomitant medication that he/she considers necessary for the patient as locally 
approved. Please refer to section 3.8 for restrictions. 
7.2 
Post Study Access to Study Treatment 
The Treatment Phase will extend from Cycle 1, Day 1 to Cycle 6, Day 21; or until study 
drug discontinuation due to either disease progression or unacceptable toxicity; or other 
reasons whichever occurs first, as listed in Section 3.9. 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.  
Patients receiving osimertinib at the time of study completion (i.e. after completion of 
treatment phase) may continue to receive osimertinib, if in the opinion of their treating 
physician they are continuing to derive clinical benefit from continued treatment or have not 
progressed clinically. They will be provided osimertinib treatment as per recommendation 
from treating physician on ethical basis. Post-trial access to osimertinib will be provided 
from local commercial supply though local distribution channel. Such patients will not be 
monitored after EOS visit.  


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8. 
Statistical Analyses by AstraZeneca 
8.1 
Statistical considerations 
• 
Analyses will be performed by AstraZeneca or its representatives.     
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to first patient 
enrolled and any subsequent amendments will be documented. 
8.2 
Sample size estimate 
The primary objective of the trial is to describe the safety profile of osimertinib in routine 
clinical practice and add to the limited burden of safety data on osimertinib currently 
available as assessed by the incidence of adverse events (AEs) (Serious and Non-serious 
AEs) observed during trial. Considering the epidemiology of metastatic NSCLC- 
adenocarcinoma subtype which are positive for EGFR sensitizing mutation and have 
progressed after EGFR-TKI based treatment in first line setting and prevalence of T790M-
mutation after such progression, a sample size of 60 patients is expected to provide the 
following exact two sided 95% confidence interval for a list of percentages of patients 
reporting at least one AE (Julious and Campbell 2012). 
Observed rate expressed as % 
(number of patients reporting at least one AE*) 
Lower Limit of CI (%) 
Upper Limit of CI (%) 
0% 
0 
6.0 
1% 
0 
7.8 
2% 
0.1 
9.5 
5% 
1.0 
13.9 
10% 
3.8 
20.5 
20% 
10.8 
32.3 
30% 
18.8 
43.2 
40% 
27.6 
53.5 
50% 
36.8 
63.2 
*the symptom could be any of the expected AE, unexpected AE or SAE. The calculation is based on the link 
between binomial and beta distributions. 
8.3 
Description of outcome variables in relation to objectives 
Analysis will be conducted to evaluate the following as available in the CRF: 
• 
Baseline 
characteristics: 
demographics, 
relevant 
medical 
history, 
disease 
characteristics, cancer treatment history. 
• 
Exposure to the study drug 
• 
Adverse events SAEs, AEs leading to dose modification or discontinuation, and AEs of 
special interest (for example interstitial lung disease/pneumonitis-like events; QTc 
prolongation events) 
• 
Death due to AE, or unknown cause (except death due to disease progression). 
8.4 
Definitions of analysis sets 
8.4.1 
Safety analysis set 
Safety analysis set will include all enrolled patients who received at least one dose of study 
medication during treatment period. 


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8.5 
Methods for statistical analyses 
Data will be summarized using descriptive statistics. Continuous variables will be 
summarized using the number of observations, mean, SD, coefficient of variation, median, 
and range as appropriate. Categorical values will be summarized using the number of 
observations and percentages as appropriate. Shift tables will be provided to determine the 
change in reported outcomes from baseline. 
8.5.1 
Analysis of the primary variable (s) 
Adverse Events 
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) and CTCAE grade and 
will be listed individually by patient. Treatment-emergent adverse events are adverse events 
with onset during the treatment phase or that are a consequence of a pre-existing condition 
that has worsened since baseline. All reported adverse events will be included in the analysis. 
For each adverse event, the percentage of subjects who experience at least 1 occurrence of 
the given event will be summarized. 
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. Any AE occurring within 28 days of 
discontinuation of investigational product (ie, the last dose 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.  
Adverse events of special interest (for example interstitial lung disease/pneumonitis-like 
events; QTc prolongation events]) will be summarized separately. 
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for 
those subjects who die, who discontinue treatment due to an adverse event, or who 
experience a severe or a serious adverse event. 
Clinical Laboratory Tests 
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be 
calculated for each laboratory analyte at baseline and for observed values and changes from 
baseline at each scheduled time point. Changes from baseline results will be presented in 
pre- versus posttreatment cross-tabulations (with classes for below, within, and above 
normal ranges). Parameters with predefined National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) toxicity grades will be 
summarized. Change from baseline to the worst adverse event grade experienced by the 
subject during the study will be provided as shift tables. A listing of subjects with any 
laboratory results outside the reference ranges will be provided. A listing of subjects with 
any markedly abnormal laboratory results will also be provided. 


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Electrocardiogram (ECG) 
Electrocardiogram data will be summarized by ECG parameter. Descriptive statistics will 
be calculated at baseline and for observed values and changes from baseline at each 
scheduled time point. Frequency tabulations of the abnormalities will be made. 
9. 
Study and Data Management by AstraZeneca 
9.1 
Training of study site personnel 
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 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 protocol, that data are being 
accurately and timely recorded in the CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed 
• 
Perform source data verification (a comparison of the data in the CRFs 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 (e.g., 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 will be available between visits if the Investigator(s) or 
other staff at the centre needs information and advice about the study conduct. 
9.2.1 
Source data 
Study sites will maintain source data in accordance with Good Clinical Practice (GCP) or local 
regulations. 
9.2.2 
Study agreements 
The investigator at each site must comply with all the terms, conditions, and obligations of 
the Study Agreement for this study. In the event of any inconsistency between this study 


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protocol and the Study Agreement, the terms of the 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 Study Agreement shall prevail. 
Agreements between the sponsor and the investigator must be in place before any study-
related procedures can take place. 
9.2.3 
Archiving of study documents 
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA). 
9.3 
Data management by delegate of AstraZeneca  
Data management will be performed by CRO, according to the Data Management Plan.  
Adverse events and medical/surgical history will be classified according to the terminology 
of the latest version the Medical Dictionary for Regulatory Activities (MedDRA). 
Medications will be classified according to the AstraZeneca Drug Dictionary. Classification 
coding will be performed by CRO. 
Data collected will include patient demographics, information needed to determine patient 
eligibility (including medical history, past and current disease characteristics, and tumour 
EGFR mutational status), exposure of the study drug (including starting dose, dose 
adjustments or discontinuations), investigator-reported efficacy (including tumour response 
and disease progression), and safety (including SAEs, AEs leading dose-modification).  
Data will be entered in the web-based data capture (WBDC) system at the Investigator’s site. 
The Investigator (or delegate) will be responsible for entering data into the WBDC system 
and according to the Investigator Instructions Manual. The Investigator Instructions Manual 
will also provide the study site with data entry instructions. The data collected through third 
party sources will be obtained and reconciled against study data. Data entered in the WBDC 
system will be immediately saved to a central database and changes tracked to provide an audit 
trail. When data have been entered, reviewed and edited, the Investigator will be notified to sign 
the CRF electronically as per the agreed project process. A copy of the CRF will be archived at 
the Investigator’s site. 
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. 
Serious Adverse Event (SAE) Reconciliation 
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational database.   


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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 and are consistent with International Conference on 
Harmonization (ICH)/Good Clinical Practice (GCP), applicable regulatory requirements and 
the sponsor’s policy on Bioethics and Human Biological Samples. 
10.2 
Patient data protection 
The Informed Consent Form will incorporate wording that complies with relevant data 
protection and privacy legislation. 
• 
Study data will be stored in a computer database, maintaining confidentiality in 
accordance with relevant data protection and privacy legislation 
• 
Patient data will be maintaining confidentiality in accordance with relevant data 
protection and privacy legislation  
• 
For data verification purposes, authorised representatives of AstraZeneca, a regulatory 
authority, an IRB may require direct access to parts of the hospital or practice source 
records relevant to the study, including patients’ medical history 
• 
All data computer processed by AstraZeneca will be identified by study code and 
enrolment code (E-code) 
10.3 
Ethics and regulatory review 
An Institutional Review Board (IRB) should approve the final study protocol, including the 
final version of the Informed Consent Form and any other written information and/or 
materials to be provided to the patients.  The Investigator will ensure the distribution of these 
documents to the applicable IRB, and to the study site staff. 
The opinion of the IRB should be given in writing. The Investigator should submit the 
written approval to AstraZeneca before enrolment of any patient into the study.  
AstraZeneca should approve any modifications to the Informed Consent Form that are 
needed to meet local requirements. 
Before enrolment of any patient into the study, the final 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 will handle the distribution of any of these documents to the national regulatory 
authorities. 
AstraZeneca will provide Regulatory Authorities, IRB and Principal Investigators with 
safety updates/reports according to local 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 


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• 
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. 
The environment where the process of consent is conducted should be determined by the 
type of research being conducted but there should always be a period where a private, 
confidential, and “safe” setting is afforded to facilitate a constructive dialogue between the 
prospective patient and the person(s) involved in obtaining consent. 
10.5 
Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the Investigator and 
AstraZeneca. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol). 
The amendment is to be approved by the relevant IRB and if applicable, also the national 
regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols. 
AstraZeneca will distribute any subsequent amendments and new versions of the protocol 
to each Principal Investigator(s). For distribution to IRB see Section 10.3. 
If a protocol amendment requires a change to a centre’s Informed Consent Form, 
AstraZeneca and the centre’s IRB are to approve the revised Informed Consent Form before 
the revised form is used. If local regulations require, any administrative change will be 
communicated to or approved by each Ethics Committee. 
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, Good 
Clinical Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), 
and any applicable regulatory requirements.  The Investigator will contact AstraZeneca 
immediately if contacted by a regulatory agency about an inspection at the centre. 


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37 (40) 
10.6 
Audits and inspections  
Authorized representatives of AstraZeneca, a regulatory authority, or an IRB/EC may perform 
audits or inspections at the study site, 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, 
analyzed, and accurately reported according to the protocol, GCP, ICH guidelines, and any 
applicable regulatory requirements. The investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the study site. 
AstraZeneca Pharma India Limited 
Block N1, 12th Floor, Manyata Embassy Business Park 
Rechenahalli, Outer Ring Road, Bangalore-560045. 


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Study Code D5161C00005 
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11. 
List of References 
Camidge, D. Ross, William Pao, and Lecia V. Sequist. 2014. “Acquired Resistance to TKIs in Solid 
Tumours: Learning from Lung Cancer.” Nature Reviews Clinical Oncology 11 (8): 473–81. 
doi:10.1038/nrclinonc.2014.104. 
Chen, Chien-Wei, Chin-Wei Kuo, Yi-Lin Chen, Chung-Liang Ho, Wu-Chou Su, and Chien-Chung 
Lin. 2017. “Successful AZD9291 Therapy in Advanced Non–Small Cell Lung Cancer after 
Failure 
of 
HM61713.” 
Journal 
of 
Thoracic 
Oncology 
12 
(6): 
e72–74. 
doi:10.1016/j.jtho.2017.02.005. 
Goss, Glenwood, Chun-Ming Tsai, Frances A Shepherd, Lyudmila Bazhenova, Jong Seok Lee, Gee-
Chen Chang, Lucio Crino, et al. 2016. “Osimertinib for Pretreated EGFR Thr790Met-
Positive Advanced Non-Small-Cell Lung Cancer (AURA2): A Multicentre, Open-Label, 
Single-Arm, Phase 2 Study.” The Lancet Oncology 17 (12): 1643–52. doi:10.1016/S1470-
2045(16)30508-3. 
Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Kosary CL, Yu M, et al. 2016. “SEER 
Cancer Statistics Review, 1975-2014 (Based on November 2016 SEER Data Submission, 
Posted to the SEER Web Site, April 2017).” Bethesda, MD: National Cancer Institute. 
https://seer.cancer.gov/csr/1975_2014/. 
Jänne, Pasi A., James Chih-Hsin Yang, Dong-Wan Kim, David Planchard, Yuichiro Ohe, Suresh S. 
Ramalingam, Myung-Ju Ahn, et al. 2015. “AZD9291 in EGFR Inhibitor–Resistant Non–
Small-Cell Lung Cancer.” New England Journal of Medicine 372 (18): 1689–99. 
doi:10.1056/NEJMoa1411817. 
Julious, Steven A., and Michael J. Campbell. 2012. “Tutorial in Biostatistics: Sample Sizes for 
Parallel Group Clinical Trials with Binary Data.” Statistics in Medicine 31 (24): 2904–36. 
doi:10.1002/sim.5381. 
Mok, Tony S., Yi-Long Wu, Myung-Ju Ahn, Marina C. Garassino, Hye R. Kim, Suresh S. 
Ramalingam, Frances A. Shepherd, et al. 2017. “Osimertinib or Platinum–Pemetrexed in 
EGFR T790M–Positive Lung Cancer.” New England Journal of Medicine 376 (7): 629–40. 
doi:10.1056/NEJMoa1612674. 
“NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)- Non-Small Cell Lung 
Cancer 
(Version 
8.2017).” 
2017. 
National 
Comprehensive 
Cancer 
Network. 
https://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf. 
Nguyen, Kim-Son H, Joel W Neal, and Heather Wakelee. 2014. “Review of the Current Targeted 
Therapies for Non-Small-Cell Lung Cancer.” World Journal of Clinical Oncology 5 (4): 
576–87. doi:10.5306/wjco.v5.i4.576. 
Noronha, Vanita, Rakesh Pinninti, Vijay M. Patil, Amit Joshi, and Kumar Prabhash. 2016. “Lung 
Cancer in the Indian Subcontinent.” South Asian Journal of Cancer 5 (3): 95. 
doi:10.4103/2278-330X.187571. 
Sequist, Lecia V., Belinda A. Waltman, Dora Dias-Santagata, Subba Digumarthy, Alexa B. Turke, 
Panos Fidias, Kristin Bergethon, et al. 2011. “Genotypic and Histological Evolution of Lung 
Cancers Acquiring Resistance to EGFR Inhibitors.” Science Translational Medicine 3 (75): 
75ra26-75ra26. doi:10.1126/scitranslmed.3002003. 
Yu, H. A., M. E. Arcila, N. Rekhtman, C. S. Sima, M. F. Zakowski, W. Pao, M. G. Kris, V. A. 
Miller, M. Ladanyi, and G. J. Riely. 2013. “Analysis of Tumor Specimens at the Time of 
Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung 
Cancers.” Clinical Cancer Research 19 (8): 2240–47. doi:10.1158/1078-0432.CCR-12-
2246. 
 
 


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APPENDIX A 
ADDITIONAL SAFETY INFORMATION 
Further Guidance on the Definition of a Serious Adverse Event (SAE) 
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 serious AE, 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 jeopardize 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 iv 
hydrocortisone treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation 
Development of drug dependency or drug abuse 
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 


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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 recognized feature of overdose of the drug? 
• 
Is there a known mechanism? 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence 
for a ‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 
 
 
 

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Protocol D5161C00005 
 
 
A prospective, multicenter, Phase-IV clinical trial to assess safety of TAGRISSOTM (Osimertinib) 
in Indian adult patients with metastatic epidermal growth factor receptor (EGFR) T790M 
mutation-positive non small cell lung cancer (NSCLC) 
 
 
 
Redacted Statistical Analysis Plan 
 
 
 
Statistical Analysis Plan 
Drug Substance 
OSIMERTINIB 
Study Code 
D5161C00005 
Version 
1.0 
Date 
17th March 2021 


 
 
  
        
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Table of Contents 
 
1. 
Introduction ...................................................................................................................................... 4 
1.1 
Study Rationale ............................................................................................................................................................................... 4 
2. 
Study Objectives .............................................................................................................................. 4 
3. 
Study Design ..................................................................................................................................... 4 
4. 
Sample Size and Power Considerations ......................................................................................... 4 
5. 
Analysis Planned .............................................................................................................................. 5 
5.1 
General Analysis Definition ........................................................................................................................................................ 5 
5.2 
Visit Schedule ................................................................................................................................................................................. 5 
5.3 
Pooling Strategy for Analysis Centers (if applicable) ........................................................................................................... 6 
5.4 
Analysis Population ....................................................................................................................................................................... 6 
6. 
Randomization and Blinding .......................................................................................................... 6 
7. 
Method of Analysis .......................................................................................................................... 6 
7.1 
Statistical Hypotheses.................................................................................................................................................................... 6 
7.2 
Interim Analysis.............................................................................................................................................................................. 6 
7.3 
Handling of Missing Data ............................................................................................................................................................ 6 
8. 
Statistical Analysis ........................................................................................................................... 7 
8.1 
Patient Disposition ......................................................................................................................................................................... 7 
8.2 
Demographic and Baseline Characteristics .............................................................................................................................. 8 
8.3 
Medical and Surgical History ...................................................................................................................................................... 8 
8.4 
Prior and Concomitant Medications .......................................................................................................................................... 8 
8.5 
Study Drug Exposure .................................................................................................................................................................... 8 
8.6 
Efficacy Analysis ........................................................................................................................................................................... 8 
8.7 
Safety Analysis ............................................................................................................................................................................... 8 
8.7.1 
Adverse Events ................................................................................................................................................................................ 8 
8.7.2 
Clinical Laboratory Tests ............................................................................................................................................................ 9 
8.7.3 
Physical Examinations................................................................................................................................................................ 10 
8.7.4 
Vital Signs ...................................................................................................................................................................................... 10 
8.7.5 
Electrocardiogram ....................................................................................................................................................................... 10 
8.7.6 
Other Safety Parameters ............................................................................................................................................................ 11 
9. 
Protocol Deviations ............................................................................. Error! Bookmark not defined. 
 
List of Abbreviations 


 
 
  
        
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Abbreviation 
Term 
AE 
Adverse Event 
ALP 
Alkaline phosphatise  
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
ATC 
Anatomic Therapeutic Class 
CI 
Confidence Interval 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
EGFR 
Epidermal Growth Factor Receptor 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NSCLC 
Non-Small Cell Lung Cancer 
PT 
Preferred Term 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
WHO 
World Health Organization 
 
 
 


 
 
  
        
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1. 
Introduction 
This statistical analysis plan (SAP) contains definition of analysis population(s), derived variables and statistical 
methods for safety analysis. 
This SAP is created on the basis of clinical study protocol D5161C00005 version 1.0 dated 06NOV2017 and case 
report form (CRF) version 1.0 dated 10JAN2018. 
 
Note: In this document any text taken directly from the protocol is italicised.  
 
1.1 
Study Rationale 
As per recommendation, current phase-IV study is planned with the aim to assess the safety of osimertinib in 
Indian patients as a post-marketing requirement. The data obtained from the present study will help to understand 
the safety profile of osimertinib in Indian patients with EGFR-T790M mutation-positive NSCLC and add to the 
limited burden of safety data on osimertinib currently available 
 
2. 
Study Objectives  
To assess the safety of osimertinib among T790M positive NSCLC patients of India.  
 
3. 
Study Design 
This is a prospective, single-arm, multicenter, phase-IV trial investigating the safety of osimertinib in Indian adult 
patients with metastatic EGFR-T790M mutation-positive NSCLC. Investigator will be trained on the locally 
approved prescribing information before the enrolment of the first patient at their site to ensure compliant and 
proper dosing of the study drug. Patients will be monitored throughout the study period for AEs of osimertinib. 
Schematic Overview of the Study 
 
 
 
4. 
Sample Size and Power Considerations 
The primary objective of the trial is to describe the safety profile of osimertinib in routine clinical practice and add 
to the limited burden of safety data on osimertinib currently available as assessed by the incidence of adverse events 28 days±7 daysScreening / Enrolment Phase (Day -6 to 0)(n=60 patients)Treatment Phase (Cycle 1 , Day 1 to Cycle 6, Day 21)End-of-Treatment Visit (Cycle 6, Day 21 or day of discontinuation if early)Follow-up (Telephonic)


 
 
  
        
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(AEs) (Serious and Non-serious AEs) observed during trial. Considering the epidemiology of metastatic NSCLC- 
adenocarcinoma subtype which are positive for EGFR sensitizing mutation and have progressed after EGFR-TKI 
based treatment in first line setting and prevalence of T790M-mutation after such progression, a sample size of 60 
patients is expected to provide the following exact two sided 95% confidence interval for a list of percentages of 
patients reporting at least one AE (Julious and Campbell 2012). 
Observed rate expressed as % 
(number of patients reporting at least 
one AE*) 
Lower Limit of CI (%) 
Upper Limit of CI (%) 
0% 
0 
6.0 
1% 
0 
7.8 
2% 
0.1 
9.5 
5% 
1.0 
13.9 
10% 
3.8 
20.5 
20% 
10.8 
32.3 
30% 
18.8 
43.2 
40% 
27.6 
53.5 
50% 
36.8 
63.2 
*the symptom could be any of the expected AE, unexpected AE or SAE. The calculation is based on the link between 
binomial and beta distributions. 
In order to enroll approximately 60 patients, it is expected that approximately 70 patients will be screened. 
 
5. 
Analysis Planned 
5.1 
General Analysis Definition 
Data will be summarized using descriptive statistics. Continuous variables will be summarized using the number 
of observations, mean, SD, coefficient of variation, median, and range as appropriate. Categorical values will be 
summarized using the number of observations and percentages as appropriate. Shift tables will be provided to 
determine the change in reported outcomes from baseline. 
The statistical analyses will be performed using Statistical Analysis System (SAS®), Version 9.4 or higher. 
 
5.2 
Visit Schedule 
Patient participation will include a Screening/Enrolment Phase, a Treatment Phase, and a Follow-up Phase.  
Phase/Visit 
Definition 
The Screening Phase 
Up to 7 days prior to Cycle 1, Day 1. 
The Treatment Phase  
From Cycle 1, Day 1 to Cycle 6, Day 21; or until study drug 
discontinuation due to either disease progression or unacceptable 
toxicity; or other reasons whichever occurs first. Each cycle of treatment 
is defined as 21 days of once daily Osimertinib treatment. 
An End-of-Treatment (EoT) Visit  
On Cycle 6, Day 21 of the study drug administration. If disease 
progression is diagnosed before Cycle 6, Day 21, then the patient will 
discontinue study drug with completion of the End-of- Treatment Visits 
on the day of progression, and will enter the Follow-up Phase. 


 
 
  
        
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The Follow-up Phase. 
It will begin once a patient discontinues study drug or on completion of 
Treatment Phase, and will continue until 28 days after last dose, death, 
loss to follow up, consent withdrawal for study participation, or study 
end, whichever occurs first. This will be considered as End-of-study 
visit. 
 
The observation period including the Enrolment Visit and telephonic end-of-study visit will be up to a maximum 
duration of approximately 23 weeks for each patient. 
 
5.3 
Pooling Strategy for Analysis Centers (if applicable) 
Not Applicable 
 
5.4 
Analysis Population 
Safety analysis set will include all enrolled patients who received at least one dose of study medication during 
treatment period. 
Note: All the data for this study will be summarized using this population. 
 
6. 
Randomization and Blinding 
Not applicable - This is a single arm and open-label study. 
 
7. 
Method of Analysis 
7.1 
Statistical Hypotheses 
No formal hypothesis testing will be conducted.  
 
7.2 
Interim Analysis 
Not Applicable 
 
7.3 
Handling of Missing Data 
Missing results/events will not be imputed 
 
Adverse events and concomitant medications with completely or partially missing assessment dates will have 
imputation performed as explained below for the purposes of calculation of durations or relativity to study 
medication. 
 
For the end of a concomitant medication or adverse event: 
 
• 
If only Day of end date is missing: 


 
 
  
        
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The last date of the month and year reported or the date of the final contact with the subject, whichever is 
earlier, will be used as the end date; 
 
• 
If Day and Month of end date are missing: 
The last date of year i.e. December 31 of the year reported or the date of the last study contact with the 
subject, whichever is earlier, will be used as the end date; 
 
• 
If Year of end date or complete end date is missing: 
If the adverse event or concurrent medication continues after the last study contact date, then no end date or 
time will be estimated. 
 
For the start of a concomitant medication or adverse event: 
 
• 
If only Day of start date is missing: 
• 
If the start year and month of medication/event are the same as that for the first dose date, then 
following approach will be used: 
➢ If the end date of medication/event is NOT before the first dose date or end date of 
medication/event is completely missing, then 
o Impute the start day as the day of first dose date; 
➢ Otherwise, impute the start day as 1. 
• 
If the start year and month of medication/event are NOT same as that for the first dose date, then 
➢ Impute the start day as 1. 
 
• 
If Day and Month of start date are missing: 
• 
If start year of medication/event is same as first dose year, then following approach will be used: 
i. 
For medication, impute the start Month as January and the Day as 1; 
ii. 
For adverse event, 
➢ If the end date of event is NOT before the first dose date or end date of event is completely 
missing, then 
o Impute the start Month and Day as the Month and Day of first dose date; 
➢ Otherwise, impute the start Month as January and the Day as 1; 
• 
If start year of medication/event is NOT same as first dose year, then 
➢ Impute start Month as January and the Day as 1. 
 
• 
If Year of start date or complete start date is missing: 
If the year of start of medication/event is missing or start date is completely missing then no start date or time 
will be imputed. 
 
Also for AE, compare the end date to the first dose date. If the AE end date is before the first dose date then the 
AE should be considered as a medical history. Otherwise, the AE will be considered as TEAE. 
 
8. 
Statistical Analysis 
8.1 
Patient Disposition 
A tabular presentation of the patient disposition will be provided. It will include the number of patients screened, 
enrolled/ assigned treatment, completed, as well as the number of dropouts, with reasons for discontinuation. All 
patients entered in the study will be accounted for in this. A listing will be presented to describe dates of screened, 


 
 
  
        
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assigned treatment, screen failed with reason, completion, early withdrawal, and the reason for early 
discontinuation, if applicable, for each patient. 
 
8.2 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics data will be listed and summarized as appropriate using the safety 
analysis set. 
 
8.3 
Medical and Surgical History 
Medical and Surgical history data will be listed and summarized by System Organ Class and Preferred Term 
according to MedDRA version 23.0 using the safety analysis set. 
 
8.4 
Prior and Concomitant Medications 
Prior medications/procedures are those that are taken only prior to initial dose of study drug and concomitant 
medications/procedures are those taken while on study drug including the ones that started before the initial dose 
of study drug. 
All prior and concomitant medications will be coded by Anatomic Therapeutic Class (ATC) and Preferred Term 
(PT) according to the World Health Organization (WHO) Drug Dictionary version March 1, 2020 and all prior 
and concomitant procedures will be coded using MedDRA Version 23.0. 
Subjects using various prior or concomitant medications or who have undergone prior or concomitant procedures 
will be listed and summarized with numbers and percentages by ATC level 2 and Preferred Terms.  
 
8.5 
Study Drug Exposure  
The extent of exposure to the study medication will be summarized and listed for safety analysis set. The extent of 
exposure to the study medication will be calculated as below: 
Exposure (days) = Last date of dosing – First date of dosing + 1. 
 
8.6 
Efficacy Analysis 
Not Applicable 
 
8.7 
Safety Analysis 
8.7.1 
Adverse Events 
All adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT) according to the 
Medical Dictionary for Regulatory Activities (MedDRA) Version 23.0. The intensity of adverse events is graded 
by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 or 
higher. 
Treatment-emergent adverse events are adverse events with onset during the treatment phase or that are a 
consequence of a pre-existing condition that has worsened since baseline. All reported adverse events will be 


 
 
  
        
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included in the analysis. For each adverse event, the percentage of subjects who experience at least 1 occurrence 
of the given event will be summarized.  
 
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. Any AE occurring within 28 days of discontinuation of investigational product (i.e., 
the last dose 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.  
 
Adverse events of special interest (for example interstitial lung disease/pneumonitis-like events; QTc prolongation 
events]) will be summarized separately.  
 
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those subjects who die, 
who discontinue treatment due to an adverse event, or who experience a severe or a serious adverse event.  
An overall summary will be provided in terms of count and percentages for: 
• 
AEs 
• 
TEAEs 
• 
Grade 3 and above TEAEs 
• 
Grade 3 and above related TEAEs 
• 
Treatment-related TEAEs 
• 
Treatment-related serious TEAEs 
• 
TEAEs leading to dose change/ interruption/ discontinuation 
• 
Treatment related TEAEs leading to dose change/ interruption/ discontinuation 
• 
Serious TEAEs 
• 
Fatal TEAEs 
• 
Related Fatal TEAEs 
Summaries in terms of count and percentages by SOC and PT will be provided for the following: 
• 
TEAEs 
• 
Treatment-Emergent SAEs 
• 
Grade 3 and above TEAEs  
• 
Treatment-related TEAEs  
• 
Grade 3 and above treatment-related TEAEs  
• 
TEAEs leading to dose change/ interruption/ discontinuation 
• 
Adverse Events of special interest 
 
8.7.2 
Clinical Laboratory Tests 
Laboratory data will be summarized by type of laboratory test. Descriptive statistics (N, Mean, SD, Median, 
Minimum and Maximum) will be calculated for each laboratory analyte at baseline and for observed values and 
changes from baseline at each cycle.  
The baseline measurement is the last predose measurement taken before Cycle1 Day1. 
Haematology/Haemostasis (whole blood)  
Clinical Chemistry (serum or plasma)  
Haemoglobin (Hb)  
Creatinine  
Leukocyte count  
Bilirubin, total  


 
 
  
        
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Leukocyte differential count (absolute count)  
Alkaline phosphatise (ALP)  
Platelet count  
Aspartate transaminase (AST)  
 
Alanine transaminase (ALT)  
 
Albumin  
 
Potassium  
 
Calcium, total  
 
Sodium  
 
Creatine kinase (CK)  
 
Changes from baseline results will be presented in pre- versus post treatment cross-tabulations (with classes for 
below, within, and above normal ranges). Parameters with predefined National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) toxicity grades will be summarized. Change from 
baseline to the worst adverse event grade experienced by the subject during the study will be provided as shift 
tables.  
Lab toxicity grades will be derived using NCI-CTCAE version 5.0. 
A listing of subjects with any laboratory results outside the reference ranges will be provided. A listing of subjects 
with any markedly abnormal laboratory results will also be provided. 
Physical Examinations 
 
A listing of physical examinations will be provided. 
8.7.3 
Vital Signs 
Descriptive statistics (N, Mean, SD, Median, Minimum and Maximum) will be provided for vital signs 
parameters (pulse rate, Systolic blood pressure, Diastolic blood pressure, weight) for the observed values and 
change from baseline at each cycle. The corresponding listing will be provided.  
The baseline measurement is the last predose measurement taken before Cycle1 Day1. 
8.7.4 
Electrocardiogram 
QTc Interval data will be descriptively summarized. Descriptive statistics (N, Mean, SD, Median, Minimum and 
Maximum) will be calculated at baseline and for observed values and changes from baseline at each scheduled time 
point. The ECG will be evaluated by the investigator and entered as “Normal” or “Abnormal” in the eCRF. If the 
ECG is evaluated as “Abnormal” the abnormality is further specified. Frequency tabulations of the abnormalities 
will be made. 
The baseline measurement is the last predose measurement taken before Cycle1 Day1. 
The number (%) of participants with maximum post-dose QTc values and maximum increases from baseline in 
the following categories will be tabulated for each cycle. 
Safety QTc interval 
 
QTc interval 
 
 
 
Absolute value 
≥450 <480 
>=480-<500     ≥480 
>=500 
Absolute change 
30- <60 
≥60 
 


 
 
  
        
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8.7.5 
Other Safety Parameters 
WHO performance status will be summarized with number and percentage for each status per cycle. 
A listing will be provided for each of the following: 
• 
WHO performance status 
• 
Pathology at Diagnosis 
• 
Tumour sample  
• 
Extent of disease 
• 
Previous cancer therapy 
• 
Previous radiotherapy 
• 
Receptor status 
• 
Pregnancy test 
• 
Ejection fraction measurements 
• 
Skin Reaction 
• 
Pregnancy report 
• 
Drug administration 
• 
Drug accountability 
• 
Drug Overdose 
• 
Hospital admission details 
 
 
9. 
Protocol Deviations 
A full list of protocol deviations reported during the study will be compiled prior to database closure. This data 
will be listed as appropriate.