GioTag: Real-world Data Study on Sequential Therapy With Gi(l)Otrif®/ Afatinib as First-line Treatment Followed by Osimertinib in Patients With EGFR Mutation Positive Advanced Non-small Cell Lung Cancer
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Boehringer Ingelheim

ABCD
 
 
 
001-MCS-90-124_RD-01 (4.0) 
TITLE PAGE 
Protocol for non-interventional studies based on existing data 
TITLE PAGE 
Document Number: 
c14668275-03 
BI Study Number: 
1200-0286 
BI Investigational 
Product(s): 
Gi(l)otrif® (afatinib) 
Title: 
GioTag: Real-world data study on sequential therapy with 
Gi(l)otrif®/ afatinib as first-line treatment followed by 
osimertinib in patients with EGFR mutation positive advanced 
non-small cell lung cancer  
Lay Title: 
The GioTag study observes how long patients with non-small 
cell lung cancer (NSCLC) take afatinib as first-line treatment 
and osimertinib as second-line treatment. 
Protocol version 
identifier: 
3.0 
Date of last version of 
protocol: 
06 Mar 2019 
PASS: 
No 
EU PAS register 
number: 
EUPAS21037 
Active substance: 
afatinib 
Antineoplastic agents, tyrosine kinase inhibitors 
ATC code: L01XE13 
Medicinal product: 
Gi(l)otrif® 50mg, 40mg, 30mg, 20mg tablet 
Product reference: 
20mg: EU/1/13/879/001, EU/1/13/879/002, EU/1/13/879/003 
30mg: EU/1/13/879/004, EU/1/13/879/005, EU/1/13/879/006 
40mg: EU/1/13/879/007, EU/1/13/879/008, EU/1/13/879/009 
50mg: EU/1/13/879/010, EU/1/13/879/011, EU/1/13/879/012 
Procedure number: 
EMEA/H/C/002280 
Joint PASS: 
No 
Research question and 
objectives: 
Primary objective: 
To determine the time on treatment of afatinib (Gi(l)otrif®) as 
first-line therapy in Epidermal Growth Factor Receptor (EGFR) 
mutation-positive followed by osimertinib in case the T790M 
resistance mutation was developed in real-world setting. Time on 
treatment is defined from the start of the first-line treatment until 
the end of the second-line treatment. 
Secondary objective: 

Boehringer Ingelheim 
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Protocol for non-interventional studies based on existing data 
BI Study Number 1200-0286 
c14668275-03
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001-MCS-90-124_RD-01 (4.0) 
To collect data on acquired resistance mechanism to osimertinib. 
Country(-ies) of study: 
Austria, Canada, Germany, Israel, Italy, Japan, Singapore, 
Slovenia, Spain, Taiwan and USA.  
Author: 
Phone: 
 
Fax: 
 
e-mail: 
 
Marketing authorisation 
holder(s): 
Date: 
06 Mar 2019 
 
Page 2 of 51 
 
Proprietary confidential information 
© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission 
 
 

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Protocol for non-interventional studies based on existing data 
BI Study Number 1200-0286 
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001-MCS-90-124_RD-01 (4.0) 
1. 
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................. 1 
1.
TABLE OF CONTENTS ....................................................................................... 3
2.
LIST OF ABBREVIATIONS ................................................................................ 5
3.
RESPONSIBLE PARTIES .................................................................................... 6
4.
ABSTRACT ........................................................................................................... 7
5.
AMENDMENTS AND UPDATES ..................................................................... 10
6.
MILESTONES ..................................................................................................... 19
7.
RATIONALE AND BACKGROUND ................................................................ 20
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 21
9.
RESEARCH METHODS .................................................................................... 22
9.1 
STUDY DESIGN ............................................................................................ 22 
9.2 
SETTING ........................................................................................................ 22 
9.2.1 
Selection of study population .................................................................. 22 
9.3 
VARIABLES .................................................................................................. 23 
9.3.1 
Exposures ................................................................................................ 24 
9.3.2 
Outcomes ................................................................................................. 24 
9.3.2.1 Primary outcomes .................................................................................. 24 
9.3.2.2 Secondary outcomes .............................................................................. 24 
9.3.3 
Covariates ................................................................................................ 25 
9.4 
DATA SOURCES ........................................................................................... 25 
9.4.1 
Source documents ................................................................................... 25 
9.4.2 
Records .................................................................................................... 25 
9.4.3 
Direct access to source data and documents ........................................... 25 
9.4.4 
Storage of records .................................................................................... 26 
9.5 
STUDY SIZE .................................................................................................. 26 
9.6 
DATA MANAGEMENT ................................................................................ 26 
9.7 
DATA ANALYSIS ......................................................................................... 26 
9.7.1 
Main analysis ........................................................................................... 26 
9.7.2 
Secondary analysis .................................................................................. 27 
9.8 
QUALITY CONTROL ................................................................................... 27 
9.9 
LIMITATIONS OF THE RESEARCH METHODS ...................................... 27 
9.10 
OTHER ASPECTS ......................................................................................... 28 

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001-MCS-90-124_RD-01 (4.0) 
9.10.1 
Statement of confidentiality .................................................................... 28 
9.10.2 
Patient completion ................................................................................... 29 
9.10.3 
Completion of study ................................................................................ 29 
9.11 
SUBJECTS ...................................................................................................... 29 
9.11.1 
Cases ........................................................................................................ 29 
9.11.2 
Controls ................................................................................................... 29 
9.12 
BIAS ................................................................................................................ 30 
10. 
PROTECTION OF HUMAN SUBJECTS .......................................................... 31 
10.1 
DATA PROTECTION AND STUDY RECORDS ........................................ 31 
10.1.1 Study approval, patient information, and informed consent ........................ 31 
10.2 
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
STUDY RELATED INJURY ......................................................................... 32 
11. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ....................................................................................................... 33 
11.1 
DEFINITIONS OF ADVERSE EVENTS ...................................................... 33 
11.2 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION  
AND REPORTING ........................................................................................ 34 
11.3 
REPORTING TO HEALTH AUTHORITIES................................................ 37 
12. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS ............................................................................................................ 38 
13. 
REFERENCES .................................................................................................... 39 
13.1 
PUBLISHED REFERENCES ......................................................................... 39 
13.2 
UNPUBLISHED REFERENCES ................................................................... 41 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS .............................................. 42 
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS ................................. 43 
ANNEX 3. ADDITIONAL INFORMATION .............................................................. 50 
ANNEX 3.1 ECOG PERFORMANCE STATUS ...................................................... 50 

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Protocol for non-interventional studies based on existing data 
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001-MCS-90-124_RD-01 (4.0) 
2. 
LIST OF ABBREVIATIONS 
ADRs 
Adverse Drug Reactions 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
BI 
Boehringer Ingelheim 
CA 
Competent Authority 
CML 
Local Clinical Monitor  
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CUP 
Compassionate Use Program 
EAP 
Early Access Program 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EGFR 
Epidermal Growth Factor Receptor 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GEP 
Good Epidemiological Practice 
GPP 
Good Pharmacoepidemiology Practice 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
IV 
Intravenous 
MAH 
Marketing Authorization Holder 
NIS 
Non-Interventional Study 
NSCLC 
Non-Small Cell Lung Cancer 
PFS 
Progression free Survival 
PD 
Progressive Disease 
PS 
Performance Score 
RDC 
Remote Data Capture 
RWD 
Real World Data 
SAE 
SOP 
Serious Adverse Event 
Standard Operating Procedures 
SEAP 
Statistical and Epidemiological Analysis Plan 
SmPC 
Summary of Product Characteristics 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
TCM 
Trial Clinical Monitor 
TKI(s) 
TMF 
Tyrosine Kinase Inhibitor(s) 
Trial Master File 
WHO 
World Health Organisation 

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Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
 
001-MCS-90-124_RD-01 (4.0) 
3. 
RESPONSIBLE PARTIES 
The study is sponsored by Boehringer Ingelheim (BI). 
 
Boehringer Ingelheim has appointed a Trial Clinical Monitor (TCM), responsible for 
coordinating the activities required in order to manage the study in accordance with 
applicable regulations and internal standard operating procedures (SOPs), directing the study 
team in the preparation, conduct, and reporting of the study, order the materials as needed for 
the study, ensures appropriate training and information of internal Local Clinical Monitors 
(CML), Clinical Research Associates (CRAs) or external Contract Research Organisation 
(CRO) members (CRO Project Managers and/or CRO CRAs), and investigators of 
participating countries. 
 
The organisation of the study in the participating countries will be done by a CRO with which 
the responsibilities and tasks will have been agreed and a written contract filed before 
initiation of the study. 
 
Data Management and Statistical evaluation will be performed by a CRO which is appointed 
by the sponsor.  
 
Tasks and functions assigned in order to organise, manage, and evaluate the study will be 
defined according to BI SOPs. A list of responsible persons and relevant local information (as 
protocol reference if applicable) are in the Investigator Site File (ISF) and in the Trial Master 
File (TMF) document. 
 
A coordinating investigator will be nominated to coordinate investigators at different sites 
participating in this multicentre study. Tasks and responsibilities for the coordinating 
investigators will be defined in a contract filed before initiation of the study.  
 
Relevant documentation on the participating (Principal) investigators and other important 
participants (e.g. their curricula vitae) will be filed in the ISF. An ISF containing all relevant 
study related documentation will be maintained according to local regulations and BI SOPs at 
each study site. A copy of the ISF documents will also be kept as an electronic TMF at BI 
according to BI SOPs. 
 
Coordinating investigator:  
Phone: 
 
Fax: 
 
E-mail: 
  

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001-MCS-90-124_RD-01 (4.0) 
4. 
ABSTRACT 
Name of company: 
 
 
Boehringer Ingelheim 
Name of finished medicinal 
product:  
Gi(l)otrif® 
 
Name of active ingredient: 
afatinib 
Antineoplastic agents,  
tyrosine kinase inhibitors 
ATC code: L01XE13 
 
Protocol date: 
Study 
number: 
Version/Revision: 
Version/Revision 
date: 
04 May 2017 
1200-0286 
3.0 
06 Mar 2019 
Title of study: 
GioTag: Real-world data study on sequential therapy with Gi(l)otrif®/ 
afatinib as first-line treatment followed by osimertinib in patients with 
EGFR mutation positive advanced non-small cell lung cancer 
Rationale and 
background: 
Afatinib (Gi(l)otrif®), an irreversible ErbB family blocker, is approved 
in EGFR-TKI (Tyrosine Kinase Inhibitor) naïve patients. Afatinib 
showed a median progression-free survival (PFS) of 11.1~13.6 months 
in previous clinical trials (LUX-Lung 3, LUX-Lung 6 and LUX-Lung 
7). However, resistance develops for most of patients and the most 
common mechanism of resistance to EGFR TKIs (> 50%) is the 
emergence of a second-site EGFR-mutation, the T790M. 
 
Osimertinib, a third-generation EGFR TKI, was approved for these 
patients whose tumours have developed the EGFR T790M mutation in 
several countries/regions (e.g. USA, EU and Japan).  
Data for osimertinib in TKI-naïve setting are expected to come soon 
from the FLAURA trial. However, resistance mechanisms of 
osimertinib indicate limited options for subsequent targeted therapy. 
 
Whether osimertinib will extend PFS versus available therapies if used 
as front-line therapies remains unknown. Investigating the time from 
start of first-line afatinib (Gi(l)otrif®) until the end of second-line 
osimertinib in this study provides insights on treatment sequence that 
can inform on the most beneficial treatment sequence for the patients. 
Research question 
and objectives: 
To determine the time on treatment of afatinib (Gi(l)otrif®) as first-line 
therapy in patients with EGFR mutation-positive NSCLC followed by 
osimertinib in case the T790M resistance mutation was developed in 
real-world setting and to collect data on osimertinib’s resistance 
mechanisms (when available). 
 
 
 

Boehringer Ingelheim 
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Protocol for non-interventional studies based on existing data 
BI Study Number 1200-0286 
c14668275-03
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
 
001-MCS-90-124_RD-01 (4.0) 
Name of company: 
 
 
Boehringer Ingelheim 
Name of finished medicinal 
product:  
Gi(l)otrif® 
 
Name of active ingredient: 
afatinib 
Antineoplastic agents,  
tyrosine kinase inhibitors 
ATC code: L01XE13 
 
Protocol date: 
Study 
number: 
Version/Revision: 
Version/Revision 
date: 
04 May 2017 
1200-0286 
3.0 
06 Mar 2019 
Study design: 
Non-interventional, multi-country, multi-centre study based on 
existing data from medical records of patients treated with afatinib 
(Gi(l)otrif®) as the first-line treatment followed by osimertinib in case 
the T790M resistance mutation was developed. 
Population: 
Site selection: 
Sites in countries meeting the following criteria: 
- Afatinib launch dates prior 2015 and known to prescribe afatinib 
(Gi(l)otrif®) on a regular basis 
- Osimertinib used in patients with EGFR T790M mutation-positive 
NSCLC within an early access program/ compassionate use program 
(EAP/CUP) or regular clinical practice; osimertinib provided via a 
clinical trial is not permitted. 
 
Main inclusion criteria: 
1. Patients with common EGFR mutations (Del19, L858R) advanced 
NSCLC being treated with afatinib (Gi(l)otrif®) in the first-line 
setting and for acquired T790M mutation with osimertinib in the 
second line; patients must have completed afatinib (Gi(l)otrif®) 
treatment and must have started osimertinib treatment at least 10 
months prior to data entry. 
2. Patients treated with osimertinib within an EAP/CUP or regular 
clinical practice; patients treated with osimertinib via a clinical 
trial are excluded. 
3. Age ≥ 18 years 
Main exclusion criteria: 
1. Patients who received drug(s) other than osimertinib as the second-
line treatment and/or patients who received drug(s) other than 
afatinib (Gi(l)otrif®) as the first-line treatment. 
2. Patients with active brain metastases at start of treatment (either 
afatinib/Gi(l)otrif® or osimertinib). 
 

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Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
 
001-MCS-90-124_RD-01 (4.0) 
Name of company: 
 
 
Boehringer Ingelheim 
Name of finished medicinal 
product:  
Gi(l)otrif® 
 
Name of active ingredient: 
afatinib 
Antineoplastic agents,  
tyrosine kinase inhibitors 
ATC code: L01XE13 
 
Protocol date: 
Study 
number: 
Version/Revision: 
Version/Revision 
date: 
04 May 2017 
1200-0286 
3.0 
06 Mar 2019 
Variables: 
Primary Outcome(s): 
Time on treatment with afatinib (Gi(l)otrif®) followed by osimertinib. 
 
Secondary Outcome(s): 
Type and proportion of acquired resistance mutations after osimertinib. 
Safety criteria: 
All adverse drug reactions (ADRs), adverse events (AEs) with fatal 
outcome and drug exposure during pregnancy will be collected 
retrospectively for pharmacovigilance. There is no intention to analyse 
the safety data in this non-interventional study (NIS) based on existing 
data. Safety data will be reviewed and analysed as part routine global 
pharmacovigilance procedures. 
Data sources: 
Non-interventional study (NIS) based on existing data from medical 
records of patients. 
Study size: 
Total enrolled: at least 190 patients 
Data analysis: 
Time on treatment will be analysed using Kaplan-Meier method, and 
the median along with two-sided 90% confidence interval will be 
displayed. 
The different types and proportion of patients with acquired resistance 
mutations after osimertinib will be summarized descriptively. 
Milestones: 
Start of data collection in Dec 2017 
End of data collection in May 2018 
Final report of study results expected in Sep 2018 
Note: Additional follow-up data collection for additional data analyses 
will be performed at least 10 months after the end of data collection of 
study primary outcomes. 

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001-MCS-90-124_RD-01 (4.0) 
5. 
AMENDMENTS AND UPDATES 
Number of global 
amendment 
 
1 
Date of protocol revision 
 
11-Sep-2017 
EudraCT number 
 
NA 
BI Study number 
 
1200-0286 
BI Active substance 
 
afatinib 
Title of protocol 
 
GioTag: Real-world data study on sequential 
therapy with Gi(l)otrif®/ afatinib as first-line 
treatment followed by osimertinib in patients 
with EGFR mutation positive advanced non-
small cell lung cancer 
 
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities 
 
 
To be implemented 
immediately in order to 
eliminate hazard –  
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval 
 
 
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as 
changes involve logistical or 
administrative aspects only 
 
 
 
Section to be changed 
 
Title Page (Change 1) 
Description of change 
 
Change 1: Revising the countries of the study 
 
Title Page: Wording changed. 
Austria, Canada, Germany, Israel, Italy, 
Japan, Singapore, Slovenia, Spain, Taiwan 
and USA. 
Rationale for change 
 
Change 1: To change the targeted countries 
according to the results of further evaluation 
on current real-world patient population.  
 
Section to be changed 
 
Section 4 (Change 2) 
Section 9.1 (Change 2) 
Section 9.2 (Change 2) 
Section 9.5 (Change 2) 

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Protocol for non-interventional studies based on existing data 
BI Study Number 1200-0286 
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Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
 
001-MCS-90-124_RD-01 (4.0) 
Number of global 
amendment 
 
1 
Description of change 
 
Change 2: Revising sample size and study 
population information 
 
Section 4: Information and wording revised 
Sample size:  
Total enrolled: at least 190 patients 
 
Section 9.1: Information and wording revised 
In total, at least 190 eligible patients are 
planned to be enrolled to this study. 
 
Section 9.2: Information and wording revised 
It is planned that around 65 study centres in 
11 countries will be participating in this non-
interventional study and at least 190 
consecutive eligible patients will be enrolled 
to the study. 
 
Section 9.2: Information and wording revised 
It is expected that approximately 3 patients 
will be enrolled at each study centre. 
 
Section 9.5: Information and wording revised 
Based on the assumption that time on 
treatment follows an exponential distribution, 
a sample size of 171 patients are expected to 
ensure at 80% chance to observe a width of 
the 90% confidence interval of median time 
on treatment smaller or equal to 10 months, 
which is considered as a reasonable estimation 
precision. Assuming 10% of censored 
observations a total of 190 patients are 
included in the study. 
Rationale for change 
 
Change 2: To change the targeted study 
sample size according to the results of further 
evaluation on current real-world patient 
population. Other study population 
information is changed due to the change of 
study sample size and study timeline. 
 
Section to be changed 
 
Section 4 (Change 3) 
Section 9.7.1 (Change 3) 
Description of change 
 
Change 3: Adding additional descriptions 
about how to handle the collected safety data 
 
Section 4: Wording added 

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Protocol for non-interventional studies based on existing data 
BI Study Number 1200-0286 
c14668275-03
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
 
 
 
001-MCS-90-124_RD-01 (4.0) 
Number of global 
amendment 
 
1 
Safety Criteria: All adverse drug reactions 
(ADRs), adverse events (AEs) with fatal 
outcome and drug exposure during pregnancy 
will be collected retrospectively for 
pharmacovigilance. There is no intention to 
analyse the safety data in this non-
interventional study (NIS) based on existing 
data. Safety data will be reviewed and 
analysed as part routine global 
pharmacovigilance procedures. 
 
Section 9.7.1: Wording revised and added 
This descriptive non-interventional study 
based on existing data is conducted within the 
conditions of the approved marketing 
authorization and there is no intention to 
analyse the safety data collected 
retrospectively in the study as part of the 
study analysis. The safety data from this 
study will be reviewed and analysed as part 
of routine global pharmacovigilance 
processes.  
Rationale for change 
 
Change 3: To specify that the review and 
analysis of collected safety data will be part of 
company routine processes. 
 
Section to be changed 
 
Section 4 (Change 4) 
Section 6 (Change 4) 
Description of change 
 
Change 4: Revising the study timeline 
 
Section 4: Information revised 
Milestones: 
Start of data collection in Dec 2017 
End of data collection in May 2018 
Final report of study results expected in Sep 
2018 
 
Section 6: Information revised 
Milestone 
Planned Date 
Start of data 
collection 
 31 Dec 2017 
End of data 
collection 
 31 May 2018 

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001-MCS-90-124_RD-01 (4.0) 
Number of global 
amendment 
 
1 
Registration in 
the EU PAS 
register 
EU PAS register 
number not yet 
assigned as the study is 
not yet registered in the 
EU PAS Register. The 
study will be registered 
shortly before the start 
of data collection. 
Final report of 
study results: 
 30 Sep 2018 
Rationale for change 
 
Change 4: Study timeline is revised based on 
the revised sample size and the evaluation 
results of current real-world patient 
population. 
 
Section to be changed 
 
Section 4 (Change 5) 
Section 9.7.1 (Change 5) 
Description of change 
 
Change 5: Wording revised (administrative 
changes) 
 
Section 4: Wording revised 
Data analysis: Time on treatment will be 
analysed using Kaplan-Meier method, and the 
median along with two-sided 90% confidence 
interval will be displayed. 
 
Section 9.7.1: Wording revised 
Time on treatment will be analysed using 
Kaplan-Meier method, and the median along 
with two-sided 90% confidence interval will 
be displayed (use the Greenwood’s formula 
for estimation of standard errors). 
 
Baseline conditions and demographics will be 
analysed with descriptive statistics. 
 
This descriptive non-interventional study 
based on existing data is conducted within the 
conditions of the approved marketing 
authorization and there is no intention to 
analyse the safety data collected 
retrospectively in the study. 
Rationale for change 
 
Change 5: Administrative changes 
 
Section to be changed 
 
Section 9.8 (Change 6) 

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001-MCS-90-124_RD-01 (4.0) 
Number of global 
amendment 
 
1 
Description of change 
 
Change 6: Adding the patient replacement 
rule 
 
Section 9.8: Wording added 
Patient replacement may be considered if 
there are major quality issues identified 
from the collected data. The decision of 
whether or not to enforce a patient 
replacement will be made by the 
sponsor/study team after evaluations. Data 
of the replaced patients will not be included 
in the final data analysis. 
Rationale for change 
 
Change 6: To exclude the data without 
acceptable quality level to ensure the quality 
and credibility of the study outcome. 
 
Section to be changed 
 
Section 11.2 (Change 7) 
Description of change 
 
Change 7: Revising the wordings of AE and 
SAE collection and reporting section 
 
Section 11.2: Wording revised 
Collection of AEs 
The following must be collected by the 
investigator in the eCRF from start of data 
collection once informed consent is signed (if 
required, or waiver for informed consent 
obtained) onwards until the end of the study 
(end of data collection): 
 
Expedited Reporting of AEs and Drug 
Exposure During Pregnancy 
The following must be reported by the 
investigator on the NIS AE form from start of 
data collection once informed consent is 
signed (if required, or waiver for informed 
consent obtained) onwards until the end of 
the study: 
Rationale for change 
 
Change 7: To specify that data collection will 
be started after obtaining the signed informed 
consent if there is no waiver for informed 
consent given by IRB/IEC. Data collection 
can be started without obtaining signed 
informed consent when waiver for informed 
consent is obtained. 
 

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001-MCS-90-124_RD-01 (4.0) 
Number of global 
amendment 
 
2 
Date of protocol revision 
 
06-Mar-2019 
EudraCT number 
 
NA 
BI Study number 
 
1200-0286 
BI Active substance 
 
afatinib 
Title of protocol 
 
GioTag: Real-world data study on sequential 
therapy with Gi(l)otrif®/ afatinib as first-line 
treatment followed by osimertinib in patients 
with EGFR mutation positive advanced non-
small cell lung cancer 
 
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities 
 
 
To be implemented 
immediately in order to 
eliminate hazard –  
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval 
 
 
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as 
changes involve logistical or 
administrative aspects only 
 
 
 
Section to be changed 
 
Section 4 (Change 1) 
Section 6 (Change 1) 
Section 9.9 (Change 1) 
Description of change 
 
Change 1: Adding descriptions of the 
additional data collection 
 
Section 4 and Section 6: Wording added 
Note: Additional follow-up data collection 
for additional data analyses will be 
performed at least 10 months after the end 
of data collection of study primary 
outcomes. 
 
Section 9.9: Wording added 
In addition, additional data collection for 
following up the time on treatment and 
patient’s status of the sub-groups (i.e. 

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Number of global 
amendment 
 
2 
patients who were still on treatment and/or 
alive at the time of data collection) will be 
performed at least 10 months after the end 
of data collection of study primary 
outcomes. 
Rationale for change 
 
Change 1: The study enrolled patients who are 
still on treatment as long as patients started 
osimertinib treatment at least 10 months prior 
to data entry because osimertinib was 
approved by most of the regions no longer 
than 1 to 1.5 years by the time of data 
collection (See Section 9.9 for the details). 
For patients who were still under osimertinib 
treatment at the time of data collection, the 
time on treatment would be censored at the 
date of data collection.  
The additional follow-up data collection may 
provide more mature real-world data on time 
on treatment of the sequential therapy with 
afatinib (Gi(l)otrif®) followed by osimertinib. 
 
 
 
Section to be changed 
 
Title Page (Change 2) 
Section 6 (Change 2) 
Description of change 
 
Change 2: Updating the EU PAS register 
number 
 
Title Page and Section 6: Information update 
EU PAS register number: EUPAS21037 
Rationale for change 
 
Change 2: To update the EU PAS register 
number 
 
Section to be changed 
 
Section 9.8 (Change 3) 
Description of change 
 
Change 3: To clarify the quality control plan  
 
Section 9.8: Wording added 
For the further quality assurance of the 
documented patient observations, a sample-
size based source data verification will be 
performed on about 30% of included patients 
(not including the additional data collected 
for follow-up analyses). 
Rationale for change 
 
Change 3: To clarify that there will be no 
source data verification planned for the 

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additional data collection for follow-up 
analyses. 
 
Section to be changed 
 
Section 11.2 (Change 4) 
Description of change 
 
Change 4: To specify that AE reporting is not 
required during the additional data collection 
period for follow-up analyses 
 
Section 11.2: Wording revised 
Collection of AEs 
The following must be collected by the 
investigator in the eCRF from start of data 
collection once informed consent is signed (if 
required, or waiver for informed consent 
obtained) onwards until the end of data 
collection of study outcomes, but will not be 
collected during the additional data 
collection period for follow-up analysis. For 
the additional data collection period for 
follow-up analyses, study outcome events 
will be collected in the CRF only for the 
purpose of analysis. 
 all ADRs (serious and non-serious)  
 all AEs with fatal outcome 
 for Japan: an AE which possibly leads to 
disability will be reported as an SAE 
 
The investigator carefully assesses whether an 
AE constitutes an ADR using the information 
below. 
 
Section 11.2: Wording added 
Expedited Reporting of AEs and Drug 
Exposure During Pregnancy 
The following must be reported by the 
investigator on the NIS AE form from start of 
data collection once informed consent is 
signed (if required, or waiver for informed 
consent obtained) onwards until the end of the 
data collection of study outcomes: 
 
Additional data collection period for 
follow-up analyses will be performed at 
least 10 months after the end of data 

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collection of study primary outcomes. All 
subjects would have discontinued afatinib 
(Gi(l)otrif®) for 10 months prior to study 
enrollment. 
 
For the additional data collection period 
for follow-up analyses, study outcome 
events will be collected in the CRF only for 
the purpose of analysis and will not be 
collected and reported on the NIS AE form. 
 
However, the investigator is encouraged to 
report all AEs related to any BI drug other 
than afatinib (Gi(l)otrif®) according to the 
local regulatory requirements for 
spontaneous AE reporting at the 
investigator’s discretion by using the 
locally established routes and AE report 
forms. The term AE includes drug 
exposure during pregnancy, and, 
regardless of whether an AE occurred or 
not, any abuse, off-label use, misuse, 
medication error, occupational exposure, 
lack of effect, and unexpected benefit. 
Rationale for change 
 
Change 4: To clarify the AE reporting rule for 
the additional data collection period and 
specify that AEs will not be collected and 
reported on the NIS AE form during the 
additional data collection period as all 
subjects would have discontinued afatinib 
(Gi(l)otrif®). 
 
 
 

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6. 
MILESTONES 
Milestone 
Planned Date 
Start of data collection 
31 Dec 2017 
End of data collection 
31 May 2018 
Registration in the EU PAS register 
EUPAS21037 
Final report of study results: 
30 Sep 2018 
Note: Additional follow-up data collection for additional data analyses will be performed  
at least 10 months after the end of data collection of study primary outcomes. 
 

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7. 
RATIONALE AND BACKGROUND 
Metastatic epidermal growth factor receptor (EGFR)-mutant lung cancers are sensitive to 
first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib and 
afatinib (P14-03814). 
 
Afatinib is an irreversible ErbB family blocker and the first marketing approval of afatinib 
was granted on 12 Jul 2013 in the US (trade name Gilotrif®) for the indication of first-line 
treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumours 
have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an 
Food and Drug Administration (FDA)-approved test. It was approved in the European Union 
(EU) on 25 Sep 2013 (trade name Giotrif®) as monotherapy indicated for the treatment of 
EGFR TKI-naïve adult patients with locally advanced or metastatic NSCLC with activating 
EGFR mutation(s). In total, marketing authorisation for Gi(l)otrif® has been granted in 70 
other countries world-wide as of today (c01802941-10). 
 
On the clinical trials LUX-Lung 3 (P13-07382), LUX-Lung 6 (P14-00758) and LUX-Lung 7 
(P16-04350), afatinib (Gi(l)otrif®) showed a median progression-free survival (PFS) of 11.1, 
11.1 and 13.6 months, respectively, for patients with EGFR common mutations (Del19 and 
L858R) treatment-naïve. Time to treatment failure in LUX-Lung 7 was 13.7 months. 
Eventually, resistance develops for most patients and the most common mechanism of 
resistance to EGFR TKIs (>50%) is the emergence of a second-site EGFR-mutation, the 
T790M (R15-6101, P09-09950). 
Explorative analysis of LUX-Lung 7 showed a median overall survival of not being reached 
for patients who started with afatinib (Gi(l)otrif®) and received subsequently osimertinib or 
olmutinib (follow-up period of 42.6 months) indicating a long-time benefit from this 
sequence (P16-13901). 
 
Osimertinib, a third generation EGFR TKI, was approved for patients whose tumours have 
developed the EGFR T790M mutation by several countries. The first marketing approval of 
osimertinib was granted on 13 Nov 2015 in the US (R16-5838). The EU and Japan also gave 
a similar approval on 03 Feb 2016 and 29 Mar 2016 separately (P16-15191, P16-15190).  
 
In addition, osimertinib has been studied in the first-line treatment in an expansion cohort 
from AURA trial, whose reported result looked promising (median PFS for the 80 mg cohort 
had not yet been reached but for the 160 mg cohort was shown to be 19.3 months)  
(R16-5840). Confirmation of these results in a phase III randomized trial is still needed to 
define the role of osimertinib in the treatment of patients with EGFR mutation-positive. 
FLAURA is comparing osimertinib to either gefitinib or erlotinib in EGFR mutant NSCLC 
treatment naïve patients and results are expected to be presented during 2017 (R16-5841). 
 
Whether osimertinib will extend PFS versus available therapies if used as front-line therapies 
remains unknown. Investigating in this real-world data (RWD) study the time from start of 
first-line afatinib (Gi(l)otrif®) until the end of second-line osimertinib in this study provides 
insights on treatment sequence that can inform on the most beneficial treatment sequence for 
the patients. 

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8. 
RESEARCH QUESTION AND OBJECTIVES 
Data from real-world setting would inform on the most beneficial treatment sequence in 
patients diagnosed with advanced EGFR mutation-positive NSCLC. 
 
Primary objective: 
To determine the time on treatment of afatinib (Gi(l)otrif®) as first-line therapy in patients 
with EGFR mutation-positive NSCLC followed by osimertinib in case the T790M resistance 
mutation was developed in real-world setting. Time on treatment is defined from the start of 
the first-line treatment until the end of the second-line treatment or death date by any cause. 
 
Secondary objective: 
To collect data on acquired resistance mechanism to osimertinib. 

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9. 
RESEARCH METHODS 
9.1 
STUDY DESIGN 
This is a non-interventional, multi-country, multi-centre cohort study based on existing data 
from medical records of patients with EGFR mutation-positive advanced NSCLC treated 
with afatinib (Gi(l)otrif®) as the first-line treatment followed by osimertinib in case the 
T790M resistance mutation was developed.  
 
In total, at least 190 eligible patients are planned to be enrolled to this study. 
 
Key study outcome: 
 
The time on treatment with afatinib (Gi(l)otrif®) followed by osimertinib.  
 
9.2 
SETTING 
It is planned that around 65 study centres in 11 countries will be participating in this non-
interventional study and at least 190 consecutive eligible patients will be enrolled to the 
study. Every patient who fulfils inclusion and exclusion criteria and agree to participate in the 
study (if a written informed consent is required for this NIS by local regulation and legal 
requirement) will be selected until the required sample size is achieved. Deceased patients 
should be enrolled whenever possible. This has to be discussed with the local authorities. It is 
expected that approximately 3 patients will be enrolled at each study centre. Investigators 
who fail to enrol at least one patient in the first 8 weeks of the study may be excluded from 
further participation. If enrolment is delayed additional countries and centres may be 
recruited. 
 
To avoid differential centre influence on study results, permission to enrol more than 15 
patients per site must be obtained from the TCM. 
 
Recruiting of patients for this study is competitive, i.e., recruitment will stop at all centres 
when it is determined that a sufficient number of patients have been enrolled. Investigators 
will be notified when the appropriate number of patients has been enrolled and recruitment is 
complete, and will not be allowed to recruit additional patients for this study.  
 
9.2.1 
Selection of study population 
Site selection: 
Sites in countries meeting the criteria below: 
 
Sites in countries with afatinib launch dates prior to 01 Jan 2015 and known to prescribe 
afatinib (Gi(l)otrif®) on a regular basis 
 
Osimertinib used in patients with EGFR T790M mutation-positive NSCLC within an 
early access program/ compassionate use program (EAP/CUP) or regular clinical 
practice; osimertinib provided via a clinical trial is not permitted. 
 
Inclusion criteria: 

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1. Patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) 
2. The tumour harbours common EGFR mutations (Del19, L858R) at start of first-line 
treatment 
3. Patients who initiated second-line osimertinib treatment for acquired T790M mutation at 
least 10 months prior to data entry, AND who were treated with afatinib (Gi(l)otrif®) in 
the first-line 
4. Patients treated with osimertinib within an EAP/CUP or regular clinical practice 
5. Age ≥ 18 years 
6. Signed and dated written informed consent per regulations (Exemption of a written 
informed consent for NIS based on existing data in countries per local regulations and 
legal requirements) 
 
Exclusion criteria: 
1. Patients who received drug(s) other than osimertinib as the second-line treatment and/or 
patients who received drug(s) other than afatinib (Gi(l)otrif®) as the first-line treatment 
2. Patients with active brain metastases at start of treatment (either afatinib/Gi(l)otrif® or 
osimertinib) 
 
Patients treated with afatinib (Gi(l)otrif®) and/or osimertinib in interventional trials are 
excluded to ensure the non-interventional setting of this study. Real-world studies such as 
ASTRIS are not affected by this exclusion (R17-0754). The threshold of start of osimertinib 
at least 10 months prior to data entry was chosen based on the median PFS result of AURA-3  
(R17-0221) to avoid early censoring and enable collection of mature data on adverse drug 
reactions (ADRs) and treatment duration. All patients fulfilling inclusion and exclusion 
criteria from a site will be entered to avoid bias. 
 
A log of all patients included into the study will be maintained in the ISF at the 
investigational site. 
 
BI reserves the right to discontinue the study overall or at a particular study site at any time 
for the following reasons: 
1. Failure to meet expected enrolment goals overall or at a particular study site. 
2. Violation of Good Clinical Practice (GCP) (as applicable), the Study Protocol, or the 
contract by a study site or investigator, disturbing the appropriate conduct of the 
study. 
 
9.3 
VARIABLES 
The following data will be collected from medical records and will be recorded in the 
electronic case report form (eCRF) by investigators (or designees) during the study period: 
 
Informed consent 
 
Demographics: age at start of afatinib (Gi(l)otrif®) treatment, gender, ethnicity 
 
Stage of disease (IIIb or IV) at start of afatinib (Gi(l)otrif®) treatment 
 
Type of mutations at initial diagnosis 
 
Sites of metastases at start of afatinib (Gi(l)otrif®) treatment 
 
Body weight and height at start of afatinib (Gi(l)otrif®) treatment 

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 
Eastern Cooperative Oncology Group (ECOG) performance score (PS) (if available) at 
start of afatinib (Gi(l)otrif®) treatment 
 
Date of start and end of afatinib (Gi(l)otrif®) treatment  
 
Starting dose of afatinib (Gi(l)otrif®) 
 
Afatinib (Gi(l)otrif®) dose modification(s) and date(s)  
 
ECOG PS (if available) at start of osimertinib treatment 
 
Type of mutations at start of osimertinib treatment 
 
Sites of metastases at start of osimertinib treatment 
 
Date of start and end of osimertinib treatment 
 
Starting dose of osimertinib 
 
Osimertinib dose modification(s) and date(s)  
 
Reason for discontinuation of each treatment (e.g. progressive disease (PD), adverse 
event (AE)) 
 
If osimertinib was provided within an EAP/CUP or prescribed as clinical practice 
 
ADRs 
 
AEs with fatal outcome 
 
Type of mutations at stop of osimertinib if available (EGFR mutations: T790M, C797S 
[if positive: in cis or in trans], Del19, L858R, other EGFR sensitizing mutation (to be 
specified), non-EGFR: to be specified) (R16-1552, P15-11024) 
 
Date of death (if available) 
 
9.3.1 
Exposures 
Afatinib (Gi(l)otrif®): 
Patients were treated with afatinib (Gi(l)otrif®) 50mg or 40mg or 30mg or 20mg tablet once 
daily as indicated in the approved labels of afatinib (Gi(l)otrif®). 
 
Osimertinib: 
Patients were/are treated with osimertinib 80 mg or 40 mg tablets once daily as indicated in 
the approved labels of osimertinib.  
Patients who started osimertinib treatment at least 10 months prior to data entry are eligible. 
 
The Summaries of Product Characteristics on Gi(l)otrif® and Osimertinib are contained in the 
ISF in the “Summary of Product Characteristics” (SmPC) section. 
 
9.3.2 
Outcomes 
9.3.2.1 
Primary outcomes 
Time on treatment with afatinib (Gi(l)otrif®) followed by osimertinib. This will be assessed 
as the time from start of afatinib (Gi(l)otrif®) as first-line treatment until the end of the 
second-line treatment (the last dose of osimertinib) or death date by any cause. 
9.3.2.2 
Secondary outcomes 
Type and proportion of acquired resistance mutations after osimertinib. 

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9.3.3 
Covariates 
NA 
 
9.4 
DATA SOURCES 
Data will be collected from patients’ medical records and recorded in (e)CRFs.  
 
9.4.1 
Source documents 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. 
The investigator may need to request previous medical records or transfer records, current 
medical records must be available. 
 
For (e)CRFs all data must be derived from source documents. 
 
9.4.2 
Records 
Case Report Forms (CRFs) for individual patients will be provided by the sponsor or 
appointed CRO via remote data capture (RDC) system or Electronic Data Capture (EDC) 
system. 
 
9.4.3 
Direct access to source data and documents 
The investigator / institution will permit study-related monitoring, audits, Institutional 
Review Board (IRB) / Independent Ethics Committee (IEC) review and regulatory 
inspection, providing direct access to all related source data / documents. eCRFs and all 
source documents, including progress notes and copies of laboratory and medical test results 
must be available at all times for review by the sponsor’s clinical study monitor, auditor and 
inspection by health authorities (e.g. FDA). The CRA/on site monitor and auditor may review 
all eCRFs, and written informed consents (if applicable). The accuracy of the data will be 
verified by reviewing the documents described in Section 9.4.1. 
 

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9.4.4 
Storage of records 
Study site (s): 
The study site(s) must retain the source documents and essential documents (including ISF) 
according to contract or the local requirements valid at the time of the end of the study 
(whatever is longer). 
 
Sponsor:  
The sponsor must retain the essential documents according to the sponsor’s SOPs. 
 
9.5 
STUDY SIZE 
It is assumed that the median time on treatment from start of the first-line treatment until the 
end of the second-line treatment or death date by any cause is 24 months (based on: 13.6 
months median PFS with afatinib (Gi(l)otrif®) in LUX-Lung 3, 13.7 months time to treatment 
failure with afatinib (Gi(l)otrif®) in LUX-Lung 7 plus 10.1 months median PFS of 
osimertinib in AURA-3, 13.2 months in the AURA study phase 2 extension component) 
(P17-01960, P17-03000). Based on the assumption that time on treatment follows an 
exponential distribution, a sample size of 171 patients are expected to ensure at 80% chance 
to observe a width of the 90% confidence interval of median time on treatment smaller or 
equal to 10 months, which is considered as a reasonable estimation precision. Assuming 10% 
of censored observations a total of 190 patients are included in the study. 
 
9.6 
DATA MANAGEMENT 
Data will be gathered in Remote Data Capture (RDC) system or Electronic Data Capture 
(EDC) system prepared by sponsor or appointed CRO. The details of data management 
procedures to ensure the quality of the data will be described in the Statistical and 
Epidemiological Analysis Plan (SEAP) available in eTMF. 
 
9.7 
DATA ANALYSIS 
9.7.1 
Main analysis 
The primary endpoint is time on treatment, which is defined as time in months from the start 
of date of afatinib (Gi(l)otrif®) treatment to the end date of osimertinib treatment or death 
date due to any cause. Time on treatment will be analysed using Kaplan-Meier method, and 
the median along with two-sided 90% confidence interval will be displayed (use the 
Greenwood’s formula for estimation of standard errors). 
In the analyses of time-to-event endpoint, missing or incomplete data are managed by 
standard survival analysis techniques. For patient still on treatment, time on treatment will be 
censored at the date of data collection. We do not expect missing start dates of afatinib 
(Gi(l)otrif®) treatment.  
 
Baseline conditions and demographics will be analysed with descriptive statistics. The 
frequency of treatment interruption and dose reduction of both afatinib (Gi(l)otrif®) and 

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osimertinib will be summarized through descriptive statistics. This descriptive non-
interventional study based on existing data is conducted within the conditions of the approved 
marketing authorization and there is no intention to analyse the safety data collected 
retrospectively in the study as part of the study analysis. The safety data from this study will 
be reviewed and analysed as part of routine global pharmacovigilance processes.  
 
9.8 
QUALITY CONTROL 
All entries in the eCRF will be stored in a database. The structure of the database is based on 
the division into sections and entry fields defined in the eCRF. To improve and ensure data 
quality, data checks will be performed automatically in the eCRF directly on electronic entry 
at the study site. 
 
Plausible value ranges for numerical data entries and logical data and list entries will be filed 
in the eCRF. The tests for consistency and completeness based on this will be performed 
during entry in the eCRF. The validity of the recorded data will therefore be ensured by the 
validations incorporated in the documentation system, which highlight incorrect or 
implausible entries to the data entry clerk/doctor. 
 
If corrections are necessary after the data are saved, these will be documented in an audit 
trail. 
For the further quality assurance of the documented patient observations, a sample-size based 
source data verification will be performed on about 30% of included patients (not including 
the additional data collected for follow-up analyses).   
 
Patient replacement may be considered if there are major quality issues identified from the 
collected data. The decision of whether or not to enforce a patient replacement will be made 
by the sponsor/study team after evaluations. Data of the replaced patients will not be included 
in the final data analysis. 
 
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by Institutional Review Boards/ Independent Ethics Committees 
(IRBs/IECs) or by regulatory authorities. The quality assurance auditor will have access to all 
medical records, the investigator’s study-related files and correspondence, and the informed 
consent documentation of this study. 
 
9.9 
LIMITATIONS OF THE RESEARCH METHODS 
Potential limitations of the study design: 
1. Site selection: 

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The study is restricted to the sites using afatinib (Gi(l)otrif®) on a regular basis and to the 
sites which are able to use osimertinib for T790M mutation tumours. By the time of data 
collection, osimertinib has been approved (and reimbursed) in most regions not longer than 1 
to 1.5 years, which limits the number of patients being treated with osimertinib.  
To overcome this feasibility limitation, patients who have received osimertinib treatment 
within an EAP/CUP are eligible as well as patients who started osimertinib treatment at least 
10 months prior to data entry, increasing the pool of eligible sites and potential patients.  
In addition, additional data collection for following up the time on treatment and patient’s 
status of the sub-groups (i.e. patients who were still on treatment and/or alive at the time of 
data collection) will be performed at least 10 months after the end of data collection of study 
primary outcomes.  
 
2. Patient population: 
Firstly, there is an immortal time bias as patients that die on afatinib (Gi(l)otrif®) will not be 
included in this study. Because of that immortal time bias, the results of the study (i.e. median 
duration from start of afatinib (Gi(l)otrif®) until the end of osimertinib) will not be 
generalizable to all patients starting first line treatment with afatinib (Gi(l)otrif®). 
 
Secondly, there is some bias as patients with long-term benefit from afatinib (Gi(l)otrif®) 
have a lower likelihood of being included in this study. Because of bias, the results of the 
study (i.e. median duration from start of afatinib (Gi(l)otrif®) until the end of osimertinib) 
will not be generalizable to all patients starting first-line treatment with afatinib (Gi(l)otrif®). 
 
Thirdly, the treatment approach investigated in this non-interventional study (NIS) provides a 
treatment solution for around 50% of the patients who start with afatinib (Gi(l)otrif®) 
treatment (as only these are expected to develop the acquired resistance T790M following an 
EGFR TKI). Currently, patients who did not acquired the T790M resistance mutation seems 
to be treated heterogeneously with no available standard of treatment so these patients are not 
included in this non-interventional study.  
 
This study has no comparator group limiting the interpretability of the results as they cannot 
be put into perspective. The only reasonable control group could be patients treated with the 
sequence of first-line osimertinib followed by afatinib (Gi(l)otrif®) however this group does 
not exist in real clinical practice as frontline use of osimertinib in EGFR-mutant NSCLC is 
not currently approved.  
 
9.10 
OTHER ASPECTS 
9.10.1 
Statement of confidentiality 
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient privacy will be ensured by using patient identification code numbers. 
 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principle 6 and 12 of the World Health 
Organisation (WHO) GCP handbook. 

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Data generated as a result of the study need to be available for inspection on request by the 
participating investigators, the sponsor’s representatives, by the IRB/IEC and the regulatory 
authorities. 
 
9.10.2 
Patient completion 
The collection of the data of patients will continue until end of data collection or withdrawal 
of consent (if applicable) which occurs first. 
 
9.10.3 
Completion of study 
The end of the study will occur when the end of data collection of the last patient’s data. No 
further data will be collected afterwards. 
 
<For Japan> 
When the study is completed, the principal investigator should inform the head of the study 
site of the completion in writing, and the head of the study site should promptly inform the 
IRB and sponsor of the completion in writing. 
 
<For EU member states> 
The IEC/ competent authority (CA) in each participating EU member state will be notified 
about the study milestones according to the respective laws.  
A final report of study data will be written only after all patients have completed the study in 
all countries (EU or non-EU) to incorporate and consider all data in the report. 
The sponsor will submit to the EU database a summary of the final study results within one 
year from the end of a study as a whole, regardless of the country of the last patient (EU or 
non-EU). 
 
9.11 
SUBJECTS 
Please refer to Section 9.2.1 Section of study population. 
 
9.11.1 
Cases 
NA 
 
9.11.2 
Controls 
NA 
 

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9.12 
BIAS 
Methodological efforts have been taken to minimize selection bias: these efforts including 
only consecutive patients meeting each of the inclusion criteria and none of the exclusion 
criteria.  
 
ECOG PS might not be recorded in all medical records and it means that not only patients 
with good performance status (PS 0-1) will be included in this study.  
 
In addition, the study is not including the impact of the patients who died during first-line 
treatment, introducing immortal time bias. Based on clinical trials LUX-Lung 3 and LUX-
Lung 6, from the 6% of the patients who have died during afatinib (Gi(l)otrif®) treatment, 
assuming that on 50% of those the T790M mutation would be detected, this NIS analysis is 
excluding results of 3% of the patients (who started the first-line treatment but did not reach 
the second-line treatment), which is not expected to be a significant impact on the study 
results. There is some bias as patients with long-term benefit from afatinib (Gi(l)otrif®) have 
a lower likelihood of being included in this study. Please refer to the Section 9.9 for the 
details.  

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10. 
PROTECTION OF HUMAN SUBJECTS 
10.1 
DATA PROTECTION AND STUDY RECORDS 
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the International Conference on Harmonisation 
(ICH) Harmonized Tripartite Guideline for GCP (to the extent applicable to the NIS setting 
and required by local regulations), Good Epidemiological Practice (GEP), Guidelines for 
Good Pharmacoepidemiology Practice (GPP), and relevant BI SOPs <For Japan> and the 
Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 
1997. Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in 
the responsibility of the treating investigator of the patient. 
 
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol, ICH GCP <For Japan> and the Japanese GCP regulations (Ministry of Health 
and Welfare Ordinance No. 28, March 27, 1997).. 
 
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalisation of the Study Report. 
 
10.1.1 Study approval, patient information, and informed consent 
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB / IEC and competent authority (CA) according to national 
and international regulations. The same applies for the implementation of changes introduced 
by amendments. 
 
In some countries, NIS based on existing data can be exempt from a written informed consent 
per local regulations and legal requirements, IRB / IEC often grants a waiver of consent for 
retrospective chart review studies. In order to avoid bias by exclusion of subjects that cannot 
be given informed consent for any reason like death, missing contact information etc., exempt 
from a written informed consent should be asked for such situations. Additionally, permission 
to include deceased patients should be requested by the local authorities. 
 
In case such a waiver is not given, prior to patient participation in the study, written informed 
consent must be obtained from each patient (or the patient’s legally accepted representative) 
according to ICH GCP and to the regulatory and legal requirements of the participating 
country. 
 
Each signature must be personally dated by each signatory and the informed consent and any 
additional patient-information form retained by the investigator as part of the study records. 
A signed copy of the informed consent and any additional patient information must be given 
to each patient or the patient’s legally accepted representative. 
 

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The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML / CRA or CRO monitors) or Clinical Quality Assurance auditors appointed 
by Boehringer Ingelheim, by appropriate IRB / IEC members, and by inspectors from 
regulatory authorities. 
 
10.2 
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
STUDY RELATED INJURY 
In the event of health injury associated with marketed product in routine medical practice, the 
sponsor is not responsible for compensation. 

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11. 
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS 
11.1 
DEFINITIONS OF ADVERSE EVENTS 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment.  
 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
 
Adverse reaction 
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors. 
 
Serious adverse event 
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria: 
- results in death, 
- is life-threatening,  
- requires in-patient hospitalization, or 
- requires prolongation of existing hospitalisation, 
- results in persistent or significant disability or incapacity, or 
- is a congenital anomaly/birth defect, 
 
Life-threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe. 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction. 
 
For Japan, an AE which possibly leads to disability will be reported as an SAE. 
 
 

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Adverse Event of Special Interest (AESI) 
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this 
study, e.g. the potential for AEs based on knowledge from other compounds in the same 
class.  
 
No AESIs have been defined for this study. 
 
11.2 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING 
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
 
Collection of AEs 
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorization. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug. For this reason the following AE collection and reporting requirements have 
been defined. 
 
The following must be collected by the investigator in the eCRF from start of data collection 
once informed consent is signed (if required, or waiver for informed consent obtained) 
onwards until the end of data collection of study outcomes, but will not be collected during 
the additional data collection period for follow-up analysis. For the additional data collection 
period for follow-up analyses, study outcome events will be collected in the CRF only for the 
purpose of analysis. 
 
 all ADRs (serious and non-serious)  
 all AEs with fatal outcome 
 for Japan: an AE which possibly leads to disability will be reported as an SAE 
 
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below. 
 
Causal relationship of AEs 
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event (AE). An adverse 
reaction, in contrast to an AE, is characterized by the fact that a causal relationship between a 
medicinal product and an occurrence is suspected. 
 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
 
Arguments that may suggest a reasonable causal relationship could be: 
 
The event is consistent with the known pharmacology of the drug 

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 
The event is known to be caused by or attributed to the drug class. 
 
A plausible time to onset of the event relative to the time of drug exposure. 
 
Evidence that the event is reproducible when the drug is re-introduced 
 
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications). 
 
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome). 
 
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished). 
 
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be: 
 
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned) 
 
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). 
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger. 
 
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned). 
 
Disappearance of the event even though the study drug treatment continues or 
remains unchanged. 
 
Intensity of AEs 
The intensity of the AE should be judged based on the following: 
Mild:  
Awareness of sign(s) or symptom(s) which is/are easily tolerated 
Moderate: 
Enough discomfort to cause interference with usual activity 
Severe: 
Incapacitating or causing inability to work or to perform usual activities 
 
Pregnancy 
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the 
study, after having taken afatinib (Gi(l)otrif®) the investigator must report any drug exposure 
during pregnancy, which occurred in a female subject or in a partner to a male subject to the 
Sponsor by means of Part A of the Pregnancy Monitoring Form. The outcome of the 
pregnancy associated with the drug exposure during pregnancy must be followed up and 
reported by means of Part B of the Pregnancy Monitoring Form. 
The ISF will contain the Pregnancy Monitoring Form for Studies (Part A and Part B). 
 
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed, 
otherwise the NIS AE form is to be completed and forwarded as well within the respective 
timelines. 
 

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Expedited Reporting of AEs and Drug Exposure During Pregnancy 
The following must be reported by the investigator on the NIS AE form from start of data 
collection once informed consent is signed (if required, or waiver for informed consent 
obtained) onwards until the end of data collection of study outcomes: 
 
Additional data collection period for follow-up analyses will be performed at least 10 months 
after the end of data collection of study primary outcomes. All subjects would have 
discontinued afatinib (Gi(l)otrif®) for 10 months prior to study enrollment. 
 
For the additional data collection period for follow-up analyses, study outcome events will be 
collected in the CRF only for the purpose of analysis and will not be collected and reported 
on the NIS AE form. 
 
However, the investigator is encouraged to report all AEs related to any BI drug other than 
afatinib (Gi(l)otrif®) according to the local regulatory requirements for spontaneous AE 
reporting at the investigator’s discretion by using the locally established routes and AE report 
forms. The term AE includes drug exposure during pregnancy, and, regardless of whether an 
AE occurred or not, any abuse, off-label use, misuse, medication error, occupational 
exposure, lack of effect, and unexpected benefit. 
 
Type of Report 
Timeline 
All Serious Adverse Drug Reactions 
(SADRs) associated with afatinib (Gi(l)otrif®) 
immediately within 24 hours 
All AEs with fatal outcome in patients 
exposed to afatinib (Gi(l)otrif®) 
immediately within 24 hours 
For Japan: AE which possibly leads to disability in 
patients exposed to afatinib (Gi(l)otrif®) 
immediately within 24 hours 
All non-serious ADRs associated with afatinib 
(Gi(l)otrif®) 
7 calendar days 
All pregnancy monitoring forms 
7 calendar days 
 
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions the physician could inform the sponsor upfront via telephone. 
This does not replace the requirement to complete and fax the NIS AE form. 
 
Information required 
For each reportable AE, the investigator should provide the information requested on the 
appropriate eCRF pages and the NIS AE form. 
 
Reporting of related AEs associated with any other BI drug 
The investigator is encouraged to report all AEs related to any BI drug other than Gi(l)otrif® 
according to the local regulatory requirements for spontaneous AE reporting at the 
investigator’s discretion by using the locally established routes and AE report forms. The 
term AE includes drug exposure during pregnancy, and, regardless of whether an AE 
occurred or not, any abuse, off-label use, misuse, medication error, occupational exposure, 

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lack of effect, and unexpected benefit. 
 
11.3 
REPORTING TO HEALTH AUTHORITIES 
Adverse event reporting to regulatory agencies will be done by the Marketing Authorization 
Holder (MAH) according to local and international regulatory requirements.  

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12. 
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS 
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalisation of the Study Report. 
 
BI intends to use data from this study to prepare peer-reviewed publications and other 
scientific communications such as abstracts, posters, and podiums presentations. 
 

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13. 
REFERENCES 
13.1 
PUBLISHED REFERENCES  
R15-6101 
Arcila ME, Oxnard GR, Nafa K, Riely GJ, Solomon SB, Zakowski MF, 
Kris MG, Pao W, Miller VA, Ladanyi M. Rebiopsy of lung cancer patients 
with acquired resistance to EGFR inhibitors and enhanced detection of the 
T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res 
17 (5), 1169-1180, 2011. 
R16-1552 
Thress KS, Paweletz CP, Felip E, et al. Acquired EGFR C797S mutation 
mediates resistance to AZD9291 in non-small cell lung cancer harbouring 
EGFR T790M. Nat Med., 21: 560-562, 2015. 
R16-5838 
AstraZeneca PLC. TAGRISSO™ (AZD9291) approved by the US FDA 
for patients with EGFR T790M mutation-positive metastatic non-small cell 
lung cancer. Issued on November 13th 2015. Available at: 
https://www.astrazeneca.com/media-centre/press-
releases/2015/TAGRISSO-AZD9291-approved-by-the-US-FDA-for-
patients-with-EGFR-T790M-mutation-positive-metastatic-non-small-cell-
lung-cancer-13112015.html 
R16-5840 
Ramalingam S, Yang JC, Lee CK, Kurata T, Kim DW, John T, Nogami N, 
Ohe Y, Jänne PA. LBA1_PR: Osimertinib as first-line treatment for EGFR 
mutation-positive advanced NSCLC: updated efficacy and safety results 
from two Phase I expansion cohorts. J Thorac Oncol Vol. 11, Suppl. 4S, 
S152-S155, 2016.  
R16-5841 
National Institutes of Health. AZD9291 Versus Gefitinib or Erlotinib in 
Patients With Locally Advanced or Metastatic Non-small Cell Lung 
Cancer (FLAURA). Available at: 
https://clinicaltrials.gov/ct2/show/NCT02296125?term=FLAURA&rank=1 
R17-0221 
Susan Mayor. Osimertinib effective in EGFR T790M-positivelung cancer. 
The Lancet Oncol, Vol. 18, No. 1, e9, 2017. 
R17-0754 
Real World Treatment Study of AZD9291 for Advanced/Metastatic EGFR 
T790M Mutation NSCLC (ASTRIS). Available at: 
https://clinicaltrials.gov/ct2/show/NCT02474355  
P09-09950 
Nguyen KS, Kobayashi S, Costa DB. Acquired resistance to epidermal 
growth factor receptor tyrosine kinase inhibitors in non-small-cell lung 
cancers dependent on the epidermal growth factor receptor pathway. Clin 
Lung Cancer 10 (4), 281-289, 2009. 
 
 
 
P13-07382 
Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater 
SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova 

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V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase 
III study of afatinib or cisplatin plus pemetrexed in patients with metastatic 
lung adenocarcinoma with EGFR mutations. J Clin Oncol 31 (27), 3327 – 
3334, 2013. 
P14-00758 
Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, 
Lee KY, Xu CR, Massey D, Kim M, Shi Y, Geater SL. Afatinib versus 
cisplatin plus gemcitabine for first-line treatment of Asian patients with 
advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-
Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 15 (2), 
213-222, 2014. 
P14-03814 
Sebastian M, Schmittel A, Reck M. First-line treatment of EGFR-mutated 
nonsmall cell lung cancer: critical review on study methodology. European 
Respiratory Review 23 (131), 92-105, 2014. 
P15-11024 
Niederst MJ, Hu H, Mulvey HE, Lockerman EL, Garcia AR, Piotrowska Z, 
Sequist LV and Engelman JA. The allelic context of the C797S mutation 
acquired upon treatment with third-generation EGFR inhibitors impacts 
sensitivity to subsequent treatment strategies. Clin Cancer Res. 21 (17), 
3924-3933, 2015. 
P16-04350 
Park K, et al. Afatinib versus gefitinib as first-line treatment of patients 
with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a 
phase 2B, open-label, randomised controlled trial. Lancet Oncol 17 (5), 
577-589, 2016. 
P16-13901 
Paz-Ares L, Tan EH, Zhang L, Hirsh V, O'Byrne K, Boyer M, et al. 
Afatinib vs gefitinib in patients with EGFR mutation-positive (EGFRm+) 
non-small-cell lung cancer (NSCLC): overall survival (OS) data from the 
phase IIb trial LUX-Lung 7 (LL7). Abstract # LBA43 presented at the 41st 
Ann Cong of the European Society for Medical Oncology (ESMO), 
Copenhagen, 7 - 11 Oct 2016. 
P16-15190 
AstraZeneca PLC. Tagrisso™ (osimertinib) approved in Japan for patients 
with EGFR T790M mutation-positive metastatic non-small cell lung 
cancer. Issued on March 29th 2016. Available at: 
https://www.astrazeneca.com/media-centre/press-releases/2016/tagrisso-
approved-in-japan-for-patients-with-egfr-t790m-mutation-positive-
metastatic-non-small-cell-lung-cancer-29032016.html 
P16-15191 
AstraZeneca PLC. TAGRISSO™ (osimertinib) approved in EU as first-in-
class treatment for patients with EGFR T790M mutation-positive 
metastatic non-small cell lung cancer. Issued on February 3rd 2016. 
Available at: https://www.astrazeneca.com/media-centre/press-
releases/2016/tagrisso-osimertinib-approved-in-eu-as-first-in-class-
treatment-for-lung-cancer-03022016.html 

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P17-01960 
Mok TS., Wu YL., Ahn MJ, Garassino MC, Kim HR, et al. Osimertinib or 
platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J 
Med, 376:629-640, February 16, 2017. 
P17-03000 
Yang JC, Ahn MJ, Kim DW, Ramalingam SS, Sequist LV, et al. 
Osimertinib in pretreated T790M-positive advanced non-small-cell lung 
cancer: AURA study phase II extension component. J Clin Oncol 35, 2017 
by American Society of Clinical Oncology. 
 
13.2 
UNPUBLISHED REFERENCES 
c01802941-10 
Investigator’s Brochure (IB): Afatinib (BIBW 2992), Indication: Oral 
Treatment of 
Cancer,1200.P1/1200.P2/1200.P3/1200.P4/1200.P5/1200.P6 
/1200.P7/1200.P8/1200.P9/1200.P10, Version 16, 06 Jul 2015 
 

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS 
1. Informed Consent Form 
2. Statistical and Epidemiological Analysis Plan (SEAP) 
 
The stand-alone documents listed above will be archived in the electronic Trial Master File. 
 

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ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS 
 
 

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ANNEX 3. ADDITIONAL INFORMATION 
ANNEX 3.1 ECOG PERFORMANCE STATUS 
 
Grade 
Definition 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, office 
work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours 
4 
Completely disabled, cannot carry on any self-care, totally confined to bed 
or chair 
5 
Dead