UpSwinG: Real World Study on TKI Activity in Uncommon Mutations and Sequencing Giotrif®
Conditions: Non-squamous, Non-Small Cell Lung Cancer
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-124_RD-01 (4.0)
TITLE PAGE
Protocol for non-interventional studies based on existing data
Document Number:
c28110847-03
BI Study Number:
1200-0316
BI Investigational
Product(s):
Gi(l)otrif® (afatinib)
Title:
UpSwinG: Real World study on TKI activity in Uncommon 
mutations and Sequencing Giotrif®
Lay Title:
The study observes how long patients with non-small cell lung 
cancer (NSCLC) benefit from treatment with Epidermal Growth 
Factor Tyrosine Kinase Inhibitor (EGFR-TKI) when given either 
for uncommon mutations or for common mutations in the 
sequence afatinib followed by osimertinib
Protocol version 
identifier:
3.0
Date of last version of 
protocol:
23 July 2019
PASS:
Yes
EU PAS register 
number:
EUPAS32098
Active substance:
Afatinib (ATC code: L01XE13), gefitinib (L01XE02), erlotinib
(L01XE03), osimertinib (L01XE35), Antineoplastic agents, 
tyrosine kinase inhibitors
Medicinal product:
Gi(l)otrif®: 50mg, 40mg, 30mg, 20mg tablet
IRESSA®: 250mg tablet
Tarceva®: 25mg, 100mg, 150mg tablet
Tagrisso®: 40mg, 80mg
Product reference:
Gi(l)otrif®:
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
IRESSA®:
250mg: EU/1/09/526/001, EU/1/09/526/002
Tarceva®:
25mg: EU/1/05/311/001
100mg: EU/1/05/311/002
150mg: EU/1/05/311/003
Tagrisso®:
40mg: EU/1/16/1086/001, EU/1/16/1086/003
80mg: EU/1/16/1086/002, EU/1/16/1086/004

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1200-0316
c28110847-03
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Procedure number:
Gi(l)otrif® : EMEA/H/C/002280
IRESSA®: EMEA/H/C/001016
Tarceva®: EMEA/H/C/000618
Tagrisso®: EMEA/H/C/004124
Joint PASS:
No
Research question and 
objectives:
Data from real-world setting would inform on the beneficial 
treatments in patients diagnosed with advanced NSCLC 
harbouring uncommon EGFR mutations and on the treatment 
sequence in patients diagnosed with advanced common EGFR 
mutation NSCLC.
Primary objective:
For both cohorts the study aims to describe the time on treatment 
until its end or death. 
More specifically, this will be evaluated for each cohort as 
follows:
Uncommon mutation cohort
To determine the time on treatment of EGFR-TKIs as first or 
second line therapy in NSCLC with uncommon Epidermal 
Growth Factor Receptor (EGFR) mutations. Time on treatment 
is defined from the start of EGFR-TKI until the end of EGFR-
TKI treatment or death date by any cause.
Sequencing cohort:
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. 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 objectives:
To determine overall survival and time on treatment until failure 
of second-line (uncommon mutation cohort only). To determine
overall response rate, and describe methodology and the material 
(liquid vs tissue) used for detection of uncommon/T790M 
mutation, These endpoints will be analysed descriptively.
Country(-ies) of study:
Up to 11 countries will participate in this study
Author:
Tel.:
Mobil:
Fax:
email:

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1200-0316
c28110847-03
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Marketing authorisation 
holder(s):
Date:
20 June 2020
Page 1 of 60
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 1200-0316
c28110847-03
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 4
2.
LIST OF ABBREVIATIONS................................................................................ 6
3.
RESPONSIBLE PARTIES.................................................................................... 7
4.
ABSTRACT........................................................................................................... 8
5.
AMENDMENTS AND UPDATES..................................................................... 16
6.
MILESTONES..................................................................................................... 22
7.
RATIONALE AND BACKGROUND................................................................ 23
7.1 UNCOMMON MUTATION COHORT............................................................... 24
7.2 SEQUENCING COHORT.................................................................................... 26
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 28
9.
RESEARCH METHODS .................................................................................... 29
9.1
STUDY DESIGN............................................................................................ 29
9.2
SETTING........................................................................................................ 29
9.2.1
Selection of study population.................................................................. 29
9.3
VARIABLES .................................................................................................. 31
9.3.1
Exposures ................................................................................................ 32
9.3.2
Outcomes................................................................................................. 32
9.3.2.1
Primary outcomes..................................................................................32
9.3.3
Covariates................................................................................................ 33
9.4
DATA SOURCES........................................................................................... 33
9.4.1
Source documents ................................................................................... 33
9.4.2
Records.................................................................................................... 33
9.4.3
Direct access to source data and documents ........................................... 33
9.4.4
Storage of records.................................................................................... 33
9.5
STUDY SIZE.................................................................................................. 34
9.6
DATA MANAGEMENT................................................................................ 35
9.7
DATA ANALYSIS......................................................................................... 35
9.8
QUALITY CONTROL................................................................................... 36
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 37
9.10
OTHER ASPECTS ......................................................................................... 38
9.10.1
Statement of confidentiality .................................................................... 38

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Protocol for non-interventional studies based on existing data
BI Study Number 1200-0316
c28110847-03
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
9.10.2
Patient completion................................................................................... 39
9.10.3
Completion of study................................................................................ 39
9.11
SUBJECTS...................................................................................................... 39
9.11.1
Cases........................................................................................................ 39
9.11.2
Controls................................................................................................... 39
9.12
BIAS................................................................................................................ 40
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 41
10.1
DATA PROTECTION and STUDY RECORDS ........................................... 41
10.1.1 Study approval, patient information, and informed consent........................ 41
10.2
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
STUDY RELATED INJURY......................................................................... 42
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 43
11.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 43
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 44
11.3
REPORTING TO HEALTH AUTHORITIES................................................ 46
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS............................................................................................................ 47
13.
REFERENCES .................................................................................................... 48
13.1
PUBLISHED REFERENCES......................................................................... 48
13.2
UNPUBLISHED REFERENCES................................................................... 51
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 52
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS ................................. 53
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 60
ANNEX 3.1 ECOG PERFORMANCE STATUS...................................................... 60

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1200-0316
c28110847-03
Proprietary confidential information © 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
2.
LIST OF ABBREVIATIONS
ACT
ADRs
Anatomical Therapeutic Chemical
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
CTL
Contract Research Organisation
Clinical Trial Leader
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
EHR
Electronic Health Record
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
TKI(s)
TMF
Tyrosine Kinase Inhibitor(s)
Trial Master File
WHO
World Health Organisation

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Protocol for non-interventional studies based on existing data
BI Study Number 1200-0316
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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 Clinical Trial Leader (CTL), 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, ordering the materials as needed 
for the study, ensuring appropriate training and information of the internal study team and 
external Contract Research Organisation (CRO) team members (e.g. 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 signed 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 CRO and 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 Study Master File (Trial Master File, TMF).
A coordinating investigator and a co-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 contracts signed 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 CRO SOPs 
at each study site. A copy of the ISF documents, as applicable, will also be kept as an 
electronic TMF at the CRO according to CRO SOPs.
Coordinating investigator:
Co-coordinating investigator:

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1200-0316
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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 (ATC code: L01XE13),
gefitinib (L01XE02), erlotinib 
(L01XE03), osimertinib 
(L01XE35), 
Antineoplastic agents, 
tyrosine kinase inhibitors
Protocol date:
31 May 2019
Study
number:
1200-0316
Version/Revision:
3.0
Version/Revision 
date:
20 June 2020
Title of study:
UpSwinG: Real World study on TKI activity in Uncommon 
mutations and Sequencing Giotrif®
Rationale and 
background:
Patients with non-small-cell lung cancer (NSCLC) represent a 
heterogeneous population; however, increased understanding of 
the molecular pathogenesis of the disease has allowed for new 
treatments using molecularly targeted anti-cancer agents. 
Currently, the most established target is the epidermal growth 
factor receptor (EGFR) (P15-00464). Four EGFR tyrosine kinase 
inhibitors (TKIs; erlotinib, gefitinib, afatinib and osimertinib) are 
currently globally available for the management of NSCLC. 
The two most common EGFR mutations (in-frame deletion in 
Exon 19 (Del19) and Point mutation in Exon 21 (L858R) 
account for >85% of all mutation-positive NSCLC cases and are 
known to confer sensitivity to EGFR TKIs (P14-02931), whereas 
the efficacy on uncommon mutation is still debated.
Although several EGFR TKIs are available for the treatment of 
EGFR mutation-positive NSCLC, the development of acquired 
resistance is inevitable. It is therefore beneficial to consider the 
optimal sequence of EGFR TKIs in order to maximize their 
clinical benefit (P18-01208).
There are limited real world data with regard to EGFR mutated, 
advanced NSCLC who are EGFR TKI naïve therefore the aim of 
this study will be to collect more information on the benefit of 

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1200-0316
c28110847-03
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 (ATC code: L01XE13),
gefitinib (L01XE02), erlotinib 
(L01XE03), osimertinib 
(L01XE35), 
Antineoplastic agents, 
tyrosine kinase inhibitors
Protocol date:
31 May 2019
Study
number:
1200-0316
Version/Revision:
3.0
Version/Revision 
date:
20 June 2020
Title of study:
UpSwinG: Real World study on TKI activity in Uncommon 
mutations and Sequencing Giotrif®
individual EGFR-TKIs treatment for the uncommon mutations 
and the overall benefit for the sequential EGFR TKI treatment 
with afatinib and osimertinib for the common EGFR mutations. 
These findings will allow for evidence-based therapy decision.
Uncommon mutation cohort: There is convincing data for 
afatinib in many uncommon mutations (L861Q, G719X, and 
S768I) which resulted in regulatory approval by EMA and FDA. 
However, uncommon mutations are very heterogeneous and 
more information on the benefit of individual EGFR-TKIs is 
needed to allow for evidence-based therapy decision. 
Furthermore, little is known about the benefit of subsequent 
therapies and OS.
Sequencing cohort: It is still unclear which therapy sequence is 
the most beneficial for patients with EGFR mutated NSCLC. A 
recent global real-world study (GioTag) provided some insights 
into the outcomes of patients treated with the sequence afatinib 
followed by osimertinib. This study enrolled mainly Caucasian 
patients; study timelines and availability of drugs led to limited 
enrolment of long-term responders and maturity of time to 
treatment failure was 52% and 31% for OS. Thus, more data 
from Asian patients and with meanwhile longer availability of 
both drugs will provide more robust data with an increased 
maturity.
Various methodologies with different sensitivities can be used 
for mutational testing. The percentage of patients qualifying for 

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1200-0316
c28110847-03
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 (ATC code: L01XE13),
gefitinib (L01XE02), erlotinib 
(L01XE03), osimertinib 
(L01XE35), 
Antineoplastic agents, 
tyrosine kinase inhibitors
Protocol date:
31 May 2019
Study
number:
1200-0316
Version/Revision:
3.0
Version/Revision 
date:
20 June 2020
Title of study:
UpSwinG: Real World study on TKI activity in Uncommon 
mutations and Sequencing Giotrif®
the sequence afatinib followed by osimertinib patients is 
depending on the methodology used. Moreover, little is known 
about the sensitivity of the different techniques for uncommon or 
compound mutation. Thus, it is of interest to learn more about 
the methods that have been used to identify uncommon mutation 
(including T790M).
Research 
question and 
objectives:
Data from real-world setting would inform on the beneficial 
treatments in patients diagnosed with advanced NSCLC 
harbouring uncommon EGFR mutations and on the treatment 
sequence in patients diagnosed with advanced common EGFR 
mutation NSCLC.
Primary objective:
For both cohorts the study aims to describe the time on treatment 
until its end or death. 
More specifically, this will be evaluated for each cohort as 
follows:
Uncommon mutation cohort:
To determine the time on treatment of EGFR-TKIs as first or 
second line therapy in NSCLC with uncommon Epidermal 
Growth Factor Receptor (EGFR) mutations. Time on treatment is 
defined from the start of EGFR-TKI until the end of EGFR-TKI 

Boehringer Ingelheim
Page 11 of 60
Protocol for non-interventional studies based on existing data
BI Study Number 1200-0316
c28110847-03
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 (ATC code: L01XE13),
gefitinib (L01XE02), erlotinib 
(L01XE03), osimertinib 
(L01XE35), 
Antineoplastic agents, 
tyrosine kinase inhibitors
Protocol date:
31 May 2019
Study
number:
1200-0316
Version/Revision:
3.0
Version/Revision 
date:
20 June 2020
Title of study:
UpSwinG: Real World study on TKI activity in Uncommon 
mutations and Sequencing Giotrif®
treatment or death date by any cause.
Sequencing cohort:
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. 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 objectives:
To determine the overall response rate, and overall survival. To 
describe methodology and the material (liquid vs tissue) used for 
detection of uncommon/T790M mutation.  To determine time on 
treatment until failure of second-line (uncommon mutation 
cohort only).
Study design:
Non-interventional, multi-country, multi-centre study based on 
existing data from medical records or electronic health records
Population:
Site selection:
Sites with access to paper / electronic medical charts/EHR that 
have treated patients according to

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1200-0316
c28110847-03
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 (ATC code: L01XE13),
gefitinib (L01XE02), erlotinib 
(L01XE03), osimertinib 
(L01XE35), 
Antineoplastic agents, 
tyrosine kinase inhibitors
Protocol date:
31 May 2019
Study
number:
1200-0316
Version/Revision:
3.0
Version/Revision 
date:
20 June 2020
Title of study:
UpSwinG: Real World study on TKI activity in Uncommon 
mutations and Sequencing Giotrif®
Inclusion criteria:
1. Adult patients
2.
diagnosed with EGFR-TKI naïve advanced EGFR 
mutated NSCLC, 
3.
being treated for EGFR mutated NSCLC within regular 
clinical practice. 
4.
Informed and privacy consent signature must be obtained 
depending on local regulations.
More specific inclusion criteria for each cohort are the following:
Uncommon mutation cohort:
5.
Patients harbouring uncommon or compound EGFR 
mutations 
6.
Patients who started with either afatinib (Gi(l)otrif®), 
gefitinib (Iressa), erlotinib (Tarceva), or osimertinib 
(Tagrisso) in the first- or second-line setting within 
regular clinical practice
7.
Patients must have started EGFR-TKI treatment at least 
12 months prior to data entry.

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1200-0316
c28110847-03
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 (ATC code: L01XE13),
gefitinib (L01XE02), erlotinib 
(L01XE03), osimertinib 
(L01XE35), 
Antineoplastic agents, 
tyrosine kinase inhibitors
Protocol date:
31 May 2019
Study
number:
1200-0316
Version/Revision:
3.0
Version/Revision 
date:
20 June 2020
Title of study:
UpSwinG: Real World study on TKI activity in Uncommon 
mutations and Sequencing Giotrif®
Sequencing cohort:
5. Patients with common EGFR mutations (Del19, L858R) 
6. Patients were treated with afatinib (Gi(l)otrif®) in the first-line 
setting and for acquired T790M mutation with osimertinib in 
the second line; 
7. Patients must have started osimertinib treatment at least 10 
months prior to data entry.
Patients treated with osimertinib within an EAP/CUP are 
allowed
Main exclusion criteria:
1.
Patients treated for EGFR mutated NSCLC within a 
clinical trial or participated in GioTag study.
2.
Patients with active brain metastases at start of EGFR-
TKI therapy
3.
For uncommon mutation cohort: Patients treated with 
osimertinib  with no further uncommon mutation than 
acquired T790M
Variables:
Primary Outcome(s):

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Protocol for non-interventional studies based on existing data
BI Study Number 1200-0316
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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 (ATC code: L01XE13),
gefitinib (L01XE02), erlotinib 
(L01XE03), osimertinib 
(L01XE35), 
Antineoplastic agents, 
tyrosine kinase inhibitors
Protocol date:
31 May 2019
Study
number:
1200-0316
Version/Revision:
3.0
Version/Revision 
date:
20 June 2020
Title of study:
UpSwinG: Real World study on TKI activity in Uncommon 
mutations and Sequencing Giotrif®
Time on treatment with EGFR-TKI(s)
Secondary outcomes:
Overall survival, ORR, methodology and material used for 
mutational testing. Uncommon cohort only: time on treatment 
until failure of second line (TTF2),
Safety criteria:
Drug exposure during pregnancy, ADRs with causality to 
Gi(l)otrif (serious or non-serious) and all fatal AEs will be 
reported to PV on the NIS AE form/Pregnancy Monitoring Form
- excluding deaths to PD of the underlying malignancy. Safety 
data will be reviewed and analysed as part of routine global 
pharmacovigilance procedures. All adverse events/reactions 
collected for the study per protocol will be summarised in the 
final study report.
Data sources:
Non-interventional study (NIS) based on existing data from 
medical records/EHR of patients.
Study size:
Total enrolled: at least 200 patients in the sequencing cohort and 
approximately 250 patients in the uncommon cohort
Data analysis:
Time on treatment and overall survival will be analysed using 
Kaplan-Meier method, and the median along with two-sided 
95% confidence interval will be displayed.
Milestones:

Start of data collection in December 2019

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1200-0316
c28110847-03
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 (ATC code: L01XE13),
gefitinib (L01XE02), erlotinib 
(L01XE03), osimertinib 
(L01XE35), 
Antineoplastic agents, 
tyrosine kinase inhibitors
Protocol date:
31 May 2019
Study
number:
1200-0316
Version/Revision:
3.0
Version/Revision 
date:
20 June 2020
Title of study:
UpSwinG: Real World study on TKI activity in Uncommon 
mutations and Sequencing Giotrif®

The end of data collection is determined by 
the sufficient number of patients enrolled and pertinent 
data entered in eDC.

Interim report: According to patients data availability the 
possibility to perform an Interim Analysis by the end of 
2020 will be considered.

Final report of study results expected in 2021

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BI Study Number 1200-0316
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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
23 July 2019
EudraCT number
Not applicable
BI Study number
1200-0316
BI Active substance
afatinib
Title of protocol
UpSwinG: Real World study on TKI activity in 
Uncommon mutations and Sequencing Giotrif®
Section to be changed
4.
Description of change
The numbering of the inclusion criteria was 
corrected:
Sequencing cohort:
6. 5. Patients with common EGFR mutations 
(Del19, L858R) 
7. 6. Patients were treated with afatinib 
(Gi(l)otrif®) in the first-line setting and for 
acquired T790M mutation with osimertinib in 
the second line; 
8. 7. Patients must have started osimertinib 
treatment at least 10 months prior to data 
entry.
9. Patients treated with osimertinib within an 
EAP/CUP are allowed 
Rationale for change
Numbering of inclusion criterion was 
incorrect.
Section to be changed
4.
Description of change
One exclusion criterion was added for the 
uncommon mutations cohort:
3. For uncommon mutation cohort: 
Patients treated with osimertinib with no 
further uncommon mutation than acquired 
T790M.
Rationale for change
Given the robust evidence for osimertinib in 
acquired T790M from randomized controlled
trial AURA-3, no further data on EGFR-TKI 
effectiveness in this indication is needed and 
respective patients should not be included in 
this study.
Section to be changed
9.2.1
Description of change
The numbering of the inclusion criteria was 

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Number of global 
amendment
1
corrected:
Uncommon mutation cohort:
6. 5. Patients harbouring uncommon or 
compound EGFR mutations 
7. 6. Patients who started with either afatinib 
(Gi(l)otrif®), gefitinib (Iressa), erlotinib 
(Tarceva), or osimertinib (Tagrisso) in the 
first- or second-line setting within regular 
clinical practice
8. 7. Patients must have started EGFR-TKI 
treatment at least 12 months prior to data 
entry.
Sequencing cohort:
6. 5. Patients with common EGFR mutations 
(Del19, L858R) 
7. 6. Patients were treated with afatinib 
(Gi(l)otrif®) in the first-line setting and for 
acquired T790M mutation with osimertinib in 
the second line; 
8. 7. Patients must have started osimertinib 
treatment at least 10 months prior to data 
entry.
9. Patients treated with osimertinib within an 
early access program/compassionate use 
program are allowed 
Rationale for change
Numbering of inclusion criterion was
incorrect.
Section to be changed
9.2.1
Description of change
One exclusion criterion was added for the 
uncommon mutations cohort:
3. For uncommon mutation cohort: 
Patients treated with osimertinib  with no 
further uncommon mutation than acquired 
T790M.
Rationale for change
Given the robust evidence for osimertinib in 
acquired T790M from randomized controlled
trial AURA-3, no further data on EGFR-TKI 
effectiveness in this indication is needed and 
respective patients should not be included in 
this study.
2

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Number of Global 
amendment
2
Date of protocol revision
20 June 2020
EudraCT number
Not Applicable
BI Study number
1200-0316
BI Active substance
afatinib
Title of protocol
UpSwinG: Real World study on TKI activity in 
Uncommon mutations and Sequencing Giotrif®
Section to be changed
EU PASS
Description of change
Information regarding EU PASS are updated
Rationale for change
EU Pass registration was completed and new 
information are now available
Section to be changed
Safety criteria
Description of change
The language has been changed to the following:
Drug exposure during pregnancy, ADRs with 
causality to Gi(l)otrif (serious or non-serious) and 
all fatal AEs will be reported to PV on the NIS AE 
form/Pregnancy Monitoring Form - excluding 
deaths to PD of the underlying malignancy. Safety 
data will be reviewed and analysed as part of 
routine global pharmacovigilance procedures. All 
adverse events/reactions collected for the study per 
protocol will be summarised in the final study 
report.
Rationale for change
It is planned to summarize all adverse 
events/reactions collected for the study per 
protocol in the final study report as requested by 
health authorities.
Section to be changed
Milestones
Description of change
Study milestnes are updated
Rationale for change
Due to the unforeseen COVID-19 outbreak, 
milestones needed to be adjusted
Section to be changed
4.
Description of change
Study size in the uncommon cohort is 

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increased from 200 to approximately 250 
patients 
Rationale for change
Sample size increased due to new feasibility data
Section to be changed
7. 
Description of change
Sample size for the uncommon cohort was in 
creased from 200 patients to about 250 patients.
Rationale for change
Sample size increased due to new feasibility data
Section to be changed
9.1
Description of change
Number of eligible patients in the uncommon 
cohort is increased from 200 to approximately 
250 patients
Rationale for change
Sample size increased due to new feasibility data
Section to be changed
9.2
Description of change

Number of eligible patients in the 
uncommon cohort is increased from 200 to 
approximately 250 patients

“and Cohort” is added to thie section to read as 
the following “To avoid differential centre 
influence on study results, permission to 
enrol more than 15 patients per site and 
cohort must be obtained from the CTL.”
Rationale for change

Sample size increased due to new feasibility 
data

The previous language was not clear enough. 
Thus, a clarification is added.
Section to be changed
9.2.1
Description of change
“adverse drug reactions (ADRs)” is deleted from 
the section to read as the following: “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 (P17-01960) to avoid early 
censoring and enable collection of mature data on 
treatment duration.”.
Rationale for change
An error in the previous protocol version is correct

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Section to be changed
Description of change
Rationale for change
Section to be changed
9.5
Description of change
Smaple size in the uncommon cohort was increased 
to approximately 250 patients.
Number of patients with frequent uncommon 
mutations was increased from 90 to 110.
Number of patients with exon20 insertions
was increased from 60 to 70.
Number of patients with compound mutations
was increased from 25 to 35.
Rationale for change
Sample size increased due to new feasibility data
Section to be changed
9.7
Description of change
This sentence was deleted: 
There is no intention to collect and/or analyse 
safety data in this non-interventional study (NIS) 
based on existing data
The following language is added:
All adverse events/reactions collected for the study 
per protocol will be summarised in the final study 
report.
Rationale for change
It is planned to summarize all adverse 
events/reactions collected for the study per 
protocol in the final study report as requested by 
health authorities
Section to be changed
11.2
Description of change
This sentence was deleted: 

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There is no intention to collect and/or analyse 
safety data in this non-interventional study (NIS) 
based on existing data
The following language is added:
All adverse events/reactions collected for the study 
per protocol will be summarised in the final study 
report.
Rationale for change
It is planned to summarize all adverse 
events/reactions collected for the study per 
protocol in the final study report as requested by 
health authorities

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6.
MILESTONES
Milestone
Planned Date
Start of data collection
December 2019
End of data collection
The end of data collection is determined by 
the sufficient number of patients enrolled and 
pertinent data entered in eDC.
Registration in the EU PAS 
register
October 2019
Interim report
According to patients data availability the possibility 
to perform an Interim Analysis by the end of 2020 will 
be considered.
Final report of study results
2021

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7.
RATIONALE AND BACKGROUND
Patients with non-small-cell lung cancer (NSCLC) represent a heterogeneous population; 
however, increased understanding of the molecular pathogenesis of the disease has allowed 
for new treatments using molecularly targeted anti-cancer agents. Currently, the most 
established target is the epidermal growth factor receptor (EGFR) (P15-00464).  Four EGFR 
tyrosine kinase inhibitors (TKIs; erlotinib, gefitinib, afatinib and osimertinib) are currently 
globally available for the management of NSCLC.
The two most common EGFR mutations (in-frame deletion in Exon 19 (Del19) and Point 
mutation in Exon 21 (L858R)) account for >85% of all mutation-positive NSCLC cases and 
are known to confer sensitivity to EGFR TKIs (P14-02931), whereas the efficacy on 
uncommon mutation is still debated.
Although several EGFR TKIs are available for the treatment of EGFR mutation-positive 
NSCLC, the development of acquired resistance is inevitable. It is therefore beneficial to 
consider the optimal sequence of EGFR TKIs in order to maximize their clinical benefit
(P18-01208)
There are limited real world data with regard to EGFR mutated, advanced NSCLC who are 
EGFR TKI naïve therefore the aim of this study will be to collect more information on the 
benefit of individual EGFR-TKIs treatment for the uncommon mutations and the overall 
benefit for the sequential EGFR TKI treatment with afatinib and osimertinib for the common 
EGFR mutations. These findings will allow for evidence-based therapy decision.
This global Real-World non-interventional, multi-country, multi-centre study will be 
collecting pre-existing data from medical records for the patient population: EGFR mutated, 
advanced NSCLC who are EGFR TKI naïve, in the following two cohorts:
1- Uncommon mutation cohort
Patient with uncommon EGFR mutations who started EGFR TKI (afatinib, 
gefinitib, erlotinib, osimertinib) in first or second line and with treatment initiated 
at least 12 months prior to data entry. About 250 eligible patients are planned to 
be enrolled.
2- Sequencing cohort
Patient with common EGFR mutations who started osimertinib in second line for 
acquired T790M at least 10 months prior to data entry. As first-line patients 
underwent afatinib. About 200 eligible patients are planned to be enrolled. 

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*Patient must have been treated with EGFR-TKI in either 1st or 2nd line, 2nd line treatment after 1st line 
EGFR-TKI is not mandatory.
Figure 7:1 Overview of the two cohorts
7.1 UNCOMMON MUTATION COHORT 
In a retrospective analysis of 1632 patients with stage IIIB-IV NSCLC, uncommon mutations 
occurred in ~16% of EGFRm+ NSCLC cases: exon 20 insertions (9%), uncommon mutations 
with Del19 or L858R complex mutations (30%) [Del19 + 18G721D; Del19 + 19L732P; 
Del19+ 20L792P; Del19+ 20S768I + 20V774M; Del19 + 21L858R + 21K860I; 21L858R + 
18E709X; 21L858R + 20S768I; 21L858R + 20V786E; 21L858R + 20T790M; 21L858R + 20 
insertion; 21L858R + 21L833Vl 21L858R + 21K860I; 21L858R + 18G719X +20 insertion]; 
uncommon mutation alone or in combination with other uncommon mutations (61%)
[18I715V; 18K716E; 18V717G; 18G719X; 19L747P; 19 insertion; 20A763_Y764 insFQEA; 
20S768I; 20G779F; 21L861Q; 18G719X + 21L861Q; 18E709X + 18G719X; 18G719X + 
20S768I; 20T790M + 21L861Q; 21M825L +21R831C; 18V703L + 18L707W +18G719X; 
18E709X + 18T710S + 18G719X; 19V742F + 19A743 V + 20H773R] (P17-07438).
Recent improvements in detection methods have indicated that ‘uncommon’ EGFR mutations 
are more prevalent than previously thought. According to the catalogue of somatic mutations 
in cancer (COSMIC) database, in 2016, 594 types of EGFR mutation had been reported [P16-
09907]. Categories of uncommon mutation include insertions in exon 19 (Ins19; 0.6% of all 
EGFR mutations) or 20 (Ins20; ~6%), as well as point mutations in exon 18 at position G719 
(G719X; ~3%), exon 21 L861Q mutations (~1%) and exon 20 S768I mutations (~1% of 
EGFR mutations) [P16-09907]. In addition, it is becoming increasingly clear that some 
patients with EGFR mutation-positive NSCLC have tumors that harbor more than one type of 
EGFR mutation, predominantly in cis, in other words, within the same EGFR allele (so-called 
‘compound’ mutations).(P19-02454, P18-10855).
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 

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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). On January 12, 2018, FDA granted approval to afatinib for a broadened 
indication in first-line treatment of patients with metastatic NSCLC whose tumours have non-
resistant EGFR mutations as detected by an FDA-approved test (P19-04170). Approval was 
based on demonstration of durable responses in a subset of 32 afatinib-treated patients with 
metastatic NSCLC harbouring non-resistant EGFR mutations (S768I, L861Q, and/or G719X) 
other than exon 19 deletions or exon 21 L858R substitutions enrolled in one of three clinical 
trials (LUX-Lung 2 [NCT00525148], LUX-Lung 3 [NCT00949650], and LUX-Lung 6 
[NCT01121393]). The confirmed overall response rate, as assessed by independent radiology 
review, was 66% (95% confidence interval 47, 81). Among the 21 responders, the proportion 
of patients with response duration of ≥12 months was 52% and the proportion with response 
durations of ≥18 months was 33%. Clinical benefit was lower in patients with de-novo 
Thr790Met and exon 20 insertion mutations. (P15-05932)
Gefitinib (IRESSA®) and erlotinib (Tarceva®) are first generation EGFR-TKIs and approved 
by EMA as monotherapy for the treatment of adult patients with locally advanced or 
metastatic non-small cell lung cancer (NSCLC) with activating mutations of EGFR-TK. FDA 
label is restricted to common mutations (Del19 and L858R).
Anecdotal data from erlotinib/gefitinib trials show variable and mainly limited responses to 
EGFR TKIs in a multitude of other EGFR mutations, eg, in Exons 18-21 or a combination of 
≥2 EGFR mutations (P16-09907) Post-hoc analyses from the NEJ002 study comparing 
gefitinib with chemotherapy showed that patients with uncommon EGFR mutations had a 
significantly shorter OS (11.9 versus 29.3 months; p < 0.001). By contrast, OS was similar 
for uncommon mutations and common mutations in the CarboPac group (n = 111; 22.8 
versus 28 months; p = 0.358)(R19-1656).
Osimertinib (Tagrisso®) is approved by EMA for the first-line treatment of adult patients 
with locally advanced or metastatic NSCLC with activating EGFR mutations, and for the 
treatment of adult patients with locally advanced or metastatic EGFR T790M mutation-
positive NSCLC. The FDA label restricts osimertinib in first line to common EGFR 
mutations. Data from a Korean phase 2 IIS showed benefit for osimertinib in 36 patients 
with G719A/C/D/S/X  L861Q , S768I, and four other mutations. The overall response rate 
was 50.0% (95% CI 32.8-67.2) and DCR was 88.9% (95% CI 78.1-99.7) (R19-1672). 
Given the robust evidence for osimertinib in acquired T790M from randomized controlled 
trial (AURA-3) (P17-01960), no further data on EGFR-TKI effectiveness in this indication 
is needed.
Dacomitinib (Vizimpro) is not approved outside common mutations and will therefore not be 
analysed.
The heterogeneity of EGFR mutations in EGFR mutation-positive NSCLC has potential 
clinical implications because different EGFR-targeted TKIs can have different activities 
against specific mutations. Therefore, treatment with EGFR TKIs that have limited efficacy 
against certain mutations may drive the clonal expansion of those insensitive mutations. A 
recent preclinical study assessed the activity of different EGFR-directed TKIs against 

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uncommon EGFR variants of unknown significance. By utilizing a high-throughput 
functional assay in Ba/F3 cells, Kohsaka et al. evaluated the sensitivity of over a hundred 
different variants of unknown significance, including compound mutations (P18-10855). 
Interestingly, afatinib showed activity against almost all mutations tested and, in many cases, 
was more potent than erlotinib and gefitinib. Afatinib also showed a broader spectrum of 
activity against uncommon EGFR variants compared with osimertinib, although, as expected, 
afatinib was less effective against T790M than osimertinib (P18-10855).
Various methodologies with different sensitivities can be used for detection of EGFR 
mutation. Little is known about the sensitivity for uncommon or compound mutation. Thus, it 
is of interest to learn more about the methods that have been used to identify patients 
harbouring tumours with uncommon mutations (R19-1655).
In summary, there seems to be only limited efficacy of first generation EGFR-TKI, and 
limited data on osimertinib who has furthermore only recently been approved for first line. In 
many countries, the labels for these drugs are restricted to common mutations, whereas 
afatinib’s efficacy has been confirmed in clinical trials and being acknowledged by regulatory 
authorities. Given this, the uncommon mutation cohort should enrol at least 50% of patients 
who were treated with afatinib. Furthermore, as patients with EGFR mutations should be 
treated in first-line as recommended by NCCN and ESMO guidelines, at least 50% of 
enrolled patients should have been treated in first line. 
Thus, more information on the benefit of individual EGFR-TKIs on individual uncommon 
mutations is needed to allow for evidence-based therapy decision. Furthermore, more 
information is needed on outcome with other systemic therapy and OS.
7.2 SEQUENCING COHORT 
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 more 
than 80 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).

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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(P19-03125).
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 the FLAURA trial. 
Osimertinib significantly prolonged PFS compared to first generation TKIs (erlotinib or 
gefitinib). Median PFS by independent review was 17.7 months in patients with common 
mutations (R18-0130).Overall survival data are still immature and so far, only 29% of the 
patients treated first-line with osimertinib received a subsequent therapy. Furthermore, as 
more than 60% have no putative resistance mechanism and even those identified are not 
druggable with approved targeted therapies, the best sequencing strategy is still under 
discussion.
A recent global real-world study (GioTag) recruited from December 2017 to May 2018 and 
provided insights into the outcomes of patients treated with the sequence afatinib followed by 
osimertinib. Time on treatment for the sequence was 27.6 months and 2 year survival rate 
being 79% (P18-09968). This study enrolled mainly Caucasian patients (59%) and 63% of 
the patients came from USA, although incidence of EGFR mutated NSCLC is much higher in 
Asian countries (R19-1657). Study timelines and availability of drugs led to limited 
enrolment of long-term responders (10-12% of patients treated with afatinib are for 3 years 
and longer on drug) (P19-03124) and maturity of time to treatment failure was 52% and 31% 
for OS. Thus, more data from Asian patients and with meanwhile longer availability of both 
drugs will provide data that are more robust with an increased maturity. At least 60% of 
enrolled patients should have Asian ethnicity.
Various methodologies with different sensitivities can be used for T790M detection. 
Recently, it could be shown that in patients who progressed under treatment with an EGFR 
TKI, the T790M positivity rate was 66% using ddPCR, but only 24% using Cobas (P19-
03686). Thus, it is of interest to learn more about the methods that have been used to identify 
patients qualifying for the sequence afatinib followed by osimertinib.
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 beneficial treatments in patients diagnosed 
with advanced NSCLC harbouring uncommon EGFR mutations and on the treatment 
sequence in patients diagnosed with advanced common EGFR mutation NSCLC.
Primary objective:
For both cohorts the study aims to describe the time on treatment until its end or death. 
More specifically, this will be evaluated for each cohort as follows:
Uncommon mutation cohort:
To determine the time on treatment of EGFR-TKIs as first or second line therapy in NSCLC 
with uncommon Epidermal Growth Factor Receptor (EGFR) mutations. Time on treatment 
is defined from the start of EGFR-TKI until the end of EGFR-TKI treatment or death date 
by any cause.
Sequencing Cohort:
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. 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 objectives:
To determine the overall response rate, and overall survival. To describe the methodology 
and material (liquid vs tissue) used for detection of uncommon/T790M mutation. Uncommon 
mutation cohort only: To determine the time on treatment until the end of the second-line 
treatment.

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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 (paper or electronic) or electronic health records of patients with 
advanced NSCLC harbouring EGFR mutations and treated with an EGFR-TKI. 
In total, at least 200 eligible patients in the sequencing cohort and approximately 250 eligible 
patients in the uncommon cohort.
Key study outcome:
Time on treatment with EGFR-TKI(s)
The study will involve secondary use of data. 
Since the collected data include also genetic data, the appropriate strategies to ensure data 
protection (such as strong authentication) will be implemented in the eCRF employed for 
data collection.
9.2
SETTING
It is planned that around 65 study centres in up to 11 countries will be participating in this 
non-interventional study and at least 200 consecutive eligible patients in the sequencing 
cohort and approximately 250 patients in the uncommon cohortfrom up to 80 sites will be 
enrolled to the study. Data extraction from local data bases might be used when possible. 
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. 
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 and cohorts must be obtained from the CTL.
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:

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Sites with access to paper/electronic medical charts/electronic health record (EHR) that have 
treated patients according to inclusion criteria:
1. Adult patients 
2. diagnosed with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-
TKI) naïve advanced EGFR mutated non-small cell lung cancer (NSCLC), 
3. treated for Epidermal Growth Factor Receptor (EGFR) mutated NSCLC within 
regular clinical practice.
4. Informed and privacy consent signature must be obtained depending on local 
regulations.
More specific inclusion criteria for each cohort are the following:
Uncommon mutation cohort:
5. Patients harbouring uncommon or compound EGFR mutations 
6. Patients who started with either afatinib (Gi(l)otrif®), gefitinib (Iressa), erlotinib 
(Tarceva), or osimertinib (Tagrisso) in the first- or second-line setting within regular 
clinical practice
7. Patients must have started EGFR-TKI treatment at least 12 months prior to data entry.
Sequencing cohort:
5. Patients with common EGFR mutations (Del19, L858R) 
6. Patients were treated with afatinib (Gi(l)otrif®) in the first-line setting and for 
acquired T790M mutation with osimertinib in the second line; 
7. Patients must have started osimertinib treatment at least 10 months prior to data entry.
Patients treated with osimertinib within an early access program/ compassionate use 
program (EAP/CUP) are allowed 
Main exclusion criteria:
1. Patients treated for EGFR mutated NSCLC within a clinical trial or participated in 
GioTag study.
2. Patients with active brain metastases at start of EGFR-TKI therapy (independent of 
treatment line)
3. For uncommon mutation cohort: Patients treated with osimertinib  with no further 
uncommon mutation than acquired T790M
Deceased patients fulfilling the eligibility criteria should be enrolled whenever possible.
Uncommon mutation cohort: Patients treated with EGFR-TKI in interventional trials are 
excluded to ensure the non-interventional setting of this study. The threshold of start of 
treatment at least 12 months respectively prior to data entry was chosen based on the median
PFS reported for patients being treated with afatinib in the LUX-Lung 2, -3, -and 6 trials 
(P15-05932) to avoid early censoring and enable collection of mature data on adverse drug 

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reactions (ADRs) and treatment duration. All patients fulfilling inclusion and exclusion 
criteria from a site will be entered to avoid bias.
Sequencing cohort: 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 (P17-01960) to avoid early censoring and enable collection of mature 
data on 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 (where applicable)

Demographics: age at start of first-line treatment, gender, ethnicity

Stage of disease (IIIb or IV) at start of first-line treatment

Type of mutations at initial diagnosis

Methodology used for mutation testing

Sites of metastases at start of treatment

Body weight and height at start of treatment

Eastern Cooperative Oncology Group (ECOG) performance score (PS) (if available) at 
start of treatment

Date of start and end of first-line treatment 

First-line treatment administered

Starting dose of EGFR-TKI (first-or second-line)

Dose modification(s) and date(s) of EGFR-TKI

ECOG PS (if available) at start of second-line treatment

Type of mutations at start of second-line treatment

Methodology (allele-specific, NGS, sequencing) and material (tissue/liquid biopsy) used 
for mutational testing

Sites of metastases at start of second-line treatment

Date of start and end of second-line treatment

Second-line treatment administered

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
Reason for discontinuation of each treatment (e.g. progressive disease (PD), adverse 
event (AE))

Best response to first and second-line treatment (as documented)

Date of death 

Bevacizumab use with TKI (Yes/No)
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®).
Erlotinib (Tarceva®):
Patients were treated with erlotinib (Tarceva®) 25mg or 100mg or 150mg tablet once daily as 
indicated in the approved labels of erlotinib (Tarceva®).
Gefitinib (IRESSA®):
Patients were treated with gefitinib (IRESSA®): 250mg tablet once daily as indicated in the 
approved labels of gefitinib (IRESSA®):
Osimertinib (Tagrisso®):
Patients were/are treated with osimertinib 80 mg or 40 mg tablets once daily as indicated in 
the approved labels of osimertinib.
The Summaries of Product Characteristics on afatinib, erlotinib, gefitinib and osimertinib are 
contained in the ISF.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
Time on treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor 
(EGFR-TKI). This will be assessed as the time from start of EGFR-TKI treatment until the 
end of treatment or death date by any cause. In the sequencing cohort it 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.
Secondary outcomes
Overall response rate, overall survival, time on treatment until failure of second-line (TTF2, 
uncommon mutation cohort only), and subsequent therapies used. Methodology and material
used for mutational testing.

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9.3.3
Covariates
NA
9.4
DATA SOURCES
Data will be collected from patients’ medical records and recorded in eCRFs or will be 
captured from electronic health records (EHR). 
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 eCRFs 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.
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).

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Sponsor: 
The sponsor must retain the essential documents according to the sponsor’s SOPs.
9.5
STUDY SIZE
Uncommon mutation cohort:
In LUX-Lung trials (1200.22, 1200.32, 1200.34), EAP (1200.45, 1200.55, 1200.66, 1200.193) 
and NIS (1200.205), 267 TKI-naïve patients were treated for uncommon mutations.

46% had one of the more frequent afatinib-sensitive uncommon mutation (G719X, 
L861Q, or S768I), 

29% had an insertion in exon 20, 

12% had a de novo T790M, 

13% had a complex or compound mutation, and 

10% had other uncommon mutations. 
For the current study, a sample size of about 250 is mainly driven by feasibility. We expect 
that this will result in approximately

110 patients with frequent uncommon mutations,

70 patients with exon20 insertions, and

35 patients with compound mutations.
Given the label (and availability) for first and third generation TKIs, we assume that the 
majority of patients with these uncommon mutations will have been treated with afatinib. At 
least 50% of enrolled patients must have been treated with afatinib. At least 50% must have 
been treated with an EGFR-TKI in first-line (see rationale).
Comparison of the different TKIs will be limited to descriptive statistics because of the 
limited numbers of patients expected to have been treated with TKI other than afatinib.
Sequencing cohort:
Based on previous data from the GioTag study and expecting a higher proportion of Asian 
patients, the median time on treatment from start of the first-line treatment until the end of the 
second-line treatment is projected to be 30 months.
Table 9.5:1 shows the expected (50th percentile) width of the 95% confidence interval to be 
13.7 months, with an 80% chance of observing a confidence interval of less than 16.2 months. 
This is based upon 200 patients with 10 percent random censoring. The width of the 
confidence interval would increase if the rate of censoring were higher.     
Table 9.5:1
95% confidence interval width for median duration of treatment with 200 
patients, 30 month underlying median duration, and increasing random 
censoring1
95% CI width

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10% censoring
20% censoring
30% censoring
50th percentile 
13.7 months
15.9 months
18.8 months
80th percentile
16.2 months
18.9 months
22.5 months
1Calculated by simulation with 10,000 iterations
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
The two cohorts will be analysed separately

Uncommon mutations

Sequencing of osimertinib after afatinib
The primary endpoint for both cohorts is time on treatment. Kaplan-Meier estimates will be 
calculated. In addition, the median will be tabulated along with the two-sided 95% 
confidence interval, using Greenwood’s variance estimate.

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The following additional endpoints will be analyzed similarly to the primary endpoint.

overall survival

time on treatment until failure of second-line (uncommon cohort only)
Patients who were not known to have discontinued treatment will be censored on the date 
they were last verified to have been on treatment.
A second round of data collection for additional follow-up may be performed in case a 
substantial proportion of patients had not discontinued treatment before the estimated median 
time on treatment at the time of the primary data collection.
Best overall response will be tabulated, as will the following:

demographics

disease characteristics

methodology and material used for mutation classification

anti-cancer drugs used prior to, or after EGFR-TKI (uncommon cohort only). 
These endpoints will be analyzed descriptively.
Within the sequencing cohort, the proportion of patients with different types of resistance 
mutations observed at the time of discontinuation of osimertinib will be categorized and 
tabulated.
In this study, data will be gathered retrospectively from patients treated within the conditions 
of the approved marketing authorization of afatinib. Drug exposure during pregnancy, ADRs 
with causality to Gilotrif (serious or non-serious) and all fatal AEs will be reported to PV on 
the NIS AE form - excluding deaths to PD of the underlying malignancy. Safety data will be 
reviewed and analysed as part routine global pharmacovigilance procedures. All adverse 
events/reactions collected for the study per protocol will be summarised in the final study report.
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 

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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. 
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:
In general, having a clearer focus on Asian countries reflects the higher incidence of EGFR 
mutations in this group.
1. a) Uncommon mutation cohort: There are no limitations coming from the site selection.
1. b) Sequencing cohort: 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 2 to 3 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. 
2. Patient population:
2. a) Uncommon mutation cohort: Firstly, there is a bias as only patients that were tested for 
uncommon mutations and were treated with an EGFR-TKI could be enrolled into this NIS. 
Because of that bias, the results of the study will not be generalizable to all patients 
harbouring an uncommon mutation.

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This study has no comparator group limiting the interpretability of the results as they cannot 
be put into perspective. The planned analyses by EGFR-TKI used includes no formal testing 
for statistical significance.
2. b) Sequencing cohort:
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 still 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 has 
only been approved recently and most patients that were prescribed with osimertinib are still 
on first-line treatment.
3. Retrospective data collection:
Other limitations are due to the retrospective nature of the study, which might lead to 
inconsistent or missing data.
Moreover, some endpoints, such as overall survival, could be not achievable as the 
retrospective window could be too narrow to catch events and most of patients would be 
censored.
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.

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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.
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
Selection 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. Furthermore, with at least 60% Asian patients to be enrolled, the study population 
will reflect the higher incidence of EGFR mutation in Asian population.
Sequencing cohort: To overcome feasibility limitation driven by availability of osimertinib, 
patients who have received osimertinib treatment within an EAP/CUP are eligible, increasing 
the pool of eligible sites and potential patients.
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®).
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. 
Immortal bias: 
Sequencing cohort: 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. 
Bias through drug availability:
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. 
Testing bias:
Only patients that were tested for uncommon / T790M mutations and were treated with an 
EGFR-TKI /osimertinib in second line could be enrolled into this NIS. Because of that bias, 
the results of the study will not be generalizable to all patients harbouring an uncommon 
mutation or being treated with afatinib in first line.

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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 CRO and BI SOPs and, for Japan, 
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 and, for Japan, 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 
give 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 (e.g. 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 Adverse Event of Special Interest (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
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.
Drug exposure during pregnancy, ADRs with causality to Gi(l)otrif (serious or non-serious) 
and all fatal AEs will be reported to PV on the NIS AE form/Pregnancy Monitoring Form -
excluding deaths to PD of the underlying malignancy. Safety data will be reviewed and 
analysed as part routine global pharmacovigilance procedures. All adverse events/reactions 
collected for the study per protocol will be summarised in the final study report.
The following must be reported on the NIS AE Form and/or Pregnancy Monitoring Form for 
Studies in case such AE/drug exposure during pregnancy information is identified in the 
course of the review of the individual records:
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®)
*Exemption applies
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. 
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below.
Exemption

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*Death due to disease progression of the underlying malignancy is a study endpoint and the 
natural course of the disease. As such it is exempted from reporting as an SAE. Progression 
of the subject's underlying malignancy will be recorded on the appropriate pages of the eCRF 
only and will not be reported on the NIS AE Form.
However, when there is evidence suggesting a causal relationship between Gi(l)otrif and the
progression of the underlying malignancy, the event must be reported as an SAE on the NIS 
AE Form and on the eCRF.
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

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.

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
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 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.
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, 
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
R17-0754
Real World Treatment Study of AZD9291 for Advanced/Metastatic EGFR 
T790M Mutation NSCLC (ASTRIS). Available at:
https://clinicaltrials.gov/ct2/show/NCT02474355
R18-0130
Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, 
Dechaphunkul LA, et al, FLAURA Investigators Osimertinib in untreated 
EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 378 
(2), 113 - 125 (2018).
R19-1655
Diaz LA, Bardelli A Liquid biopsies: genotyping circulating tumor DNA. J 
Clin Oncol 32 (6), 579 - 586 (2014)
R19-1656
Watanabe S, Minegishi Y, Yoshizawa H, Maemondo M, Inoue A, 
Sugawara S, et al Effectiveness of gefitinib against non-small-cell lung 
cancer with the uncommon EGFR mutations G719X and L861Q. J Thorac 
Oncol 9 (2), 189 - 194 (2014).
R19-1657
Zhang YL, Yuan JQ, Wang KF, Fu XH, Han XR, Threapleton D, et al The
prevalence of EGFR mutation in patients with non-smallcell lung cancer: a 
systematic review and meta-analysis. Oncotarget 7 (48), 78985 - 78993 
(2016).
R19-1672
Ahn MJ, Cho JH, Sun JM, Lee SH, Ahn JS, Park K, et al An open-label,
multicenter, phase II single arm trial of osimertinib in non-small cell lung 
cancer patients with uncommon EGFR mutation (KCSG-LU15- 09). J Clin 
Oncol 36:15 (2018).

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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 
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.
P14-02931
Roskoski R The ErbB/HER family of protein-tyrosinekinases and cancer. 
Pharmacol Res 79, 34 - 74 (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.
P15-00464
Zer A, Leighl N. Promising targets and current clinical trials in metastatic 
non-squamous NSCLC. Front Oncol 4, 329 (2014).
P15-05932
Yang JCH, Sequist LV, Geater SL, Tsai CM, Mok TSK, Schuler M, 
Yamamoto N, Yu CJ, Ou SHI, Zhou C, Massey D, Zazulina V, Wu YL
Clinical activity of afatinib in patients with advanced non-small-cell lung 
cancer harbouring uncommon EGFR mutations: a combined post-hoc 
analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol 16 
(7), 830 - 838 (2015).
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.
P16-09907
Kobayashi Y, Mitsudomi T Not all epidermal growth factor receptor
mutations in lung cancer are created equal: perspectives for individualized 
treatment strategy. Cancer Sci 107 (9), 1179 - 1186 (2016).

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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
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.
P17-07438
Shen YC, Tseng GC, Tu CY, Chen WC, Liao WC, Chen WC, et al 
Comparing the effects of afatinib with gefitinib or erlotinib in patients with 
advanced-stage lung adenocarcinoma harboring non-classical epidermal 
growth factor receptor mutations. Lung Cancer (Neth) 110, 56 - 62 (2017).
P18-01208
Hirsh V. Turning EGFR mutation-positive non-small-cell lung cancer into 
a chronic disease: optimal sequential therapy with EGFR tyrosine kinase 
inhibitors. Therapeutic Advances in Medical Oncology, First Published 
January 22, 2018, doi: 10.1177/1758834017753338; 2018.
P18-09968
Hochmair MJ, Morabito A, Hao D, Yang CT, Soo RA, Yang JCH, et al. 
Sequential treatment with afatinib and osimertinib in patients with EGFR 
mutation-positive non-small-cell lung cancer: an observational study. 
Future Oncology, published Online:19 Oct 2018, doi: 10.2217/fon-2018-
0711; 2018. p.2861-2874.
P18-10855
Kohsaka S, Petronczki M, Solca F, Maemondo M Tumor clonality and
resistance mechanisms in EGFR mutation-positive non-small-cell lung 
cancer: implications for therapeutic sequencing. Future Oncol 15 (6), 637 -
652 (2019).
P19-02454
Russo A, Franchina T, Ricciardi G, Battaglia A, Picciotto M, Adamo V
Heterogeneous responses to epidermal growth factor receptor (EGFR) 
tyrosine kinase inhibitors (TKIs) in patients with uncommon EGFR 
mutations: new insights and future perspectives in this complex clinical 
scenario. Int J Mol Sci 20 (6), 1431 (2019).
P19-03124
Schuler M, Paz-Ares L, Sequist LV, Hirsh V, Lee KH, Wu YL, et al First-
line afatinib for advanced EGFRm+ NSCLC: analysis of long-term 
responders in the LUX-Lung 3, 6, and 7 trials. Lung Cancer (Neth) 133, 10 
- 19 (2019).
P19-03125
Park K, Bennouna J, Boyer M, Hida T, Hirsh V, Kato T, et al Sequencing
of therapy following first-line afatinib in patients with EGFR mutation-
positive non-small cell lung cancer. Lung Cancer (Neth) 132, 126 - 131 

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(2019).
P19-03686
Buder A, Setinek U, Hochmair MJ, Schwab S, Kirchbacher K, Keck A, et 
al. EGFR mutations in cell-free plasma DNA from patients with advanced 
lung adenocarcinoma: improved detection by droplet digital PCR. Targeted 
Oncol 2019;14(2):197-203.
P19-04170
FDA broadens afatinib indication to previously untreated, metastatic 
NSCLC with other non-resistant EGFR mutations. Available at:
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-
broadens-afatinib-indication-previously-untreated-metastatic-nsclc-other-
non-resistant-egfr
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 Study Master File 
(Trial Master File).

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ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS

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001-MCS-90-124_RD-01 (4.0)

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001-MCS-90-124_RD-01 (4.0)

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001-MCS-90-124_RD-01 (4.0)

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001-MCS-90-124_RD-01 (4.0)

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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

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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clinical-trial-protocol-version-03
UpSwinG: Real World study on TKI activity in Uncommon mutations  and
Sequencing Giotrif
Approval-Team Member Medicine
21 Jul 2020 16:30 CEST
Approval
Safety Evaluation
Therapeutic Area
21 Jul 2020 16:36 CEST
Approval
of Global
Epidemiology
21 Jul 2020 17:10 CEST
Verification-Paper Signature
Completion
24 Jul 2020 15:12 CEST

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Meaning of Signature  
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