J-REGISTER: Japanese REal-world Data for Treatment of Afatinib (GIotrif®) in First-line Setting and Subsequent Therapies for Patients With Advanced EGFR Mutation-positive Lung Adenocarcinoma
Conditions: Non-squamous, Non-Small Cell Lung Cancer
Sponsor: Boehringer Ingelheim

001-MCS-90-124_RD-01 (4.0)
 
Protocol for non-interventional studies based on existing data
 
Document number:
N/A
BI study number:
1200-0322
BI investigational
product(s):
Giotrif® (afatinib)
Title:
J-REGISTER: Japanese REal-world data for treatment of 
afatinib (GIotrif®) in first-line setting and Subsequent Therapies 
for patients with advanced EGFR mutation-positive lung 
adenocarcinoma
Lay title:
Non-interventional study for real-world data of afatinib 
treatment in first-line setting and of subsequent therapies for 
patients with advanced EGFR mutation-positive lung 
adenocarcinoma 
Protocol version 
identifier:
2.0
Date of last version of 
protocol:
PASS:
No
EU PAS register 
number:
N/A
Active substance:
Afatinib (ATC code: L01XE13)
Medicinal product:
Giotrif®: 50mg, 40mg, 30mg, 20mg tablet
Product reference:
Giotrif®:
20mg: Japan/22600AMX00017000
30mg: Japan/22600AMX00018000
40mg: Japan/22600AMX00019000
50mg: Japan/22600AMX00020000
Procedure number:
N/A
Joint PASS:
No
Research question and 
objectives:
Determination of time on treatment (TOT) related to afatinib
treatment as first-line therapy in patients with EGFR mutation-
positive NSCLC.
Country(-ies) of study:
Japan
Not applicable

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Author:
Tel.:
Fax:
email: 
Marketing authorisation 
holder(s):
Date:
4 September 2020
Page 1 of 42
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001-MCS-90-124_RD-01 (4.0)
1.
TABLE OF CONTENTS
 
.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 7
3.1
Sponsor.............................................................................................................. 7
3.2
Sponsor's medical expert................................................................................... 7
3.3
Contract research organisation.......................................................................... 7
3.4
Investigators and study site personnel............................................................... 8
3.5
Statistical analysis............................................................................................. 8
3.6
Data management.............................................................................................. 9
3.7
Pharmacovigilance............................................................................................ 9
3.8
Quality assurance .............................................................................................. 9
4.
ABSTRACT......................................................................................................... 10
5.
AMENDMENTS AND UPDATES..................................................................... 14
6.
MILESTONES..................................................................................................... 15
7.
RATIONALE AND BACKGROUND................................................................ 16
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 19
9.
RESEARCH METHODS .................................................................................... 20
9.1
STUDY DESIGN............................................................................................ 20
9.2
SETTING........................................................................................................ 20
9.2.1
Selection of study population.................................................................. 20
9.3
VARIABLES .................................................................................................. 22
9.3.1
Exposures ................................................................................................ 23
9.3.2
Outcomes................................................................................................. 23
9.3.2.1
Primary outcomes..................................................................................23
9.3.2.2
Secondary outcomes..............................................................................23
9.3.3
Covariates................................................................................................ 24
9.4
DATA SOURCES........................................................................................... 24
9.4.1
Source documents ................................................................................... 24
9.4.2
Records.................................................................................................... 24
9.4.3
Direct access to source data and documents ........................................... 24

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9.4.4
Storage of records.................................................................................... 25
9.5
STUDY SIZE.................................................................................................. 25
9.6
DATA MANAGEMENT................................................................................ 25
9.7
DATA ANALYSIS......................................................................................... 26
9.7.1
Safety analysis......................................................................................... 26
9.8
QUALITY CONTROL................................................................................... 26
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 27
9.10
External and internal validities ....................................................................... 28
9.11
OTHER ASPECTS ......................................................................................... 28
9.11.1
Statement of confidentiality .................................................................... 28
9.11.2
Patient completion................................................................................... 29
9.11.3
Completion/termination of study ............................................................ 29
9.12
SUBJECTS...................................................................................................... 30
9.13
BIAS................................................................................................................ 30
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 31
10.1
DATA PROTECTION and STUDY RECORDS ........................................... 31
10.2
Study approval ................................................................................................ 31
10.3
Patient information, and informed consent..................................................... 31
10.4
cOMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
STUDY RELATED INJURY......................................................................... 33
10.5
Predictable benefit and risk............................................................................. 33
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 34
11.1
Definitions of adverse events.......................................................................... 34
11.2
Adverse event and serious adverse event collection and reporting................. 35
11.3
Reporting to health authorities........................................................................ 37
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
informaiton / RESULTS...................................................................................... 38
12.1
Registry........................................................................................................... 38
12.2
Publication ...................................................................................................... 38
12.3
Research funding............................................................................................. 38
12.4
Conflict of interest........................................................................................... 38
13.
REFERENCES .................................................................................................... 39
13.1
PUBLISHED REFERENCES......................................................................... 39
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 41

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ANNEX 2. ADDITIONAL INFORMATION.............................................................. 42
ANNEX 2.1 ECOG PERFORMANCE STATUS...................................................... 42
2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
ATC
Anatomical Therapeutic Chemical
BI
Boehringer Ingelheim
CI
Confidence Interval
CRO
Contract Research Organisation
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EGFR
Epidermal Growth Factor Receptor
EGFR-TKI
Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor
eTMF
Electronic Trial Master File
HR
Hazard Ratio
ICF
Informed Consent Form
IRB
Institutional Review Board
ISF
Investigator Site File
LL3
LUX-Lung 3 study
NBI
Nippon Boehringer Ingelheim
NIS
Non-Interventional Study
NSCLC
Non-Small Cell Lung Cancer
OS
Overall Survival
PD
Progressive Disease
PFS
Progression Free Survival
PS
Performance Status
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan

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001-MCS-90-124_RD-01 (4.0)
SOP
Standard Operating Procedures
TMF
Trial Master File
TOT
Time on Treatment
TOT1
First-line TOT
TTF
Time-to-Treatment Failure
TTP
Time to Progression
UMIN
University hospital Medical Information Network

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Tel.: 
The responsible person prepares the draft SAP and statistical analysis.
3.6
DATA MANAGEMENT
Tel.: 
The responsible person for data management has the responsibility of preparing the data 
management plan and is responsible for the operation of data management.
3.7
PHARMACOVIGILANCE
Tel.:
 
Tel.: 
The responsible person for pharmacovigilance has the responsibility of safety reporting.
3.8
QUALITY ASSURANCE
The responsible person for quality assurance prepares the audit plan and conducts an audit.

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001-MCS-90-124_RD-01 (4.0)
4.
ABSTRACT
Name of company:
Nippon Boehringer Ingelheim Co., Ltd.
Name of finished medicinal product:
Giotrif®
Name of active ingredient:
Afatinib (ATC code: L01XE13)
Antineoplastic agents
Tyrosine kinase inhibitors
Protocol date:
4 Sep 2020
Study number:
1200-0322
Version/Revision:
1.0
Version/Revision 
date:
-
Title of study:
J-REGISTER: Japanese REal-world data for treatment of afatinib 
(GIotrif®) in first-line setting and Subsequent Therapies for patients with 
advanced epidermal growth factor receptor (EGFR) mutation-positive lung 
adenocarcinoma
Rationale and 
background:
Afatinib was commercialised on 7 May 2014 in Japan for treatment of 
patients with metastatic non-small cell lung cancer (NSCLC) whose 
tumours have activating epidermal growth factor receptor (EGFR) 
mutations, and the approval of afatinib was based on the results observed 
in the pivotal trial LUX-Lung 3 study (LL3).
There is a dearth of information regarding afatinib treatment in first-line 
setting, such as proportion of acquired resistance of T790M mutation, 
treatment status of subsequent therapy for patients having acquired 
resistance other than T790M mutation, and existence of consistent time on 
treatment (TOT) with afatinib followed by osimertinib for Japanese 
patients comparing to Asian patients in GioTag study which was 
conducted as an international non-interventional study (NIS).
Although retrospective analyses of Japanese patients enrolled in LL3 or 
other related studies showed consistent results between the studies, the 
available sample size is very limited to be conclusive for the consistency. 
Therefore, the better sequence of treatment in use of EGFR tyrosine kinase 
inhibitor (TKI) is still unclear for patients with harbouring EGFR 
mutation.
Based on the background, a NIS was planned to observe TOT related to 
afatinib treatment in the first-line setting with TOT of subsequent therapies 
in patients with EGFR mutation-positive NSCLC. 
Research question 
and objectives:
The primary objective is to confirm TOT related to afatinib treatment as 
first-line therapy (TOT1) in patients with EGFR mutation-positive 
NSCLC. The TOT of subsequent second-line therapy (TOT2) would be 
extracted in secondary objectives. The observation in the real-world setting 
of the time from the start of the first-line afatinib until the end of 
subsequent treatment in this study will provide insights on the sequence of 
treatment for patients. The Japanese healthcare system will enable this 
study to evaluate multiple treatment options after afatinib treatment.

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-
This study was designed as a non-interventional, multi-centre study 
from existing data of patients who were treated with afatinib in the 
first-line setting in each study site after the launch of Giotrif® on 7 
May 2014 on a regular basis; their information will be chosen. In first 
round of data extraction, the data will be extracted retrospectively 
once patients are enrolled into this study. A second round of data 
extraction for additional follow-up for information of survival will be 
performed one year after completion of first round data extraction.
Study design:
Non-interventional, multi-centre study from existing data of patients 
treated with afatinib as the first-line treatment
Population:
The patients who were treated with afatinib in the first-line setting in each 
study site after the launch of Giotrif® on 7 May 2014 on a regular basis; 
their information will be chosen.
Inclusion criteria
All patients will be consecutively included from each study site, if all the 
following criteria are present:
1.
Patients with EGFR mutation-positive advanced NSCLC
2.
Patients who were/are treated with afatinib in the first-line setting at 
least 20 months* prior to data entry
3.
Patients 20 years of age or older at the time of consent
4.
Patients who provided consent to participate in this study (for cases 
of death or lost to follow-up, instructions from the Ethics 
Committee [EC] / Institutional Review Board [IRB] at each site 
should be followed)
*Inclusion will be restricted to patients with treatment initiation with 
afatinib at least 20 months prior to enrolment to avoid early censoring.
Exclusion criteria
Patient will not be included if any of the following criteria are present:
1.
Any contraindication to afatinib as specified in the label of Giotrif®
2.
Patients treated with afatinib within an interventional trial
3.
Patients with active brain metastases at start of afatinib treatment*
* Patients with non-active brain metastases (asymptomatic state) are 
eligible.

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Variables:
Patient and disease characteristics:
-
The status of informed consent and its date
-
Patient birthday
-
Gender
-
Smoking status at the start of afatinib treatment
-
Body weight and height at the start of afatinib treatment
-
Eastern Cooperative Oncology Group (ECOG) performance status 
(PS) (if available) at the start of afatinib treatment
-
Stage (IIIb, IIIc or IV) at the start of afatinib treatment
-
Previous treatment status to NSCLC and its setting (e.g. adjuvant 
[eligible except for afatinib treatment] or first-line setting [ineligible])
-
Type of EGFR mutations at initial diagnosis of NSCLC
Treatment pathways (details of treatments received):
-
Dates of start and end of afatinib treatment
-
Starting dose of afatinib
-
Modified dose of afatinib and dates of start and end for each 
modification
-
The progression status of brain metastasis in several lines
-
Type of EGFR mutations at the start of subsequent treatment in the 
second-line setting
-
Drug name of the subsequent treatment in the second-line setting
-
Dates of start and end of subsequent treatment in the second-line 
setting
-
Modified dose of subsequent treatment in the second-line setting and 
dates of start and end for each modification
-
Date of death
-
Reason for discontinuation of treatment in several lines (progressive 
disease [PD], adverse event [AE], or other[s])
-
Last date of confirmed survival or death at second round data 
extraction
Follow-up data will be extracted for the same patients, who were enrolled 
at patient recruitment period, one year after completion of first round 
(second round) during the study period.
Outcomes:
Primary outcome will be assessed as:
-
The time from the start of afatinib (Giotrif®) as first-line treatment 
until the end of afatinib treatment or death date by any cause (TOT1)
Secondary outcomes will be assessed as:

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-
TOT from the start of afatinib until end of subsequent therapies in the 
second-line setting or death date by any cause
-
TOT from start of the second-line treatment until end of the second-
line treatment or death by any cause (TOT2) Overall survival (OS) 
and survival rate at 18 and 36 months
-
Time to initial dose reduction of afatinib
-
Proportion of patients with dose modifications of afatinib
Safety criteria:
Drug exposure during pregnancy, adverse drug reactions (ADRs) with 
causality to Giotrif® (serious or non-serious) and all fatal AEs will be 
reported to pharmacovigilance on the NIS AE Form/Pregnancy Monitoring 
Form - excluding deaths to PD of the underlying malignancy (see Section 
11.2). Safety data will be reviewed and analysed as part of routine global 
pharmacovigilance procedures.
All AEs and ADRs collected per study protocol will be included and 
summarised in the final study report.
Data sources:
Data will be extracted from patients’ existing data and recorded in 
electronic case report forms (eCRFs).
Study size:
It is planned to enrol approximately 1000 patients across 50 sites.
Data analysis:
TOT with afatinib (TOT1) will be analysed using Kaplan-Meier method, 
and the median along with two-sided 95% confidence interval (CI) will be 
displayed (using the Greenwood’s formula for estimation of standard 
errors).
In the analyses of TOT1, missing or incomplete data will be managed by 
standard survival analysis techniques. Patients who are still on treatment or 
who are not known to have discontinued treatment will be censored on the 
date they are last verified to have been on treatment. 
Continuous variables will be presented as mean, median, minimum, 
maximum, Q1, Q3e, and standard deviation.
Categorical variables will be presented as absolute and relative frequency.
Milestones:
Start of data extraction in Q1 2021
End of data extraction in Q4 2022
Final report of study results expected in Q2 2023

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5.
AMENDMENTS AND UPDATES

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6.
MILESTONES
Milestone
Planned Date
Start of data extraction
Q1 2021
End of data extraction
Q4 2022
Registration in University 
hospital Medical
Information Network 
(UMIN)
Register number not yet assigned as the study is not 
yet registered. The study will be registered shortly 
before the start of data extraction.
Final report of study results
Q2 2023

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7.
RATIONALE AND BACKGROUND
Afatinib was commercialised on 7 May 2014 in Japan for treatment of patients with 
metastatic non-small cell lung cancer (NSCLC) whose tumours have activating epidermal 
growth factor receptor (EGFR) mutations 1, and the approval of afatinib was based on the 
results observed in the pivotal trial LUX-Lung 3 study (LL3).
In LL3, a total of 1269 patients were screened, and 345 patients were randomly assigned to 
treatment (afatinib or chemotherapy in the first-line setting). Median progression free survival 
(PFS) was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR]: 
0.58, 95% confidence interval [CI]: 0.43 to 0.78, p=0.001) 2. The Japanese group showed an 
extension of PFS compared to the LL3 overall. Median PFS was 13.8 months for afatinib and 
6.9 months for chemotherapy (HR: 0.38, 95% CI: 0.20 to 0.70, p=0.0014). The Japanese 
group in the afatinib arm showed 14.0 months in time on treatment (TOT) and an extension 
of median overall survival (OS) compared to the LL3 overall. In the meantime, the adverse 
event (AE) grade tended to be higher in Japanese group. The most common treatment-related 
AEs (all-grade) with afatinib in the Japanese population were diarrhoea (100.0%), rash/acne 
(100.0%), nail effects (92.6%), and stomatitis (90.7%). Although grade 3 diarrhoea and 
rash/acne occurred in Japanese patients receiving afatinib, these AEs did not lead to 
discontinuation. Compared with the overall LL3 population, Japanese patients were more 
likely to have an AE leading to dose reduction (57.2% vs 75.9%, respectively) 3.
In the real-world data from RealGiDo study, there were no new safety signals and there were 
fewer grade ≥3 adverse drug reactions (ADR)s (28.4% versus 48.9%) and serious adverse 
events (SAEs) (5.2% versus 14.0%) than in afatinib arm of LL3. The median time-to-
treatment failure (TTF) and median time to progression (TTP) in the first-line setting were 
18.7 and 20.8 months, respectively, and were not impacted by reduced starting dose or dose 
modification 4. Based on the outcomes from LL3 and RealGiDo, it is assumed that afatinib 
treatment duration under general practice in Japan may have been extended by improving 
experience of treatment management in comparison with LL3 where the treatment setting 
was the same as the general practice.
Although EGFR Tyrosine Kinase Inhibitors (TKI) provides significant clinical benefit in 
patients with EGFR-mutant NSCLC, approximately 50–70% of the patients acquire T790M 
resistance mutation 5, 6, 7, 8, 9. Based on a result of a real-world molecular testing in the patients 
with Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) treatment 
failure in Japan, the EGFR T790M secondary mutation was detected in 25.8% of the patients. 
The detection rate of T790M was limited 10.
Osimertinib was commercialised on 25 May 2016 in Japan as a third generation EGFR-TKI 
and a standard of care for patients whose tumour developed the acquired T790M resistance 
mutations during previous EGFR-TKI treatments. The reason for approval condition was 
replaced to the result from AURA3 study after the results were available. The result of this 
study shows 10.1 months of median PFS with the osimertinib (HR: 0.30, 95% CI: 0.23 to 
0.41, p<0.001) after the first-line EGFR-TKI (gefitinib: 59%, erlotinib: 34% and afatinib: 
7%) in comparison with the chemotherapy (4.4 months) 11.

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The real-world data from GioTag study suggested the sequential treatment of afatinib 
followed by osimertinib was one of the effective treatment options. Overall median TOT was 
about 27.6 months (with 14.3 months of median TOT with osimertinib) in all patients with 
T790M mutation. Furthermore, a median TOT of 46.7 months in the Asian group tended to 
be prolonged (19.6 months of median TOT with osimertinib) 12.
In FLAURA study, osimertinib has shown the extension of the median PFS as 18.9 months 
(HR: 0.46, 95% CI: 0.37 to 0.57, p<0.001) in patients with previously untreated, EGFR 
mutation-positive advanced NSCLC in comparison with first-generation EGFR-TKI 
(gefitinib: 66%, erlotinib: 34%) 13.
Although osimertinib was approved as the first-line setting based on the results of FLAURA 
study, osimertinib is only option for patients with acquired T790M mutation after treatment 
with EGFR-TKI. The significant difference on OS data between osimertinib and first-
generation EGFR-TKI as standard of care were reported for intention to treat population 14. 
However, the difference of OS was notably small for Asian population (HR: 1.00, 95% CI: 
0.75 to 1.31). Also, afatinib was not included in FLAURA, difference on OS benefit is still 
unclear between osimertinib and afatinib in Asian patients.
Afatinib and osimertinib have demonstrated significant extension of median PFS versus first-
generation EGFR-TKI, however these is no direct comparison as first-line setting between 
two compounds.
Based on the retrospective analysis of Japanese patients enrolled in LL3, of the Japanese 
patients who were assigned to afatinib and had discontinued afatinib (47 patients), 18 patients 
(38%) received platinum-based combination chemotherapy, eight patients (17%) received 
first-generation EGFR-TKI, and two patients (4%) received single agent chemotherapy in 
second-line setting 15. The median TOT with first-generation EGFR-TKI was similar and 
range of TOT was broader in comparison with platinum-based chemotherapy in second-line 
setting (median [range]: 4.1 [0.7–15.7] versus 4.0 [0.4–41.0]).
A retrospective analysis of 1660 Japanese patients with EGFR mutation-positive NSCLC 
reported a median OS of 30.8 months, with EGFR-TKIs representing major components of 
the treatment regimens used in the real-world setting. It was common for Japanese patients in 
this cohort to switch between EGFR-TKIs and to receive multiple courses of EGFR-TKI 
therapy, suggesting that switching and re-challenge are common practice in Japan and might 
further extend the survival of patients with EGFR mutation-positive NSCLC 16. There is no 
inconsistency between the results of Japanese subgroup in LL3 and Japanese retrospective 
analysis mentioned above, however the available sample size from Japanese subgroup in LL3 
is very limited to be conclusive for the consistency. Also, osimertinib was given to only one 
Japanese patient in second-line setting in LL3 15. Therefore, the better sequence of treatment 
in use of EGFR-TKI is still unclear for patients with harbouring EGFR mutation.
In addition, there is a dearth of information regarding afatinib treatment in first-line setting, 
such as proportion of acquired resistance of T790M mutation, treatment status of subsequent 
therapy for patients having acquired resistance other than T790M mutation, and existence of 

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consistent TOT with afatinib followed by osimertinib for Japanese patients comparing to 
Asian patients in GioTag study which was conducted as an international non-interventional 
study (NIS).
Even in patients without T790M mutation, Japan has an effective and easily accessible 
healthcare system and reimbursement policies. Therefore, Japanese patients can receive the 
opportunity for more treatment options.
Based on the background, NIS was planned to observe TOT related to afatinib treatment in 
first-line setting with TOT of subsequent therapies in patients with EGFR mutation-positive 
NSCLC. The observation in this real-world setting of the time from the start of the first-line 
afatinib until the end of subsequent treatment in this study will provide insights on the 
sequence of treatment for patients. The Japanese healthcare system will enable this study to 
evaluate multiple treatment options after afatinib treatment.

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8.
RESEARCH QUESTION AND OBJECTIVES
The primary objective is to confirm TOT related to afatinib treatment as the first-line therapy 
(TOT1) in patients with EGFR mutation-positive NSCLC. The TOT of subsequent second-
line therapy (TOT2) would be extracted in secondary objectives. The observation in the real-
world setting of the time from the start of the first-line afatinib until the end of subsequent 
treatment in this study will provide insights on the sequence of treatment for patients. The 
Japanese healthcare system will enable this study to evaluate multiple treatment options after 
afatinib treatment.
This study was designed as a non-interventional, multi-centre study from existing data of 
patients who were treated with afatinib in the first-line setting in each study site after the 
launch of Giotrif® on 7 May 2014 on a regular basis; their information will be chosen. In first 
round of data extraction, the data will be extracted retrospectively once patients are enrolled 
into this study. A second round of data extraction for additional follow-up for information of 
survival will be performed one year after completion of first round data extraction.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a non-interventional, multi-centre study from existing data of patients treated with 
afatinib as the first-line treatment.
In total, about 1000 eligible patients in 50 sites are planned to be enrolled to this study.
The study will involve secondary use of data. Since the extracted data will also include 
genetic data, the appropriate strategies to ensure data protection (such as strong 
authentication) will be implemented in the electronic case report forms (eCRF) employed for 
data extraction.
9.2
SETTING
It is planned that around 50 study sites in Japan will be participating in this NIS and about 
1000 eligible patients will be enrolled to the study consecutively per each site. Every patient 
who fulfils inclusion and exclusion criteria and agree to participate in the study will be 
selected until the required sample size is achieved. Deceased patients should be enrolled 
whenever possible. Instructions from the Ethics Committee (EC) / the Institutional Review 
Board (IRB) at each site should be followed. Investigators who fails 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 sites may be recruited.
Recruiting of patients for this study is competitive, i.e., recruitment will stop at all sites when 
it is determined that a sufficient number of patients have been enrolled. A maximum of 
50 patients (5% of all patients) will be limited for enrolment per site to avoid differential 
study site influence on study results. 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
Patient selection:
The patients who were treated with afatinib in the first-line setting in each study site after the 
launch of Giotrif® on 7 May 2014 on a regular basis; their information will be chosen.
Inclusion criteria
All patients will be consecutively included from each study site, if all the following criteria 
are present:
1. Patients with EGFR mutation-positive advanced NSCLC
2. Patients who were/are treated with afatinib in the first-line setting at least 20 months* 
prior to data entry

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g
Patients treated with afatinib (Giotrif®) in interventional trials are excluded to ensure the non-
interventional setting of this study. All patients fulfilling inclusion and exclusion criteria from 
a study site will be enrolled to avoid bias. A log of all patients included in the study will be 
maintained in the Investigator Site File (ISF) at the study site.
9.3
VARIABLES
The following data will be extracted retrospectively from existing data for patients who 
received afatinib (Giotrif®) as first-line treatment during the period from launch of afatinib 
(Giotrif®) to at least 20 months prior to the time point of enrolment of patients (first round), 
and follow-up for information of survival will be extracted for the same patients one year 
after completion of first round during the study period (second round). These data will be 
recorded in the eCRF by investigators (or designees):
Patient and disease characteristics:

The status of informed consent and its date

Patient birthday

Gender

Smoking status at the start of afatinib treatment

Body weight and height at the start of afatinib treatment

Eastern Cooperative Oncology Group (ECOG) performance status (PS) (if available) at 
the start of afatinib treatment

Stage (IIIb, IIIc or IV) at the start of afatinib treatment

Previous treatment status to NSCLC and its setting (e.g. adjuvant [eligible except for 
afatinib treatment] or first-line setting [ineligible])

Type of EGFR mutations at initial diagnosis of NSCLC
Treatment pathways (details of treatments received):

Dates of start and end of afatinib treatment

Starting dose of afatinib

Modified dose of afatinib and dates of start and end for each modification

The progression status of brain metastasis in several lines

Type of EGFR mutations at the start of subsequent treatment in the second-line setting

Drug name of the subsequent treatment in the second-line setting

Dates of start and end of subsequent treatment in the second-line setting

Modified dose of subsequent treatment in the second-line setting and dates of start and 
end for each modification

Date of death

Reason for discontinuation of treatment in several lines (progressive disease (PD), AE, 
or other[s])

Last date of confirmed survival or death at second round data extraction

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Figure Timing and variables of data extraction
9.3.1
Exposures
Afatinib (Giotrif®):
Patients were treated with afatinib (Giotrif®) 50, 40, 30, or 20 mg tablet once daily as 
indicated in the approved labels of afatinib (Giotrif®).
The Summary of Product Characteristics on afatinib is contained in the ISF.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
The primary outcome of this study is TOT with afatinib in TOT1. This will be assessed as the 
time from the start of afatinib (Giotrif®) as first-line treatment until the end of afatinib 
treatment or death date by any cause.
9.3.2.2
Secondary outcomes

TOT from the start of afatinib until end of subsequent therapies in the second-line 
setting or death by any cause

TOT from start of the second-line treatment until end of the second-line treatment or 
death by any case (TOT2), OS and survival rate at 18 and 36 months

Time to initial dose reduction of afatinib

Proportion of patients with dose modifications of afatinib

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9.3.3
Covariates
NA.
9.4
DATA SOURCES
Data will be extracted from patients’ existing data and recorded in eCRFs.
9.4.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data extracted. Source documents are filed at the study 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 existing data or transfer records, and current 
existing data must be available.
For eCRFs, all data must be derived from source documents.
9.4.2
Records
Case report forms for individual patients will be provided by Nippon Boehringer Ingelheim 
(NBI) or appointed the contract research organisation (CRO) via Electronic Data Capture 
(EDC) system.
9.4.3
Direct access to source data and documents
The investigator / study site will permit study related monitoring, audits, EC / IRB 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 NBI’s clinical study monitor, 
auditor and inspection by health authorities (e.g. FDA). The clinical research associate / 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.S_9_4_1

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9.4.4
Storage of records
Study site (s):
The study site(s) must retain the source documents and essential documents (including ISF) 
according to contract or the local requirements valid at the time of the end of the study
(whatever is longer).
NBI:
NBI must retain the essential documents according to BI’s SOPs.
It is the responsibility of NBI to inform the investigator / study site as to when these 
documents no longer need to be retained. After the retention period will pass over, the data 
will be disposed appropriately under protection of the privacy.
9.5
STUDY SIZE
It is assumed that the median time on treatment with afatinib (TOT1) is 13.1 months 
according to the result of Japanese data in LL3 17.
Based on the assumption that TOT1 follows an exponential distribution with a median of 
13.1 months and 5% of censoring probability, the table below shows the required sample size 
to keep the expected 95% CI within the specified width.
Table 9.5.1
95% confidence interval width (months)
2
3
4
5
Sample size
698
313
178
116
nQuery Version 8.5.0.0
In order to get the estimate of median TOT1 in overall study population with sufficient 
precision, at least 698 patients will be needed.
Considering the other objectives of this study to estimate the median TOT1 in subgroups of 
mutation and the feasibility of patient recruitment, 1000 patients will be enrolled to increase 
the precision of the estimate within each subgroup as much as possible.
9.6
DATA MANAGEMENT
Data will be extracted in EDC system prepared by NBI or appointed CRO. The details of data 
management procedures to ensure the quality of the data will be described in the Statistical 
Analysis Plan (SAP) available in electronic Trial Master File.

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9.7
DATA ANALYSIS
TOT1 will be analysed using Kaplan-Meier method, and the median along with two-sided 
95% CI will be displayed (using the Greenwood’s formula for estimation of standard errors).
In the analyses of TOT1, missing or incomplete data will be managed by standard survival 
analysis techniques. Patients who are still on treatment or who are not known to have 
discontinued treatment will be censored on the date they are last verified to have been on 
treatment.
Continuous variables will be presented as mean, median, minimum, maximum, Q1, Q3, and 
standard deviation.
Categorical variables will be presented as absolute and relative frequency.
The secondary outcomes will be analysed similarly to the primary outcome.
The subgroup analysis is also planned. The subgroup categories described below will likely 
need to be modified, depending upon the numbers of patients observed in each potential 
subgroup. Some analyses might be limited to listings of data, or not performed, for categories 
with few patients.
Subgroups:

Patient and disease characteristics at the start of afatinib treatment [Outcomes
analysed: TOT1, TOT, OS, Time to initial dose reduction of afatinib]
o
baseline EGFR mutation status (common/uncommon and each 
mutation type; Del19, G719X, S768I, L858R, L861Q, Ins 20, Other)
o
ECOG PS (0/1, >=2)
o
brain metastases (Yes, No)

Type of EGFR mutation status at the initiation of second-line treatment 
(T790M + / − / unknown [not confirmed]) [Outcomes analysed: TOT, TOT2]

Type of treatment class for subsequent treatment in second-line setting
[Outcomes analysed: TOT, TOT2]

Initial dose of afatinib (Patients starting afatinib 40 mg will be analysed)
[Outcomes analysed: TOT1, TOT, OS, Time to initial dose reduction of 
afatinib]
9.7.1
Safety analysis
All AEs and ADRs collected per study protocol will be included and summarised in the 
interim safety analysis and 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 

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the division into sections and entry fields defined in the eCRF. To improve and ensure data 
quality, data checks will be performed automatically in the eCRF directly on electronic entry 
at the study site.
Plausible value ranges for numerical data entries and logical data and list entries will be filed 
in the eCRF. The tests for consistency and completeness based on this will be performed 
during entry in the eCRF. The validity of the recorded data will therefore be ensured by the 
validations incorporated in the documentation system, which highlight incorrect or 
implausible entries to the investigator or study site personnel.
If corrections are necessary after the data were saved, these will be documented in an audit 
trail.
For the further quality assurance of the documented patient observations, the CRO will 
perform a sample size-based source data verification on about 10% of included patients.
In accordance with the monitoring instruction, which will be separately prepared, persons in 
charge of monitoring should confirm that the study has been conducted in compliance with 
“Ethical Guidelines for Medical and Health Research Involving Human Subjects” and the 
protocol. When source data verification is conducted, after confirmation of various procedure 
manuals specified in the study, data in the source documents and entry in the EDC system 
should be cross-checked to confirm the integrity, accuracy and consistency of extracted data. 
After the completion of monitoring activities, monitoring reports should be prepared. In 
addition, persons in charge of monitoring should not leak information which he/she can 
obtain in the course of his/her work without any justifiable cause even after he/she is no 
longer engaged in the relevant work.
Patient replacement may be considered if there are major quality issues identified from the 
extracted data. The decision of whether or not to enforce a patient replacement will be made 
by NBI / 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 NBI or NBI’s 
designees or by ECs / IRBs or by regulatory authorities. The quality assurance auditor will 
have access to all existing data, 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:
The study results may be limited by the participation in the study of only those sites, that 
prescribe Giotrif® on a regular basis to ensure sufficient patient recruitment.
2. Patient population:

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Patients treated by investigators with less experience might experience more side effects 
during their treatment with Giotrif®.
3. Retrospective data collection:
The limitation may be due to data availability. Since no additional data will be extracted for 
the study purpose except from source data on existing data, the data which are not available 
in the existing data of patients will be considered as missing data.
External validity is provided by the broad inclusion criteria but limits to patients treated 
within the label, start dose of afatinib and at the selected, experienced sites.
9.10
EXTERNAL AND INTERNAL VALIDITIES
External validity
All patients will be consecutively included from each study site, if they meet all criteria for 
the patient selection. Subgroup analysis for patients who received 40 mg of afatinib initial 
dose will be performed to be compared with overall population in this study as real-world 
setting and LL3 as clinical trial setting.
Internal validity
All entries in the eCRF will be stored in a database. The structure of the database is based on 
the division into sections and entry fields defined in the eCRF. To improve and ensure data 
quality, data checks will be performed automatically in the eCRF directly on electronic entry 
at the study site.
The accuracy of data for external/internal validities, this will be ensured through the source 
data verification.
9.11
OTHER ASPECTS
9.11.1
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.
Medical information of subjects will be shared only with the parties directly involved in the 
study. All data will be coded before sharing. Subjects’ personal information will not be used 
in any documents. Only investigators and their teams, or several persons in charge in the 
organisation working with NBI of the study will be able to access the coded data and the 
information by which name of each subject can be identified. The third parties involved in the 
study and the parties of NBI shall comply with up-to-date standards for privacy. Once all 
information by which each subject can be identified is deleted from extracted data, the data 
will be determined as anonymised and considered as non-personal data.

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Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with “Ethical Guidelines for Medical and Health 
Research Involving Human Subjects”, “Act on the Protection of Personal Information” and 
related notifications which are applicable to the protection of personal information for 
subjects.
The parties involved in this study should give due consideration for the protection of personal 
information and privacy of subjects, and the information extracted for this study will be 
anonymised. However, a specific individual can be identified if a correspondence table is 
checked. The table will be stored by a personal information manager at the study sites under 
strict security.
The data of each subject and other information related to the study might be shared after 
anonymising for scientific and medical studies, such as sharing with researchers, disclosure 
of study information, sharing of the results with subjects participating the study, and 
disclosure of the results through publication. All information by which subjects can be 
identified will be deleted prior to data disclosure to protect privacy of subjects.
For the purpose of checking the quality of the study, NBI and a person who is entrusted by 
NBI with a task to support implementation of the study (e.g. monitor) may review the 
information which is not anonymised, such as existing data. Even in such cases, these parties 
are obliged to maintain confidentiality of subjects’ data and the personal information will be 
protected. Personal information which can be obtained only through the conduct of this study 
must not be leaked without any valid reason. The same will be applicable even after the 
parties involved in the present study have left their posts.
Data extracted as a result of the study need to be available for inspection on request by the 
participating investigators, NBI’s representatives, by the EC / IRB and the regulatory 
authorities.
9.11.2
Patient completion
The extraction of the data of patients will continue until end of data extraction or withdrawal 
of consent (if applicable) which occurs first.
9.11.3
Completion/termination of study
The end of the study will occur when the end of data extraction of the last patient’s data. No 
further data will be extracted afterwards.
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 
EC and NBI, of the completion in writing.

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NBI reserves the right to discontinue the study overall or at any particular study site at any 
time for the following reasons:
1. Failure to meet expected enrolment goals overall or at any particular study site.
2. Violation of the Study Protocol, “Ethical Guidelines for Medical and Health Research 
Involving Human Subjects” or the contract by a study site, disturbing the appropriate 
conduct of the study.
When interruption or termination of the study is decided upon, NBI and the CRO will 
document the reasons and the method to be used to inform enrolled subjects and study sites as 
soon as possible.
9.12
SUBJECTS
Please refer to Section 9.2.1 for Selection of study population.
9.13
BIAS
Methodological efforts have been taken to minimise selection bias: these efforts including 
only consecutive patients meeting each of the inclusion criteria and none of the exclusion 
criteria.
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 (Giotrif®) treatment, 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.

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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 
“Ethical Guidelines for Medical and Health Research Involving Human Subjects” and 
relevant CRO’s and BI’s SOPs. Standard medical care (prophylactic, diagnostic and 
therapeutic procedures) remains in the responsibility of the treating investigator of the 
patient.
The investigator should inform NBI 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 and “Ethical Guidelines for Medical and Health Research Involving Human 
Subjects”.
10.2
STUDY APPROVAL
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective EC / IRB before enrolment of subjects. The same applies for the 
implementation of changes introduced by amendments. Principal investigators are 
responsible for submitting and obtaining initial and continuing review of this study by their 
EC / IRB via the heads of study sites.
10.3
PATIENT INFORMATION, AND INFORMED CONSENT
Before enrolment, investigators or study site personnel should provide patients with 
information sheet approved by EC / IRB and describe following details, which should include 
in the information sheet.
1. Name of the study and the fact that permission for the conduct of the study has been 
obtained from the head of the study site
2. Names of the study site and the principal investigator
3. Objective and significance of the study
4. Method and period of the study
5. Reason why the patient has been selected as a subject
6. Costs to be paid by subjects and expected risks/benefits
7. The fact that subjects can withdraw their consent anytime even after they give 
consent to participate in or continue the study
8. The fact that subjects do not receive any disadvantages by refusing or withdrawing 
their consent to participate in or continue the study
9. Methods for the publication of information related to the study

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10. The fact that the subject can obtain or access the study protocol or documents related 
to methods of the study when they demand it in a manner which does not interfere 
with the protection of personal information of other subjects or securement of the 
originality of this study, as well as methods for obtaining or accessing such materials
11. Handling of personal information (including method of anonymisation)
12. Methods for storing and discarding samples/information
13. Status of conflict of interest (source of funding, possible conflict of interest, and 
relationships of investigators or other personnel with associated organisation)
14. Response to inquiries from subjects and related parties
15. Any financial burden for the subject (explanation of medical expense needs under 
general practice conditions)
16. If there is any possibility that samples/information obtained from subjects will be 
used for future research which cannot be identified at the time when informed consent 
is obtained from subjects, etc. or provided to other research study sites, the fact that 
such provision of samples/information may occur and details of such provision which 
can be assumed at the time of informed consent
17. Information about disclosure of personal information
18. The fact that subjects will not be paid for providing samples/information
19. The patient must be informed that his / her existing data may be examined by 
authorised monitors (e.g. CRO monitors) or Clinical Quality Assurance auditors 
appointed by NBI, by appropriate EC / IRB members, and by inspectors from 
regulatory authorities
The investigator or study site personnel, under the principal investigator's responsibility, 
should fully inform the participating patient on all aspects of the study including the 
information sheet. Patients should be informed to the fullest extent possible about the study, 
in language and terms they are able to understand.
Prior to a patient’s participation in the study, the Informed Consent Form (ICF) should be 
signed, name filled in and personally dated by the patient and/or their legally acceptable 
representative, and by the person who conducted the informed consent discussion. A copy of 
the signed and dated ICF will be provided to the patient.
EC / IRB may grant a waiver of consent for deceased patients. 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. Instructions from EC / IRB at each site should be followed.
If the consent is obtained from legally acceptable representative(s), the relationship between 
the patient and the legally acceptable representative should be documented on the ICF and be 
filed appropriately. Legally acceptable representative(s) should preferentially be parents, 
guardians of minor, relatives except for minors, or legal representatives.

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10.4
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
STUDY RELATED INJURY
Data will be extracted from patients treated within the conditions of the approved marketing 
authorisation of afatinib in this study, and all treatments are administered under the patients’ 
medical insurance policy, therefore, participation in this study will not cause any study 
related injuries, and participants in the study will pay their medical expenses.
In the event of health injury associated with marketed product in routine medical practice, 
NBI is not responsible for compensation.
10.5
PREDICTABLE BENEFIT AND RISK
Data will be extracted from patients in routine medical practice, therefore there are no 
changes in the therapeutic strategy for the subjects. There is no particular benefit or risk for 
subjects participating in this study. 

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
11.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An 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 AE 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 authorisation include off-label use, 
overdose, misuse, abuse and medication errors.
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 hospitalisation, 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 judgement 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 hospitalisation but might jeopardise 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 hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
An AE which possibly leads to disability will be reported as an SAE.
Adverse event of special interest (AESI)

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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 authorisation. 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 Giotrif® (serious or non-serious) 
and all fatal AEs will be reported to pharmacovigilance 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 AEs and ADRs collected per study protocol will be included and 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 (Giotrif®)
immediately within 24 hours
All AEs with fatal outcome in patients
exposed to afatinib (Giotrif®)
*Exemption applies
immediately within 24 hours
AE which possibly leads to disability in patients 
exposed to afatinib (Giotrif®)
immediately within 24 hours
All non-serious ADRs associated with afatinib 
(Giotrif®)
7 calendar days
Drug exposure during pregnancy
7 calendar days
The same timelines apply if follow-up information becomes available for the respective 
events.

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The investigator carefully assesses whether an AE constitutes an ADR using the information 
below.
Exemption
*Death due to disease progression of the underlying malignancy is a study outcome 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 Giotrif® and the
progression of the underlying malignancy, the event must be reported as an SAE on the NIS 
AE Form and eCRF.
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 AE. An adverse reaction, in 
contrast to an AE, is characterised by the fact that a causal relationship between a medicinal 
product and an occurrence is suspected.
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including the 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 aetiologies that could explain the event (e.g. pre-
existing 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 the 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 five half-lives).

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Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the study drug treatment continues or 
remains unchanged.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe: Incapacitating or causing an 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 (Giotrif®) the investigator must report any drug exposure 
during pregnancy, which occurred in a female subject to NBI by means of Part A of the 
Pregnancy Monitoring Form. The outcome of the pregnancy associated with 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 Giotrif®
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
AE reporting to regulatory agencies will be done by the Marketing Authorisation Holder 
according to local and international regulatory requirements.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY INFORMAITON / RESULTS
12.1
REGISTRY
The study plan and summary of this study will be recorded and published at the database 
“University hospital Medical Information Network (UMIN) Centre 
(https://www.umin.ac.jp/)”.
12.2
PUBLICATION
The rights of the investigator and of NBI about the publication of the results of this study are 
described in the investigator contract. As a rule, no study results should be published prior to 
the finalisation of the Study Report.
NBI intends to use data from this study to prepare peer-reviewed publications and other 
scientific communications such as abstracts, posters, and podiums presentations.
12.3
RESEARCH FUNDING
This study will be conducted as an industry-sponsored observational study with research 
funding provided by the study sponsor, NBI. NBI will take the ultimate responsibility for this 
study and delegate the operation of this study to the CRO. NBI will be involved in the 
protocol development, the CRO selection and advisement, reviewing and approving SAP, 
interpretation of study results, and confirmation of data management plan, however, will not 
be directly involved in the data management, source document verification at study sites, and 
statistical analysis.
12.4
CONFLICT OF INTEREST
NBI appropriately oversees the study conduct to ensure neutrality and equity in the 
management of any conflict of interest in accordance with local regulations, which may affect 
the interpretation of the results.
Investigators and study site personnel ensure that their conflict of interest will be confirmed 
by their local ECs or Conflict of Interest Committees in accordance with each site’s 
regulations, which may affect to the study plan and/or an interpretation of the study results. 
The status of that conflict of interest will be documented in the ICF, and consent should be 
obtained from patients after explanation is provided. When the study results are disclosed, the 
conflict of interest should be documented in detail in accordance with publication policies or 
guidelines of the appropriate academic society and its journal.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
1. Giotrif® Japanese package insert
2. J Clin Oncol 31(2013)3327-3334
Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. 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.
3. Cancer Sci 106(2015)1202–1211
Kato T, Yoshioka H, Okamoto I, Yokoyama A, Hida T, Seto T, et al. Afatinib versus 
cisplatin plus pemetrexed in Japanese patients with advanced non-small cell lung 
cancer harboring activating EGFR mutations: Subgroup analysis of LUX-Lung 3. 
Cancer Sci 106(9), 1202-1211, 2015.
4. Lung Cancer 127(2019)103-111
Halmos B, Tan EH, Soo RA, Cadranel J, Lee MK, Foucher P, et al. Impact of 
afatinib dose modification on safety and effectiveness in patients with EGFR 
mutation-positive advanced NSCLC: Results from a global real-world study 
(RealGiDo). Lung Cancer 127, 103-111, 2019.
5. Clin. Cancer Res 17(2011)1169–80
Arcila ME, Oxnard GR, Nafa K, Riely GJ, Solomon SB, Zakowski MF, et al. 
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.
6. Sci Transl Med 3(2011)75ra26
Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et 
al. Genotypic and histological evolution of lung cancers acquiring resistance to 
EGFR inhibitors. Sci Transl Med 3(75), 75ra26, 2011.
7. Clin Cancer Res 19(2013)2240-7
Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of 
tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 
patients with EGFR-mutant lung cancers. Clin Cancer Res 19(8), 2240-7, 2013.
8. Oncotarget 7(2016)12404–12413
Wu SG, Liu YN, Tsai MF, Chang YL, Yu CJ, Yang PC, et al. The mechanism of 
acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung 
adenocarcinoma patients. Oncotarget 7(11),12404-13, 2016.

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9. Target. Oncol 14(2019)75–83
Hochmair MJ, Buder A, Schwab S, Burghuber OC, Prosch H, Hilbe W, et al. Liquid-
Biopsy-Based Identification of EGFR T790M Mutation-Mediated Resistance to 
Afatinib Treatment in Patients with Advanced EGFR Mutation-Positive NSCLC, and 
Subsequent Response to Osimertinib. Target Oncol 14(1), 75-83, 2019.
10. Oncology and Therapy 6(2018)203-215
Seto T, Nogami N, Yamamoto N, Atagi S, Tashiro N, Yoshimura Y, et al. Real-
World EGFR T790M Testing in Advanced Non-Small-Cell Lung Cancer: A 
Prospective Observational Study in Japan. Oncology and Therapy 6, 203-215, 2018.
11. New Engl J Med. 376(2017)629-640
Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, et al. 
Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer. N 
Engl J Med 376(7), 629-640, 2017.
12. Future Oncol. 14(2018)2861-2874
Hochmair MJ, Morabito A, Hao D, Yang CT, Soo RA, Yang JC, et al. Sequential 
treatment with afatinib and osimertinib in patients with EGFR mutation-positive non-
small-cell lung cancer: an observational study. Future Oncol 14(27), 2861-2874, 
2018.
13. New Engl J Med. 378(2018)113-125
Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, 
et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung 
Cancer. N Engl J Med 378(2), 113-125, 2018.
14. New Engl J Med. 382(2020)41-50
Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al. 
Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. 
N Engl J Med 382(1), 41-50, 2020.
15. Future Oncol. 16(2020)49-60 
Yoshioka H, Kato T, Okamoto I, Tanaka H, Hida T, Seto T, et al. Therapies after 
first-line afatinib in patients with EGFRm+ NSCLC in Japan: retrospective analysis 
of LUX-Lung 3. Future Oncol 16(4), 49-60, 2020
16. Jpn J Clin Oncol. 46(2016)462-467
Inoue A, Yoshida K, Morita S, Imamura F, Seto T, Okamoto I, et al. Characteristics 
and overall survival of EGFR mutation-positive non-small cell lung cancer treated 
with EGFR tyrosine kinase inhibitors: a retrospective analysis for 1660 Japanese 
patients. Jpn J Clin Oncol 46(5), 462-7, 2016.
17. Oncology Research, 26(2018), pp. 1031–1036
Fujiwara A, Yoshida M, Fujimoto H, Nakahara H, Ito K, Nishihama K, et al. A 
Retrospective Comparison of the Clinical Efficacy of Gefitinib, Erlotinib, and 
Afatinib in Japanese Patients With Non-Small Cell Lung Cancer. Oncol Res 26(7), 
1031-1036, 2018.

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

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ANNEX 2. ADDITIONAL INFORMATION
ANNEX 2.1 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