A Regulatory Requirement Post-marketing Surveillance Study to Monitor the Safety and Efficacy of GIOTRIF® (Afatinib Dimaleate, 20mg, 30mg, 40mg, q.d) in Korean Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) With Epidermal Growth Factor Receptor (EGFR) Mutations or Patients With Locally Advanced or Metastatic NSCLC of Squamous Histology Progressing on or After Platinum-based Chemotherapy
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Boehringer Ingelheim

TITLE PAGE
Non-Interventional Study Protocol
Doc. No.: c02597942-07
BI Study No.:
1200.235
BI Investigational
Products:
afatinib dimaleate
Title:
A regulatory requirement post-marketing surveillance study to monitor 
the safety and efficacy of GIOTRIFP®
P(afatinib dimaleate, 20mg, 30mg, 
40mg, q.d) in Korean patients with locally advanced or metastatic non-
small cell lung cancer (NSCLC) with Epidermal Growth Factor 
Receptor (EGFR) mutations or patients with locally advanced or 
metastatic NSCLC of squamous histology progressing on or after 
platinum-based chemotherapy
Clinical Phase:
IV
Trial Clinical 
Monitor:
Phone: 
   Fax: 
Principal 
Investigator:
Not Applicable
Status:
Revised Protocol 
Version and Date:
Version : 7
Date : 18 May 2020
                         Page 1 of 64
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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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Non-interventional study protocol                      Protocol revision 
18 May 2020
BI Trial No.: 1200.235
Doc. No.: c02597942-07
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NON-INTERVENTIONAL STUDY PROTOCOL SYNOPSIS
Name of company/Marketing Authorisation 
Holder:
Tabulated
Study Protocol
Boehringer Ingelheim Korea
Name of finished product:
GIOTRIFP®
Name of active ingredient:
afatinib dimaleate
Protocol date:
Trial number:
Revision date:
18 May 2020
07 May 2014
1200.235
Title of study:
A regulatory requirement post-marketing surveillance study to monitor the safety and 
efficacy of GIOTRIFP®
P(afatinib dimaleate, 20mg, 30mg, 40mg, q.d) in Korean patients 
with locally advanced or metastatic non-small cell lung cancer (NSCLC) with 
Epidermal Growth Factor Receptor (EGFR) mutation(s) or  patients with locally 
advanced or metastatic NSCLC of squamous histology progressing on or after 
platinum-based chemotherapy
Principal    
Investigator:
Not Applicable
Study site(s) :
Multi-centre study
Clinical phase:
IV
Objectives:
To monitor the safety profile and efficacy of GIOTRIFP®
P(afatinib dimaleate, q.d) in 
Korean patients with locally advanced or metastatic non-small cell lung cancer 
(NSCLC) with Epidermal Growth Factor Receptor (EGFR) mutation(s) or patients with 
locally advanced or metastatic NSCLC of squamous histology progressing on or after 
platinum-based chemotherapy in a routine clinical practice setting
Methodology:
Observational prospective, non-interventional, open-label, multi-centre national study
No. of patients: 
Total entered:
1,149 approximately
each treatment: Single arm (N=1,149 approximately)
Diagnosis:
-
Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) 
with Epidermal Growth Factor Receptor (EGFR) mutation(s)
-
Patients with locally advanced or metastatic NSCLC of squamous histology 
progressing on or after platinum-based chemotherapy

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Non-interventional study protocol                      Protocol revision 
18 May 2020
BI Trial No.: 1200.235
Doc. No.: c02597942-07
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Name of company/Marketing Authorisation 
Holder:
Tabulated
Study Protocol
Boehringer Ingelheim Korea
Name of finished product:
GIOTRIFP®
Name of active ingredient:
afatinib dimaleate
Protocol date:
Trial number:
Revision date:
18 May 2020
07 May 2014
1200.235
Main criteria for 
inclusion:
Inclusion Criteria: 
1)
Patients who have been started on GIOTRIFP®
P  in accordance with the 
approved label in Korea 
2)
Age ≥19 years at enrolment
3)
Patients who have signed on the patient consent form
Exclusion Criteria:
1)
Known hypersensitivity to afatinib or any of its excipients
2)
Patients with rare hereditary conditions of galactose intolerance, the Lapp 
lactase deficiency or glucose-galactose malabsorption
3)
Patients for whom GIOTRIFP®
P is contraindicated according to the local label
Test product(s) :
afatinib dimaleate
dose:
20 mg, 30 mg, 40 mg q.d
mode of admin. : Oral administration
Comparator
product(s):
Not applicable
dose:
mode of admin. :
Duration of treatment:Treatment duration for   1) short-term surveillance: 8±2 weeks
                                       2) long-term surveillance: 24±2 weeks and 48±2 weeks
Study duration: 6 years. (MFDS set GIOTRIFP®
Pre-examination period from  29 January
2014 to 28 January 2020. Interim report planned biannually for the 
initial two years and annually thereafter by April 2020.)
Criteria for 
effectiveness: 
Disease Assessment will be based on the assessment of cancer related symptoms and, if 
available, radiologic assessments as per standard of care at the site.
Criteria for safety:
All reported adverse events in patients who take at least one dose of GIOTRIFP®
P based
on the current authorized label in Korea will be noted.
Endpoints pertaining to safety will be presented as incidence rates of adverse events
Statistical methods:
Descriptive statistics

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Non-interventional study protocol                      Protocol revision 
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BI Trial No.: 1200.235
Doc. No.: c02597942-07
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FLOW CHART
Data points
Baseline
Follow-
up 1
Follow-
up 2
Follow-
up 3
Follow-up 4
Visit Number
1
2
3
4
N/A
Week/s
0
8±2
24±2
48±2
End of PMS Period
Informed consent
X
Inclusion / Exclusion
X
Diagnosis
X
EGFR positive
X
Platinum-based chemotherapy
X
Demographics
X
Medical history
X
Concomitant medications
X
X
X
X
Physical examination
X
X
X
X
GIOTRIFP® 
PAdministration status
X
X
X
X
Safety Laboratory Testing – Optional P1)
X
X
X
X
Effectiveness endpoints P2)
X
X
X
Adverse events
X
X
X
Study completion
X
X
X
Overall survival P3)
X
1) Laboratory testing is optional at this study and may be performed at the discretion of investigator and in accordance to the current 
standard of care. 
2) Disease Assessment will based on the assessment of cancer related symptoms and, if available, radiologic assessments as per standard of 
care at the site.
3) Collection of information on death. In the case of OS data of the survived subject at the end of the study (Visit 4) is not available, 
information should be collected by telephone, letter contact with the patient. In Korea public records may be utilized to assess the 
mortality status for patients lost to follow up or where mortality information is not readily available through 3 attempted contacts. A 
formal study visit is not required.

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Non-interventional study protocol                      Protocol revision 
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BI Trial No.: 1200.235
Doc. No.: c02597942-07
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TABLE OF CONTENTS
TITLE PAGE .................................................................................................... 1
NON-INTERVENTIONAL STUDY PROTOCOL SYNOPSIS.................. 2
FLOW CHART................................................................................................. 4
TABLE OF CONTENTS ................................................................................. 5
ABBREVIATIONS........................................................................................... 8
1.
INTRODUCTION................................................................................... 10
1.1
MEDICAL BACKGROUND............................................................................10
1.2
DRUG PROFILE...............................................................................................11
2.
RATIONALE, OBJECTIVES, AND BENEFIT-RISK 
ASSESSMENT ........................................................................................ 12
2.1
RATIONALE FOR PERFORMING THE STUDY.......................................12
2.2
STUDY OBJECTIVES......................................................................................12
2.2.1
Primary objective...................................................................................12
2.2.2
Secondary objective ...............................................................................12
2.3
BENEFIT-RISK ASSESSMENT .....................................................................12
3.
DESCRIPTION OF DESIGN AND STUDY POPULATION............ 13
3.1
OVERALL DESIGN AND PLAN....................................................................13
3.1.1
Administrative structure of the study..................................................13
3.1.2
Study method..........................................................................................13
3.2
DISCUSSION OF STUDY DESIGN................................................................13
3.3
SELECTION OF POPULATION....................................................................14
3.3.1
Main diagnosis for study entry.............................................................14
3.3.2
Inclusion criteria....................................................................................14
3.3.3
Exclusion criteria ...................................................................................14
3.3.4
Removal of patients from therapy or assessments..............................14
3.3.4.1 Removal of individual patients (therapy or assessments) ..........14
3.3.4.2 Discontinuation of the study by the sponsor ..............................14
3.3.5
Subjects of special investigation ...........................................................15
4.
TREATMENTS....................................................................................... 16
4.1
PRESCRIBED TREATMENTS TO BE OBSERVED...................................16
4.1.1
Identity of test products and comparator products............................16
4.1.2
Method of assigning patients to treatment groups .............................16
4.1.3
Selection of doses in the study...............................................................16
4.1.4
Drug assignment and administration of doses for each patient ........16
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................17
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ...............................................................................................17
4.2.2
Restrictions.............................................................................................17
4.2.2.1 Restrictions regarding concomitant treatment............................17
4.2.2.2 Restrictions on diet and life style ...............................................17

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BI Trial No.: 1200.235
Doc. No.: c02597942-07
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5.
VARIABLES AND THEIR ASSESSMENT ........................................ 18
5.1
SAFETY..............................................................................................................18
5.1.1
Endpoints of safety.................................................................................18
5.1.2
Assessment of adverse events................................................................18
5.1.2.1 Definitions of adverse events .....................................................18
5.1.2.2 Adverse event and serious adverse event reporting ...................21
5.1.3
Assessment of safety laboratory parameters.......................................22
5.1.4
Assessment of other safety parameters................................................22
5.2
EFFECTIVENESS.............................................................................................22
5.2.1
Endpoints of effectiveness .....................................................................22
5.2.2
Assessment of effectiveness ...................................................................22
5.3
ITEMS OF INVESTIGATION ........................................................................22
5.3.1
Demographic data..................................................................................22
5.3.2
Medical/surgical history and pre-treatment experience ....................23
5.3.3
Concomitant medication .......................................................................23
5.3.4
Drug administration status ...................................................................23
5.3.5
Information on the site ..........................................................................24
5.3.6
Main points of study and details of study method ..............................24
5.4
ENDPOINTS OF SUBJECTS EVALUATION ..............................................24
5.4.1
Subject evaluation items........................................................................24
5.4.1.1 Number of cases who accepted the study...................................24
5.4.1.2 Number of cases subject who collected CRF.............................24
5.4.1.3 Number of dropouts....................................................................24
5.4.1.4 Number of cases subject to safety evaluation ............................24
5.4.1.5 Number of cases subject to efficacy evaluation...........................25
6.
SURVEILLANCE PLAN ....................................................................... 26
6.1
VISIT SCHEDULE............................................................................................26
6.2
DETAILS OF STUDY PROCEDURES AT SELECTED VISITS ...............26
6.2.1
Screening and run-in periods................................................................26
6.2.2
Treatment periods..................................................................................26
6.2.2.1 Visit 1 – Baseline Visit...............................................................26
6.2.2.2 Visit 2 (8±2 weeks from Visit 1)................................................26
6.2.2.3 Visit 3 (24±2 weeks from Visit 1)..............................................27
6.2.2.4 Visit 4 (48±2 weeks from Visit 1)..............................................27
6.2.3
End of trial and follow-up period.........................................................28
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE ........................................................................................ 29
7.1
STATISTICAL DESIGN - MODEL................................................................29
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................29
7.3
PLANNED ANALYSES....................................................................................29
7.3.1 Demographics and Baseline Characteristics analyses...........................29
7.3.2
Safety analyses........................................................................................29
7.3.2.1 Adverse Events by Demographics and Baseline Characteristics.30
7.3.2.2 Adverse Events by Preferred Terms ............................................30

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7.3.3
Main analyses of effectiveness...............................................................31
7.3.3.1 Progression-free survival .............................................................31
7.3.3.2 Tumour response according to investigator’s assessment ...........32
7.3.3.3 Overall Survival...........................................................................33
7.3.3.4 Demographics and Baseline Characteristics analyses of 
effectiveness ...............................................................................33
7.3.4
Interim analyses .....................................................................................34
7.4
HANDLING OF MISSING DATA ..................................................................34
7.5. RANDOMISATION ..........................................................................................34
7.6
DETERMINATION OF SAMPLE SIZE........................................................34
8.
DATA PROTECTION, STUDY RECORDS ....................................... 35
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................35
8.2
DATA QUALITY ASSURANCE.....................................................................35
8.3
RECORDS..........................................................................................................36
8.3.1
Source documents ..................................................................................36
8.3.2
Direct access to source data and documents........................................36
8.3.3
Storage of records ..................................................................................36
8.4
PROCEDURES FOR REPORTING ADVERSE EVENTS ..........................37
8.4.1
Time windows.........................................................................................37
8.4.2
Documentation of adverse events and patient narratives ..................37
8.5
STATEMENT OF CONFIDENTIALITY.......................................................37
8.6
PUBLICATION POLICY.................................................................................37
9.
REFERENCES........................................................................................ 38
9.1
PUBLISHED REFERENCES ..........................................................................38
9.2
UNPUBLISHED REFERENCES.....................................................................39
10. APPENDICES ......................................................................................... 40
10.1 ELECTRONIC CASE REPORT FORM........................................................40
10.2 SAE/ SPECIAL INTEREST OF AE REPORT FORM / NON-
SERIOUS ADVERSE REACTION REPORT................................................40
10.3 PREGNANCY MONITORING FORM ..........................................................40
10.4 LIST OF ALWAYS SERIOUS ADVERSE EVENTS....................................40
10.5 GIOTRIFP®P PRESCRIPTION INFORMATION FOR KOREA ..............40
11. SUMMARY OF NIS PROTOCOL MODIFICATIONS..................... 41

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BI Trial No.: 1200.235
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ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
ALT (SGPT)
Alanine Amino Transferase (Serum Glutamate Pyruvate Transaminase)
AST (SGOT)
Aspartate Amino Transferase (Serum Glutamic Oxaloacetic 
Transaminase)
BI
Boehringer -Ingelheim
BSC
Best Supportive Care
CA
Competent Authority
CR
Complete Response
CRF
Case Report Form
CRO
Contract Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Disease Control Rate
ECG
Electrocardiogram
eCRFs
electronic Case Report Forms
EDC
Electronic Data Capture
EGFR
EGFR TKI 
Epidermal Growth Factor Receptor
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
GCP
IB
Good Clinical Practice
Investigator’s Brochure
ICH
International Conference on Harmonization
ID
ILD
Identification
Interstitial lung disease
IRB
Institutional Review Board
ISF
Investigator Study File
KIMS
Korea Index of Medical Specialties
KPAC
Korean Pharmaceutical Affairs Code
KPMA
Korea Pharmaceutical Manufacturers Association
KRPIA
Korean Research based Pharmaceutical Industry Association 
LPVM
Local PharmacoVigilance Manager
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MFDS
Ministry of Food and Drug Safety
MPM
MTD
Medical Project Manager
Maximum Tolerated Dose
NCE
New Chemical Entity
NIS
Non-Interventional Study
NSCLC
Non-Small-Cell Lung Cancer
OR
OS
Objective Response
Overall Survival
PD
Progressive Disease
PFS
Progression-Free Survival
rNIS
regulatory Non Interventional Study

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RP
Partial Response
SAEs
Serious Adverse Events
SD
Stable Disease
SUSARs
Suspected Unexpected Serious Adverse Reactions
TSAP
Trial Statistical Analysis Plan

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer-related deaths in many 
countries, including Korea. The prognosis for advanced stage disease has improved modestly 
in the past 20 years. With an overall 5-year survival rate of only 15% the treatment of this 
disease clearly remains a major clinical challenge [40TUR05-0876U40T]. 
While systemic chemotherapy has demonstrated modest activity in advanced NSCLC, novel 
targeted therapies based on specific molecular and biological characteristics of lung cancer 
have emerged as a new treatment paradigm. Among the molecules most extensively studied 
are the Epidermal Growth Factor Receptors (EGFR) or the Subclass I of the superfamily of 
transmembrane tyrosine kinase receptors [40TUR06-1301U40T,
40TUR06-1302U40T]. 
Aberrant activation of EGFR frequently observed in a variety of malignant tumours can be 
induced by different molecular mechanisms including receptor overexpression, mutation, 
ligand-dependent receptor dimerization, and ligand-independent activation. Overexpression 
of EGFR has been detected in 40% to 80% of NSCLC patients [40TUR06-1301U40T, 40TUR06-1393U40T, 
40TUR06-1394U40T]. However, recent clinical experiences with specific EGFR-Tyrosine Kinase 
Inhibitors (TKI) have demonstrated tumour regression in only 10% to 15% of unselected 
NSCLC patients [40TUR05-0876U40T, 40TUR06-1301U40T, 40TUR06-1306U40T]. 
In the randomized Phase III trials 1200.32 and 1200.34, afatinib demonstrated superiority
over chemotherapy in patients with EGFR mutation positive stage IIIB/IV NSCLC who were
chemotherapy-naive and EGFR TKI therapy- naïve. In both phase III trials, treatment with 
afatinib significantly improved PFS as well as secondary endpoints of objective response rate 
and time to deterioration of cancer-related symptoms including cough and dyspnea. With
improvements, as demonstrated in trial 1200.32, in median PFS of 4.2 months (11.1 vs 6.9 
months) in the overall population and 6.7 months (13.6 vs 6.9 months) in patients with 
common mutations. Afatinib offers a clinically relevant first-line treatment option for such 
patients [40TUU12-1199-01U40T, 40TUU13-1625-01U40T].
The thorough analysis of the large safety database of afatinib showed that treatment with 
afatinib effectively delays disease progression in patients with NSCLC harbouring EGFR 
mutations in any line of therapy. This clinically meaningful delay in progression is associated 
with improvements in regard to the global health status and lung cancer [40TUU12-1482-01U40T].
The adverse event profile of afatinib is determined by its EGFR tyrosine-kinase targeting
mode of action, with the most common events being diarrhoea and the grouped terms 
ash/acne and stomatitis. The thorough analysis of the large safety database of afatinib showed 
that the most frequent adverse events of afatinib are predictable, related to its mode of action, 
and manageable by close monitoring, proactive treatment, and treatment interruption and 
dose reduction according to the well-defined dose reduction scheme [40TUU12-1482-01U40T].

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1.2
DRUG PROFILE
For the latest information on the drug profile of afatinib, please refer to the current local 
prescribing information of GIOTRIFP®
P(Attachment 5).

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2.
RATIONALE, OBJECTIVES, AND BENEFIT-RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE STUDY
According to the local regulations, when a new chemical entity (NCE) is registered, a 
regulatory non interventional study (rNIS) of an extended period (4 or 6 years) should be 
conducted. Such rNIS can provide supplementary data to monitor the safety of NCEs in a 
real-life situation. Data collected in randomised clinical trials with strict inclusion/exclusion
criteria and rigorous monitoring schemes have limitations.
This is a observational prospective, non-interventional, open-label, multi-centre national 
study. It will provide additional safety information of GIOTRIFP®
P(afatinib dimaleate, q.d) in 
Korean patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) 
with Epidermal Growth Factor Receptor (EGFR) mutation(s) or in patients with locally 
advanced or metastatic NSCLC of squamous histology progressing on or after platinum-
based chemotherapy in a routine clinical practice setting.
2.2
STUDY OBJECTIVES
2.2.1
Primary objective
To monitor the safety profile of GIOTRIFP®
P(afatinib dimaleate, q.d) as first line treatment in 
Korean patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) 
with Epidermal Growth Factor Receptor (EGFR) mutation(s) or in patients with locally 
advanced or metastatic NSCLC of squamous histology progressing on or after platinum-
based chemotherapy in a routine clinical practice setting.
2.2.2
Secondary objective
To evaluate the tolerability and efficacy of GIOTRIFP®
P(afatinib dimaleate, q.d) as first line 
treatment in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) 
harboring EGFR mutation(s) or in patients with locally advanced or metastatic NSCLC of 
squamous histology progressing on or after platinum-based chemotherapy.
2.3
BENEFIT-RISK ASSESSMENT
Patients will be managed according to the local practice guidelines. The choice of treatment
will be solely at the discretion of the participating physician. GIOTRIFP®
Pwill be administered 
according to the approved label in Korea. Hence there are no additional risks to patients by 
participating in this rNIS. 

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3.
DESCRIPTION OF DESIGN AND STUDY POPULATION
3.1
OVERALL DESIGN AND PLAN 
This rNIS is a observational prospective, non-interventional, open-label, multi-centre national 
study. As per regulation, the re-examination period extends from 29 Jan 2014 until 28 Jan 
2020. However, active enrolment is to be initiated in Oct 2014 after finalizing the re-
imbursement agreement with the authority. Before initiation of the study, any newly reported 
adverse events collected from other sources such as spontaneous cases, literature cases etc
will be closely monitored. The last patient follow up is expected in Jan 2020.
3.1.1
Administrative structure of the study
This study will be managed by a project manager of Boehringer Ingelheim Korea. Data 
management and statistics will be outsourced to a qualified contract research organization 
(CRO).
3.1.2
Study method
This study will be carried out in the manner of successive survey that the investigator will be 
asked to successively write in the case report forms(CRFs) from the subject who was initially 
administered the drug following the study start date to the requested number of subjects 
without omission. Prior to initiation of the study, written contract shall be concluded, and this 
contract shall be concluded with the head of the site or the investigator with his/her consent. 
3.2
DISCUSSION OF STUDY DESIGN
This is a single arm study with afatinib dimaleate.
Loss to follow up
All efforts will be made to minimize loss to follow up, particularly in the tracking of lost 
patients. To the extent possible, occurrence of adverse event, at minimum, for patients lost to 
follow up will be obtained. This allows assessing the impact of informative censoring due to 
treatment discontinuation. Also, patients lost to follow up will be characterized compared to 
the remaining patients and reason and time point of loss to follow up will be evaluated.
Confounding
As in any observational study, confounding may affect the estimation of associated between 
drug exposure and outcome of interest and statistical techniques. However, as only major 
confounders for selected research questions can be captured, residual (unmeasured) 
confounding may remain.

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3.3
SELECTION OF POPULATION
A total of 1,149 patients will be enrolled at approximately 50 sites by as many as 50 or more 
NIS physicians. To minimize the selection bias at the site level, the goal is to have 
participating centers reflect a balance between general hospitals and clinics for surveillance. 
The treating physicians will mainly be pulmonologist and oncologists. To minimize the 
selection bias, consecutive patients from each site who meet inclusion criteria will be enrolled 
in this study.
3.3.1
Main diagnosis for study entry
Patients diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC)
with EGFR mutation(s) or patients diagnosed with locally advanced or metastatic NSCLC of 
squamous histology progressing on or after platinum-based chemotherapy will be included.
3.3.2
Inclusion criteria

Patients who have been started on GIOTRIFP®
P  in accordance with the approved label 
in Korea 

Age ≥19 years at enrolment

Patients who have signed on the patient consent form
3.3.3
Exclusion criteria

Known hypersensitivity to afatinib or any of its excipients

Patients with rare hereditary conditions of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption

Patients for whom Afatinib is contraindicationed according local label of GIOTRIFP®
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients (therapy or assessments)
This section is not applicable.
3.3.4.2
Discontinuation of the study by the sponsor
Boehringer Ingelheim Korea reserves the right to discontinue the study overall or at a 
particular study site at any time for the following reasons:

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1. Emergence of any effectiveness/safety information that could significantly affect 
continuation of the study
2. Violation of applicable local regulations, the NIS protocol, or the contract by a study site 
or participating physician, disturbing the appropriate conduct of the study.
3.3.5
Subjects of special investigation
Any investigation for the elderly, pregnant women, and patients with renal impairment and 
hepatic impairment will not be separately conducted, and further investigation into cases 
collected from this study may be taken into account according to the outcome of retrospective 
analysis.

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4.
TREATMENTS
4.1
PRESCRIBED TREATMENTS TO BE OBSERVED
4.1.1
Identity of test products and comparator products
GIOTRIFP®
P will be prescribed according to the local label and at the discretion of the treating 
physician. Since this is a non-interventional study, the drug will not be supplied by the 
sponsor. Furthermore, the sponsor will not cover the expenses related to other medications 
taken by the patient, interventions, procedures, or diagnostic tests. 
4.1.2
Method of assigning patients to treatment groups
The choice of treatment is fully at the discretion of the physician and the patient. There is no 
treatment assignment by a third party.
4.1.3
Selection of doses in the study
The starting dose and the dose reduction schedule are based on the current authorized label in 
Korea.
4.1.4
Drug assignment and administration of doses for each patient
The physicians indicate doses and timing based on the current authorized label in Korea.
EGFR mutation status should be assessed when GIOTRIFP®
Pis administered as the 1Pst
P line treatment to 
patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).
GIOTRIFP®
P 40mg should be administered orally, once daily, at least 1 hour before a meal or
at least 3 hours after a meal. GIOTRIFP®
P should be taken without food and tablets should be 
swallowed whole with water. 
GIOTRIFP®
P should be interrupted when following adverse drug reactions occur; 

ADR ≥ NCI CTCAEP1
P grade 3

Diarrhoea ≥ grade 2 of not less than 2 days even during ongoing treatment of anti-
diarrhoeal medicines

Skin related adverse reaction  ≥ grade 2 (prolonged (not less than 7 days) or 
intolerable)

Renal impairment patient  ≥ grade 2
P1 
PNational Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v 3.0 
If adverse drug reaction is recovered to not more than Grade 1, GIOTRIFP®
P should be re-
administered with dose reduction by 10mg.
GIOTRIFP®
P should be discontinued permanently for following cases;

Severe bullous, blistering and exfoliative skin conditions

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
Interstitial Lung Disease

Severe hepatic impairment

Prolonged ulcerative keratitis

Left ventricular dysfunction

Severe or intolerable adverse reaction at the regimen of 20mg once daily
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
The protocol will allow additional drugs considered necessary for the patient’s welfare to be 
prescribed at the discretion of the treating physician. It is required, however, to record the 
details of all concomitant medication administered to the patient during the course of 
treatment in eCRF. This includes concomitant therapies started one month prior to 
GIOTRIFP®
P initiation until the patient completes the final follow-up visit.
4.2.1
Rescue medication, emergency procedures, and additional treatments
Please refer to the current local label.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Please refer to the current local label.
4.2.2.2 Restrictions on diet and life style
Please refer to the current local label.

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5.
VARIABLES AND THEIR ASSESSMENT
5.1
SAFETY
5.1.1
Endpoints of safety
All reported adverse events in patients who take at least one dose of GIOTRIFP®
P based on the 
current authorized label in Korea will be noted.
Endpoints pertaining to safety will be presented as incidence rates of adverse events and will 
include:

adverse events

unexpected adverse events

serious adverse events

drug-related adverse events

adverse events leading to discontinuation 

adverse events leading to dose reduction

adverse events by intensity, outcome of the event, causality 
5.1.2
Assessment of adverse events
5.1.2.1
Definitions of adverse events
UAdverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.
USerious Adverse Event
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for 
any other reason if it is an important medical event when based upon appropriate medical 
judgement which may jeopardise the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions.
The following hospitalizations are not considered to be serious adverse events (SAEs)
because there is no “adverse event” (i.e., there is no untoward medical occurrence) associated

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with the hospitalization:

Hospitalizations for respite care

Planned hospitalizations required by the protocol

Hospitalization planned prior to informed consent (where the condition requiring
the hospitalization has not changed post study drug administration)

Hospitalization for administration of study drug or insertion of access for
administration of study drug.
UAlways serious adverse events
BI has defined a list of adverse events that are considered as “always serious” (Attachment 4) 
by fulfilling the criterion “medically important event” by definition and are therefore judged 
as serious. If a non-serious AE meets this definition, a query will be raised. The investigator 
must verify the description and seriousness of the event. If the event description is correct, 
the item “serious” needs to be ticked and an SAE has to be reported in expedited fashion. The 
list of these adverse events can be found via the eCRF system
UAdverse drug reaction
Adverse drug reaction (ADR) refers to any harmful, unintended reaction to the 
pharmaceutical product of any dose at which a causal relationship with the pharmaceutical
product cannot be ruled out.
UNon Serious Adverse Drug Reaction
Non Serious Adverse Drug Reaction (NSADR) is defined as any ADR which does not meet 
the SAE criteria. 
UIntensity of adverse event
The intensity of the AE should be defined based on the following three categories and 
according to medical and scientific judgment:
Mild:
Transient symptoms which are subjective or objective but no interference with 
the patient’s daily activities. No change in dosage is needed to continue the 
treatment.
Moderate:
Marked symptoms with moderate interference with the patient’s daily 
activities. Reduced dosage or unplanned treatment is necessary for the relief of 
adverse events.
Severe:
Considerable and unacceptable interference with the patient’s daily activities. 
Discontinuation of the study drug is required because of significant adverse 
events.

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To ensure that no confusion or misunderstanding of the difference between the terms ‘serious’ 
and ‘severe’ which are not synonymous, it should be noted that SAE does not necessarily 
correspond to serious or not serious AE to severe ones. All SAEs will be reported regardless 
of the intensity as mentioned above.
UCausal relationship of adverse event
Medical judgment will be used to determine the causal relationship, after 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. Assessment of causal relationship will be recorded in the eCRF. 
Related
a. Certain: An event occurring in a plausible time relationship to drug administration and that 
cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (dechallenge) should be clinically plausible. The event must be 
definitive pharmacologically or phenomenologically, using a satisfactory rechallenge 
procedure if necessary.
b. Probable/Likely: An event with a reasonable time sequence to administration of the drug, 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows 
a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not 
required to fulfill this definition.
c. Possible: An event with a reasonable time sequence to administration of the drug, but 
which could also be explained by concurrent disease or other drugs or chemicals. Information 
on drug withdrawal may be lacking or unclear.
d. Conditional/Unclassified: Case of requiring more data or reviewing the additional data for 
the appropriate assessment
e. Unassessable/Unclassifiable: Case that it cannot be judged and complemented or 
confirmed due to the insufficient or contradictory information
Unrelated
a. Unlikely: An event with a temporal relationship to drug administration which makes a 
causal relationship improbable, and in which other drugs, chemicals or underlying disease 
provide plausible explanations.
UWorsening of the underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the (e)CRF.
UWorsening of underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an
(S)AE in the eCRF.

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If progressive disease occurs and is associated with symptoms , the term “Progressive
Disease” should not be reported as AE, however, signs and symptoms of progressive disease
will be reported as an (S)AE (if applicable). Exception to this: Death due to progressive
disease and where no signs or symptoms are available should be reported as “malignant
neoplasm progression”.
UChanges in vital signs, ECG, physical examination, and laboratory test results 
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an (S)AE in the (e)CRF, if they are judged clinically relevant by the NIS
physician.
5.1.2.2
Adverse event and serious adverse event reporting
All adverse events occurred from the signing date on ICF to 28 days after last administration 
date of medication need to be collected, documented and reported to the sponsor using the 
AE reporting form of eCRF (Attachment 1). All SAEs must be reported within 24 hours of 
occurrence via telephone/fax to the Local PV Manager (LPVM) of BI Korea using the SAE 
report form (Attachment2). If any new or further information to these events is available, a 
follow-up SAE report has to be sent to BI. All SAEs and non-serious AEs must include a 
causal relationship assessment from the physician. 
Non-serious ADR must be reported using eCRFs and NIS AE form within 7 calendar days, 
and all other Adverse Events must be reported using eCRFs within 2 weeks to the Sponsor. 
UContact details:  
Local PV Manager
Tel:  
Fax:  
Address: 
 
UPregnancy
Rarely, patients taking part in regulatory non interventional studies can get pregnant. Once a 
patient enrolled into the study and exposed to GIOTRIFP®
Pbecomes pregnant, the NIS
physician will stop the drug and report immediately to the sponsor. Drug exposure during 
pregnancy has to be reported immediately (within 24 hours or next business day, whichever 
is shorter) to LPVM. Furthermore, the details of all the drugs to which the patient exposed at 
the time of pregnancy will be recorded. The outcome of the pregnancy associated with the 

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drug exposure will be assessed. In the absence of an (S)AE, only the Pregnancy Monitoring 
Form (Attachment 3) for NIS, not the SAE form is to be completed. 
5.1.3
Assessment of safety laboratory parameters
This section is not applicable.
5.1.4
Assessment of other safety parameters
This section is not applicable.
5.2
EFFECTIVENESS
5.2.1
Endpoints of effectiveness
Disease Assessment will be based on the assessment of cancer related symptoms and, if 
available, radiologic assessments as per standard of care at the site.
Data regarding tumour assessments that are performed according to local standard of care for 
NSCLC may contribute to:

Progression-Free Survival (PFS), defined as time from the date of the first 
administration of afatinib to the date of progression or to the date of death, whichever 
occurs first

Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive 
Disease (PD) will be assessed by the investigator according to local standard pattern 
of care for NSCLC.

Overall Survival (OS), defined as time from the date of the first administration of 
afatinib to the date of death.
No specific tumour measurements are required per trial protocol.
5.2.2
Assessment of effectiveness
Data of Disease Assessment to be collected at each visit; Visit 1: Baseline / Visit 2 : 
8±2weeks / Visit 3 : 24±2weeks / Visit 4 : 48±2weeks.
In the case of OS data of the survived subject at the end of the study (Visit 4) is not available, 
the information should be collected by telephone, letter contact with the patient at the end of 
the PMS study period. 
5.3
ITEMS OF INVESTIGATION
5.3.1
Demographic data
For demographic evaluation, following background information of subjects shall be recorded:  

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
Subject signed date 

Subject study number 

Gender

Pregnancy

Height

Weight

Year/month of birth (age)

Smoking
5.3.2
Medical/surgical history and pre-treatment experience
The medical/surgical history to be collected and the treatment experience prior to 
administration of this drug includes:  

Date of diagnosis

Date of EGFR test 

Medical history 

Previous surgical experience for the medical history 

Previous chemotherapy 

Previous radiotherapy
5.3.3
Concomitant medication
Information on concomitant medication that is to be collected includes:   

Brand name or generic name 

Daily dose 

Unit

Indication 

Start date

Date of discontinuation or continuation 
5.3.4
Drug administration status
Information on the drug administration status includes:   

Dose

Start date

Date of discontinuation or continuation

Dose changes

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5.3.5
Information on the site
Information on the site includes:  

Hospital name 

Department 

Physician name 
5.3.6
Main points of study and details of study method
If a particular trend or change associated with safety is found from spontaneous adverse event 
report during this study, special investigation into the relevant item shall be planned and 
implemented. Also, the situations of occurrence of any unexpected adverse drug reactions or 
adverse events whose causal relationship with the drug has not been established and 
frequency is extremely low, which have not appeared in the course of development of the 
drug during the study period, shall be intensively observed and investigated.  
5.4
ENDPOINTS OF SUBJECTS EVALUATION
5.4.1
Subject evaluation items
5.4.1.1
Number of cases who accepted the study
This number means the planned number of cases as specified in the contract concluded with 
the investigator (physician) prior to initiation of the study.  
5.4.1.2
Number of cases subject who collected CRF
This number means the number of cases who signed the informed consent form to participate 
in the study as subject, and have record of taking GIOTRIFP®
P once at least.  
5.4.1.3
Number of dropouts
These cases include those who signed the informed consent form to participate in this study 
as subject but did not meet any of the inclusion criteria, do not have any prescription record 
of GIOTRIFP®
P, have prescription record but have not been followed up by the physician 
following prescription, and started administration prior to the signed date. 
5.4.1.4
Number of cases subject to safety evaluation
These cases include those who signed the informed consent form to participate in this study 
as subject, took GIOTRIFP®
P according to the approved label once at least, and were followed 
up via phone/mail/visit by the physician once or more.  

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5.4.1.5 Number of cases subject to efficacy evaluation
These cases include those who signed the informed consent form to participate in this study 
as subject, visited as per the study schedule, took GIOTRIFP®
P, and were evaluated for the 
efficacy.  

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6.
SURVEILLANCE PLAN
6.1
VISIT SCHEDULE
The flow chart at the front of the protocol summarizes the data to be collected at each 
visit(recommended visit schedule – Visit 1: Baseline / Visit 2 : 8±2weeks / Visit 3 : 
24±2weeks / Visit 4 : 48±2weeks). The procedures are further described below.
6.2
DETAILS OF STUDY PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in periods
This section is not applicable as this is a non-interventional study.
6.2.2
Treatment periods
As per regulations, enrolled patients will be followed up for 8 or 24 or 48 weeks treatment 
period. There will be a visit window of ±2 weeks. To minimize the selection bias at the site 
level, the goal is to have participating centers reflect a balance between general hospitals and 
clinics for surveillances.
6.2.2.1
Visit 1 – Baseline Visit
Upon patient enrolment, the following will be recorded on the patient’s eCRF.

Visit date

Informed consent form ; Date of Informed consent

Diagnosis: date of the diagnosis of locally advanced or metastatic non-small cell lung 
cancer (NSCLC) with EGFR mutation(s)  or patients with locally advanced or metastatic 
NSCLC of squamous histology progressing on or after platinum-based chemotherapy

Inclusion/exclusion criteria

Medical history

Demographic data: year of birth(age), gender, pregnancy, height, weight, smoking 
statusBaseline visit Concomitant medications: Record all medications have been taken at 
least once since one month prior to the baseline visit

Physical examination

Safety Laboratory Tests: laboratory testing is optional at this visit and may be performed 
at the discretion of the investigator and in accordance to the current standard of care. 

Dose of GIOTRIFP®
P given
At Visit 1, the patient will be requested to contact the treating physician in the event of any 
adverse events noted after initiating GIOTRIFP®
Ptreatment.
6.2.2.2
Visit 2 (8±2 weeks from Visit 1)
After 8±2 weeks from Visit 1, the patients will return for follow-up. The followings will be noted 
and recorded in the eCRF: 

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
Visit date

Physical examination

Concomitant medications including new medications taken since last visit: any change in 
the concomitant medications (dose and dosing intervals) 

Any change of GIOTRIFP®
P given

Effectiveness endpoints : Disease Assessment

Any changes in laboratory tests if there is any lab result which was clinically significant 
compared to data before GIOTRIFP®
P therapy (This data is collected on the basis of 
medical need, i.e. independent of the NIS) 

Any adverse events noted 

Study completion status 
6.2.2.3
Visit 3 (24±2 weeks from Visit 1)
After 24±2 weeks from Visit 1, the patients will return for follow-up. The followings will be 
noted and recorded in the eCRF: 

Visit date

Physical examination

Concomitant medications including new medications taken since last visit: any change in 
the concomitant medications (dose and dosing intervals) 

Any change of GIOTRIFP®
P given

Effectiveness endpoints : Disease Assessment

Any changes in laboratory tests if there is any lab result which was clinically significant 
compared to data before GIOTRIFP®
P therapy (This data is collected on the basis of 
medical need, i.e. independent of the NIS) 

Any adverse events noted 

Study completion status 
6.2.2.4
Visit 4 (48±2 weeks from Visit 1)
After 48±2 weeks from Visit 1, the patients will return for follow-up. The followings will be 
noted and recorded in the eCRF: 

Visit date

Physical examination

Concomitant medications including new medications taken since last visit: any change in 
the concomitant medications (dose and dosing intervals) 

Any change of GIOTRIFP®
P given

Effectiveness endpoints : Disease Assessment

Any changes in laboratory tests if there is any lab result which was clinically significant 
compared to data before GIOTRIFP®
P therapy (This data is collected on the basis of 
medical need, i.e. independent of the NIS) 

Any adverse events noted 

Study completion status 

NIS physician’s electronic signature for data integrity

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6.2.3
End of trial and follow-up period
Patients with adverse events noted at the final follow-up visit or upon premature discontinuati
on of GIOTRIFP®
P will be monitored further until the resolution of those adverse events. 
Alternatively, those patients will be followed up until the NIS physician and sponsor agree th
at no further follow-up is necessary. The survived subject at the end of the study (Visit 4) is 
not available, the information should be collected by telephone, letter contact with the patient 
at the end of the PMS study period. 

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
Details are provided in the statistical Trial Statistical Analysis Plan (TSAP).
7.1
STATISTICAL DESIGN - MODEL
In this non-interventional study, all statistical analyses will be descriptive. Data of 
characteristics and other status of patients will be described and proportions including the 
confidence intervals will be provided. 
7.2
NULL AND ALTERNATIVE HYPOTHESES
No hypotheses are tested. (See 40TUSection 7.1U40T)
7.3
PLANNED ANALYSES
7.3.1 Demographics and Baseline Characteristics analyses
Data for the demographics and baseline characteristics in safety analysis set is demonstrated by 
descriptive statistics. In the descriptive statistics, number of subjects, mean, standard deviation, 
median, minimum and maximum will be calculated for continuous variables, and frequency and 
percentage will be presented for categorical variables. 
The following demographics and baseline characteristics will be reported.
< Demographic information > 
- Age, Gender, Pregnancy, Height, Weight, Smoking status, Pediatric group (Under 19 years), 
Geriatric group (65 years or older), Other medical history and its classification, Kidney disorder, 
Liver disorder, Subjects whose drug administration period of long-term (24 weeks or more)
< Medication information > 
- Giotrif administration status (Total administration period of Giotrif, Total administration dose of 
Giotrif), Concomitant medication and its classification,Reason of prematurely study withdrawal.
7.3.2
Safety analyses
Demographic and baseline characteristics will be summarized descriptively for the entire 
cohort of eligible patients.
Adverse events (AEs) will be coded according to the latest version of Medical Dictionary for 
Drug Regulatory Affairs (MedDRA) coding system. Concomitant therapies will be coded 

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according to the latest version of KIMS (Korea Index of Medical Specialties) coding system. 
The trial database will not be locked until coding is complete. 
Safety analyses will be based on all patients treated, i.e. all patients who received at least one 
dose of GIOTRIFP®
Pbased on the current authorized label in Korea. However, if data for 
patients who have been treated with GIOTRIFP®
P beyond the scope of approved label are 
collected, separate safety analyses will be performed. Safety analyses will be performed 
based on demographics and baseline characteristics. Each endpoint will be analyzed by each 
indication (‘locally advanced or metastatic non-small cell lung cancer (NSCLC) with 
Epidermal Growth Factor Receptor (EGFR) mutation(s)’ or ‘locally advanced or metastatic 
NSCLC of squamous histology progressing on or after platinum-based chemotherapy’).
In the safety analysis set, the number of subjects with AEs and the number of AEs will be 
calculated. Also, the incidence proportion of AEs will be estimated with its 95% confidence 
interval.
Patients lost to follow up will be characterized compared to the remaining patients and reason 
and time point of loss to follow up will be evaluated.
7.3.2.1 Adverse Events by Demographics and Baseline Characteristics
For the AE(s) by demographics and baseline characteristics in the safety analysis set:
- The number of subjects to whom AE occurred and the number of AEs will be calculated.
- The incidence proportion of AEs and its 95% confidence interval will be estimated. Chi-
square test or Fisher’s exact test will be used for comparing between subcategories of each 
demographics and baseline characteristics.
- If necessary, analysis for the impact of the safety may be carried out using logistic multiple 
regression analysis. In general, the variables corresponding to the baseline characteristics 
listed in 40TUsection 7.3.1U40T are used as an independent variable. However, as considering the 
structure and characteristics of the collected data, the variables used for the actual analysis 
can be added or subtracted.
7.3.2.2 Adverse Events by Preferred Terms
All AEs recorded in the CRF will be classified by body organs and terms under the 
classification standard of MedDRA terms, and all AEs excluding the AEs where causal 
relationship with Giotrif is “Unlikely” will be treated as AEs which causality cannot be 
excluded (hereafter “Adverse Drug Reaction (ADR)”).
For subjects to whom AE occurred, the incidence proportion of AEs and the number of AEs 
will be summarized. Details are as follows.

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①The frequency and percentage of the number of AEs according to serious adverse event, 
intensity, outcome of the event, action taken, causality, therapy of the event will be calculated.
②All AEs will be classified into the preferred terms according to serious adverse event, 
intensity, outcome of the event, action taken, causality, therapy of the event. The frequency 
and percentage of the number of each AE will also be calculated.
③The number of subjects and the number of AE/ADR, Serious AE/Serious ADR, 
unexpected AE/ADR, unexpected Serious AE/unexpected Serious ADR will be calculated 
according to the preferred terms. In this case, the following subgroups are presented 
separately. Also, the incidence proportion and its 95% confidence interval will be estimated.
④Preferred terms of Serious AE/Serious ADR, unexpected AE/ADR will be presented 
respectively according to the proportion of AE in the local product document.
⑤For subjects excluded from the safety analysis set†, the number of subjects and the 
number of AE/ADR, Serious AE/Serious ADR, unexpected AE/ADR, unexpected Serious 
AE/unexpected Serious ADR will be calculated according to the preferred terms. Also, the 
incidence proportion and its 95% confidence interval will be estimated.
†Subject excluded from safety analysis set: ‘Subjects who have not taken Giotrif’ and ‘Follow-up 
failure’ of patients excluded from safety analysis sets will be excluded (Reflecting the Ministry of 
Food and Drug Safety (MFDS) guideline).
7.3.3
Main analyses of effectiveness
Effectiveness analysis shall be conducted for subjects of the effectiveness analysis set. Each 
endpoint will be analyzed by each indication (‘locally advanced or metastatic non-small cell 
lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) mutation(s)’ or 
‘locally advanced or metastatic NSCLC of squamous histology progressing on or after 
platinum-based chemotherapy’).
The final effectiveness assessment of “Improved” will be classified as “Effective”, 
“Unchanged” will be classified as “No changed”, and “Worsening of symptoms due to cancer” 
will be classified as “Worsened”. The effectiveness rate and its 95% confidence intervals will 
be estimated with exact method
7.3.3.1 Progression-free survival
Progression-free survival is the time from start of treatment to the date of disease progression 
or death, whichever comes first.
UFor patients with known date of progression:

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Progression-free survival [days] = date of progression (or of death if no earlier 
progression) – (date of start of treatment) + 1 
UFor patients known not to have progressed, i.e., those remaining on trial drug:
Progression-free survival (censored) [days] = date of last contact showing no disease 
progression or death - (date of start of treatment) + 1.
Patients with unknown progression status or unknown date of progression will be 
censored at the last contact date, refer to 40TUSection 7.4U40T for more detail.
Kaplan-Meier estimates and 95% confidence intervals for the 25th, median, and 75th 
percentiles of the survival distribution will be calculated for progression-free survival, using 
Greenwood’s standard error estimate. Kaplan-Meier curves will be produced without 
confidence intervals.
7.3.3.2 Tumour response according to investigator’s assessment
Each patient will be assigned to one of the following categories:
1. Complete response (CR)
2. Partial response (PR)
3. Stable disease (SD)
4. Progressive disease (PD)
5. Not evaluable for response, reasons to be specified (e.g. early death, tumour 
assessments incomplete, etc.)
Time to tumour response is defined as the time from the start of treatment to the date of 
first recorded CR or PR.
The duration of tumour response is the time from first documented CR or PR to the time 
of progression or death (or date of censoring for PFS).
Patients whose best assessment is stable disease, partial, or complete response will be 
considered to have achieved disease control. Duration of disease control will be the same 
as time to progression, but restricted to patients who achieve disease control.
Descriptive statistics will be calculated for the duration of objective tumour response and 
disease control. Finally, the proportion of patients in each response category will be 
tabulated, if feasible (confirmation of response not required). Two-sided 95% confidence 
intervals will be given for the calculated best response rate. Best response is defined as 
the best individual response from the date of the first administration until the earliest 
recording of PD, death or end of treatment (as long as no other anti-cancer therapy has 
been given).

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7.3.3.3 Overall Survival
Overall Survival (OS), defined as time from the date of the first administration of afatinib to 
the date of death.
UFor patients with known date of death:
OS [days] = date of death – (date of start of treatment) + 1 
UFor patients known not death case:
OS (censored) [days] = date of last contact showing no death - (date of start of treatment) 
+ 1.
Kaplan-Meier estimates and 95% confidence intervals for the 25th, median, and 75th 
percentiles of the survival distribution will be calculated for OS, using Greenwood’s standard 
error estimate. Kaplan-Meier curves will be produced without confidence intervals.
7.3.3.4 Demographics and Baseline Characteristics analyses of effectiveness
The effectiveness by factor was classified into 3 categories of ‘Improved’, ‘Unchanged’, and 
‘Worsened’ based on the evaluation of cancer-related symptoms at last visit to evaluate the 
improvement rate. 
The improvement rate will be analyzed according to the baseline characteristics listed in 
below Chisquare test or Fisher’s exact test will be used for comparing between subcategories 
of each baseline characteristic and will be estimated with its 95% confidence interval.
- Age, Gender, Pregnancy, Height, Weight, Smoking status, Pediatric group (Under 19 years), 
Geriatric group (65 years or older), Other medical history and its classification, Kidney disorder, 
Liver disorder, Subjects whose drug administration period of long-term (24 weeks or more)
If necessary, analysis for the impact of the change from baseline to last visit may be carried 
out using multiple regression analysis. In general, the variables corresponding to the baseline 
characteristics listed in 40TUsection 7.3.1U40T are used as an independent variable. However, as 
considering the structure and characteristics of the collected data, the variables used for the 
actual analysis can be added or subtracted.
The effectiveness rate will be analyzed according to the baseline characteristics listed in 
40TUsection 7.3.1U40T Chi-square test or Fisher’s exact test will be used for comparing between 
subcategories of each baseline characteristic and will be estimated with its 95% confidence 
interval.

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7.3.4
Interim analyses
In accordance with local regulation for rNIS, interim analyses are planned biannually for the 
initial two years and annually thereafter. 
7.4
HANDLING OF MISSING DATA
Missing or incomplete AE dates are imputed according to BI standards.

For PFS, if a patient is known to have progressed, but the date of progression is not 
attainable, the last date when the patient was assessed will be used as date of 
progression.
For PFS, if a patient’s vital status or progression status is unknown at the follow-up visit, the 
patient will be censored at the last contact date.
7.5.
RANDOMISATION
This section is not applicable as this is a non-interventional study.
7.6
DETERMINATION OF SAMPLE SIZE
With sample size of 1,149, ADR with an incidence of 0.26% can be detected in at least one 
patient with a probability of 95%, including interstitial lung disease(ILD, incidence 0.7%) listed 
in Korean FPI for GIOTRIF®
In case of Japan GIOTRIFP® rPMS, planned sample size was 1,500. To detect an ADR with an 
incidence of 0.20% (or 0.30%) or greater in at least one patient with a probability of 95% (or 
99%), at least 1500 patients needed to be entered and have at least one observation after treatment.
The following AEs listed in the Risk Management Plan for GIOTRIF®: diarrhoea, rash/acne, nail 
effect and interstitial lung disease (include ILD-like event)
As per regulation, long-term surveillance is necessary for the indication. Since locally advanced 
or metastatic non-small cell lung cancer (NSCLC) is chronic disease, it might be restrictive to 
collect safety and effectiveness data in short-term (8±2weeks) period, all patients will be 
enrolled for longer-term (24±2weeks and 48±2weeks) surveillance. 

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8.
DATA PROTECTION, STUDY RECORDS
The International Conference on Harmonization/Harmonized Tripartite Guideline for Good 
Clinical Practice (ICH/GCP) does not often apply to NIS as most elements are relevant for 
controlled clinical trials. However, in this NIS, all attempts will be made to adhere, as close 
as possible, to the standards of ICH/GCP. 
The protocol of this regulatory requisite NIS will be submitted to the Ministry of Food And 
Drug Safety (MFDS) for notification. It is not a local requirement in Korea to obtain 
Institutional Review Board (IRB) approval for the conduct of regulatory requisite NIS. 
However, the protocol of this NIS will be submitted to IRBs whenever required or requested 
by these institutions. This study will be conducted in accordance with the Standards for Re-
examination of New Medicines notified by MFDS, Korean Pharmaceutical Affairs Code 
(KPAC), Enforcement Regulation of KPAC and other applicable local laws and industry 
code (including but not limited to the Regulations on Fair Competition in the Trade of 
Medicines of KPMA and KRPIA). 
Boehringer Ingelheim Korea will submit periodic reports during re-examination period, and 
the final report to MFDS upon study completion. The periodic report for the final year will be 
substituted with the final report. When required, the interim reports and the final report will 
be submitted to the IRBs as well. 
8.1
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 the competent authority (CA) according to the local 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the study, written patient consent form shall be obtained from 
each patient (or the patient’s legally accepted representative). Each signature must be 
personally dated by each signatory and the patient consent and any additional patient-
information form retained by the NIS physician as part of the study records. A signed copy of 
the patient consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The patient must be informed that his/her personal study-related data will be used by 
Boehringer Ingelheim Korea in accordance with the local data protection law. The level of 
disclosure shall also be explained to the patient.
The patient shall be informed that his/her medical records may be examined by authorised 
monitors (MPMs) or Clinical Quality Assurance auditors appointed by sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 

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auditor will have access to all medical records, the participating physician’s study-related 
files and correspondence, and the data release agreement documentation of this study.
8.3
RECORDS
All of the clinical data will be captured via a web-based EDC (Electronic Data Capture) 
System. The site staff will enter and edit the data via a secure network, with secure access 
features (username, password and secure identification – an electronic password system). A 
complete electronic audit trail will be maintained. The treating physician will approve the 
data using an electronic signature.
Patients will not be identified on the eCRF by name. Appropriate coded identification (i.e., 
patient number) will be used. The treating physician will make a separate confidential record 
of these details (patient identification code list) to permit identification of all patients enrolled 
in this study in case follow-up is required. Likewise, any supporting documentation will be 
redacted of any patient identifying information, and the patient ID number clearly written on 
the documents.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents will be filed at the treating physician’s site.
It is necessary that the data entered in the eCRFs that are transcribed from the source 
documents are consistent with the source documents or the discrepancies need to be 
explained. The treating physician may need to request previous medical records, transfer 
records, and current medical records. 
8.3.2
Direct access to source data and documents
The NIS physician / site will permit study-related monitoring, audits and regulatory 
inspection, providing direct access to all related source data/documents. All source 
documents including eCRFs will be made available for review by sponsor’s Medical Project 
Manager (MPM) or designees and inspection by health authorities (e.g., MFDS). The MPM
and auditor may review all eCRFs, and written data release agreements. The accuracy of the 
data will be verified by reviewing the documents described in 40TUSection 8.3.1U40T.
8.3.3
Storage of records
The NIS physician and the site are jointly responsible for maintaining essential study 
documents for 3 years after completion of the study (defined as termination date of re-
examination period) by the Pharmaceutical Affairs Law and shall take measures to prevent 
accidental or premature destruction of these documents. 

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8.4
PROCEDURES FOR REPORTING ADVERSE EVENTS
8.4.1
Time windows
All AEs, serious and non-serious, occurring during the course of the rNIS will be collected,
documented and reported to the sponsor by the investigator on the appropriate eCRF. 
Reporting will be done according to the specific definitions and instructions detailed
in the ‘Adverse Event Reporting’ section of the site materials (that include all necessary
documents, the protocol, instructions for conducting rNIS, the package insert etc.).
The investigator has the responsibility to report AEs during the specified observational phase.
All AEs will be reported in accordance with Section 5.1.2.2.
8.4.2
Documentation of adverse events and patient narratives
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to the local 
regulatory requirements.
For each AE, the investigator will provide the onset, end, intensity, outcome, seriousness and
action taken with GIOTRIFP®
P tablets. The investigator will determine the relationship of
GIOTRIFP®
Ptablets to all AEs as defined in the 'Adverse Event Reporting' section of the
physician binder.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this study will be considered 
confidential and disclosure to third parties will be prohibited with the exceptions noted 
below. Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data will be made available to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated from the 
study will be made available for inspection on request by the participating physicians, the 
sponsor and/or its representatives and/or designees, by the IRBs/IECs and the regulatory 
authorities.
8.6
PUBLICATION POLICY
Boehringer Ingelheim, to the best of their ability will support the process of free exchange of 
relevant scientific information. Any publication of the result of this NIS study must be 
consistent with the Boehringer Ingelheim publication policy.

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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P08-06904     Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, Padera 
RF, Shapiro GI, Baum A, Himmelsbach F, Rettig WJ, Meyerson M, Solca F, 
Greulich H, Wong KK. BIBW2992, an irreversible EGFR/HER2 inhibitor 
highly effective in preclinical lung cancer models. Oncogene, advance online 
publication, 14 April 2008; doi:10.1038/onc.2008. 109: 4702 - 4711.
P09-12297
Regales L, Gong Y, Shen R, Stanchina E de, Vivanco I, Goel A, Koutcher JA,
Spassova M, Ouerfelli O, Mellinghoff IK, Zakowski MF, Politi KA, Pao W. 
Dual targeting of EGFR can overcome a major drug resistance mutation in 
mouse models of EGFR mutant lung cancer. J Clin Invest 2009; 119 (10), 
3000 – 3010.
P12-05170      Kim Y, Ko J, Cui ZY, Abolhoda A, Ahn JS, Ou SH, Ahn MJ, Park K. The 
EGFR T790M mutation in acquired resistance to an irreversible second-
generation EGFR inhibitor. Mol Cancer Ther 2012; 11 (3), 784 – 791.
R05-0876
Schrump DS, Altorki NK, Henschke CL, Carter D, Turrisi AT, Gutierrez ME. 
Non-small cell lung cancer. Cancer: principles and practice of oncology, 7th 
Edition, DeVita VT, Hellman S, Rosenberg SA (eds.), Lippincott Williams 
and Wilkins. 2005; 753-809.
R06-1301
Lynch TJ, Adjei AA, Bunn PA, Eisen TG, Engelman J, Goss G, et al      
Summary statement: Novel agents in the treatment of lung cancer: Advances 
in epidermal growth factor receptor-targeted agents. Clin Cancer Res. 2006; 
12(14 Suppl.): 4365-4371.
R06-1302
Engelman JA, Cantley LC. The role of erbB family members in non-small cell 
lung cancers sensitive to epidermal growth factor receptor kinase inhibitors. 
3Prd
P Cambridge Con on Novel Agents in the Treatment of Lung Cancer: 
Advances in EGFR-Targeted Agents, Cambridge, 23-24 Sep 2005. Clin 
Cancer Res. 2006; 12(14 Suppl.): 4372-4376.
R06-1306
Jaene PA, Johnson BE. Effect of epidermal growth factor receptor tyrosine 
kinase domain mutation on the outcome of patients with non-small cell lung 
cancer treated with epidermal growth factor receptor tyrosine kinase 
inhibitors. P3rd
P Cambridge Con on Novel Agents in the Treatment of Lung 
Cancer: Advances in EGFR-Targeted Agents, Cambridge, 23-24 Sep 2005. 
Clin Cancer Res. 2006; 12(Suppl.14): 4416-4420.

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R06-1393
Johnson BE, Jaenne PA. Epidermal growth factor receptor mutations in 
patients with non-small cell lung cancer. Cancer Res. 2005; 65(17): 
7525-7529.
R06-1394
Doroshow JH. Targeting EGFR in non-small-cell lung cancer. N Engl J Med. 
2005; 353(2): 200-202.
9.2
UNPUBLISHED REFERENCES
U12-1199-01
  LUX-Lung 3; A randomised, 
open-label, phase III study ofBIBW 2992 versus chemotherapy as first-line 
treatment for patientswith stage IIIB or IV adenocarcinoma of the lung 
harbouring anEGFR-activating mutation. 04-July-2012.
U13-1625-01
 LUX-Lung 6: A
randomised, open-label, phase III study of BIBW 2992 versus chemotherapy
as first-line treatment for patients with stage IIIB or IV adenocarcinoma of the
lung harbouring an EGFR-activating mutation. 24 April 2013.
U12-1482-01 
 Clinical Summary: Afatinib film-coated tablets,
20 mg, 30 mg, 40 mg, 50 mg. 25 July 2012.

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10.
APPENDICES
10.1
ELECTRONIC CASE REPORT FORM
Please refer to “ELECTRONIC CASE REPORT FORM” in site file or in electronic CRF web 
page for the latest version. 
10.2
SAE/ SPECIAL INTEREST OF AE REPORT FORM / NON-SERIOUS 
ADVERSE REACTION REPORT
Please refer to “SAE/ NON-SERIOUS ADVERSE REACTION REPORT” in site file or in 
electronic CRF web page for the latest version. 
10.3
PREGNANCY MONITORING FORM
Please refer to “PREGNANCY MONITORING FORM” in site file or in electronic CRF web 
page for the latest version. 
10.4
LIST OF ALWAYS SERIOUS ADVERSE EVENTS
Please refer to “List of Always Serious Adverse Event” in site file or in electronic CRF web 
page for the latest version. 
10.5
GIOTRIFP®
P PRESCRIPTION INFORMATION FOR KOREA
Please refer to “GIOTRIF® Prescription Information for Korea” in site file or in electronic 
CRF web page for the latest version. 

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11.
SUMMARY OF NIS PROTOCOL MODIFICATIONS
Summary of Modifications Sheet (SOMS)
Number of Protocol modification
1
Date of Protocol modification
30-Jul-2014
BI Trial number
1200.235
BI Product(s)
Afatinib
Title of protocol
A regulatory requirement post-marketing 
surveillance study to monitor the safety and 
efficacy of GIOTRIF®(afatinib dimaleate, 
20mg, 30mg, 40mg, q.d) in Korean patients 
with locally advanced or metastatic non-small 
cell lung cancer (NSCLC) with Epidermal 
Growth Factor Receptor (EGFR) mutations
To be implemented only after 
approval of the 
IRB/IEC/Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent Authority 
to be notified of change with 
request for approval
Can be implemented without 
IRB/IEC/ Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
Section to be changed
3.1.2
Study method
Description of change
Was added to :
This study will be carried out in the manner of 
successive survey that the investigator will be 
asked to successively write in the case report 
forms(CRFs) from the subject who was 
initially administered the drug following the 
study start date to the requested number of 
subjects without omission. Prior to initiation of 
the study, written contract shall be concluded, 
and this contract shall be concluded with the 
head of the site or the investigator with his/her 

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consent. 
Rationale for change
Request by Korea Authorities (MFDS)
Section to be changed
3.3.5   Subjects of special investigation 
Description of change
Was added to :
Any Investigation for the elderly, pregnant 
women, and patients with renal impairment 
and hepatic impairment will not be separately 
conducted, and further investigation into cases 
collected from this study may be taken into 
account according to the outcome of 
retrospective analysis.
Rationale for change
Request by Korea Authorities (MFDS)
Section to be changed
5.3 OTHER
Description of change
5.3 OTHER
This section is not applicable.
5.3.1
Demographic data
This section is not applicable.
Was changed to :
5.3
Items of investigation
5.3.1
Demographic data
For demographic evaluation, following 
background information of subjects shall be 
recorded:  
Subject signed date 
Subject study number 
Gender
Pregnancy
Height
Weight
Year/month of birth (age)
Smoking
5.3.2
Medical/surgical history and pre-
treatment experience
The medical/surgical history to be collected 
and the treatment experience prior to 
administration of this drug includes:  
Date of diagnosis
Date of EGFR test 
Medical history 
Previous surgical experience for the medical 

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history 
Previous chemotherapy 
Previous radiotherapy
5.3.3
Concomitant medication 
Information on concomitant medication that is 
to be collected includes:   
Brand name or generic name 
Daily dose 
Unit
Indication 
Start date
Date of discontinuation or continuation 
5.3.4
Drug administration status
Information on the drug administration status 
includes:   
Dose
Start date
Date of discontinuation or continuation
Dose changes
5.3.5
Information on the site  
Information on the site includes:  
Hospital name 
Department 
Physician name 
5.3.6
Main points of study and details of 
study method 
If a particular trend or change associated with 
safety is found from spontaneous adverse 
event report during this study, special 
investigation into the relevant item shall be 
planned and implemented. Also, the situations 
of occurrence of any unexpected adverse drug 
reactions or adverse events whose causal 
relationship with the drug has not been 
established and frequency is extremely low, 
which have not appeared in the course of 
development of the drug during the study 
period, shall be intensively observed and 
investigated.  
Rationale for change
Request by Korea Authorities (MFDS)

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Section to be changed
5.4  APPROPRIATENESS OF 
MEASUREMENTS
Description of change
5.4  APPROPRIATENESS OF 
MEASUREMENTS
This section is not applicable. 
Was changed to : 
5.4
Endpoints of subjects Evaluation
5.4.1
Subject evaluation items 
5.4.1.1   Number of cases who accepted the 
study 
This number means the planned number of 
cases as specified in the contract concluded 
with the investigator (physician) prior to 
initiation of the study.  
5.4.1.2 Number of cases subject who collected 
CRF 
This number means the number of cases who 
signed the informed consent form to 
participate in the study as subject, and have 
record of taking GIOTRIF® once at least.  
5.4.1.3 Number of dropouts 
These cases include those who signed the 
informed consent form to participate in this 
study as subject but did not meet any of the 
inclusion criteria, do not have any prescription 
record of GIOTRIF® , have prescription 
record but have not been followed up by the 
physician following prescription, and started 
administration prior to the signed date. 
5.4.1.4 Number of cases subject to safety 
evaluation 
These cases include those who signed the 
informed consent form to participate in this 
study as subject, took GIOTRIF® once at 
least, and were followed up by the physician 
once or more.  
5.4.1.5 Number of cases subject to efficacy 
evaluation 
These cases include those who signed the 
informed consent form to participate in this 
study as subject, visited as per the study 
schedule, took GIOTRIF®, and were 

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evaluated for the efficacy.
Rationale for change
Request by Korea Authorities (MFDS)
Number of Protocol modification
2
Date of Protocol modification
01-Oct-2014
BI Trial number
1200.235
BI Product(s)
Afatinib
Title of protocol
A regulatory requirement post-marketing 
surveillance study to monitor the safety and 
efficacy of GIOTRIF®(afatinib dimaleate, 
20mg, 30mg, 40mg, q.d) in Korean patients 
with locally advanced or metastatic non-small 
cell lung cancer (NSCLC) with Epidermal 
Growth Factor Receptor (EGFR) mutations
To be implemented only after 
approval of the 
IRB/IEC/Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent Authority 
to be notified of change with 
request for approval
Can be implemented without 
IRB/IEC/ Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
Section to be changed
All pages
Description of change
Doc. No.: c02597942-02
Was changed to: 
Doc. No.: c02597942-03
Rationale for change
Changed document number in the BIRDS
Section to be changed
All pages
Description of change
Date : 30 Jul 2014
Was changed to: 
Date : 01 Oct 2014
Rationale for change
As per Protocol Amendment

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Section to be changed
Cover page 
Description of change
Version : 2
Was changed to: 
Version : 3
Rationale for change
As per Protocol Amendment 
Section to be changed
3.3.2
Inclusion criteria
Description of change

Age ≥ 18 years at enrolment
Was deleted
Rationale for change
As per local prescribing information
Section to be changed
5.1.2.2 Adverse event and serious adverse 
event reporting
Description of change
All adverse events occurring from the start of 
GIOTRIFP® 
Ptreatment up to 7 days after last 
follow-up visit need to be collected, 
documented and reported to the sponsor using
the AE reporting form of eCRF (Attachment 
1).
Was changed to : 
All adverse events occurred from the signing 
date on ICF to 28 days after last administration 
date of medication need to be collected, 
documented and reported to the sponsor using 
the AE reporting form of eCRF (Attachment 
1).
Rationale for change
Comments from the Local PV
Number of Protocol modification
3
Date of Protocol modification
04-Oct-2014
BI Trial number
1200.235
BI Product(s)
Afatinib
Title of protocol
A regulatory requirement post-marketing 
surveillance study to monitor the safety and 
efficacy of GIOTRIF®(afatinib dimaleate, 
20mg, 30mg, 40mg, q.d) in Korean patients 
with locally advanced or metastatic non-small 
cell lung cancer (NSCLC) with Epidermal 
Growth Factor Receptor (EGFR) mutations

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BI Trial No.: 1200.235
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To be implemented only after 
approval of the 
IRB/IEC/Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent Authority 
to be notified of change with 
request for approval
Can be implemented without 
IRB/IEC/ Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
Section to be changed
All pages
Description of change
Doc. No.: c02597942-03
Was changed to: 
Doc. No.: c02597942-04
Rationale for change
Changed document number in the BIRDS
Section to be changed
All pages
Description of change
Date : 01 Oct 2014
Was changed to: 
Date : 04 Oct 2014
Rationale for change
As per Protocol Amendment
Section to be changed
Cover page 
Description of change
Version : 3
Was changed to: 
Version : 4
Rationale for change
As per Protocol Amendment 
Section to be changed
3.1  OVERALL DESIGN AND PLAN 
Description of change
However, active enrolment is to be initiated in 
May 2015 after finalizing the re-imbursement 
agreement with the authority.
Was changed to: 
However, active enrolment is to be initiated in 
Oct 2014 after finalizing the re-imbursement 

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18 May 2020
BI Trial No.: 1200.235
Doc. No.: c02597942-07
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agreement with the authority.
Rationale for change
Change of the date for the reimbursement 
agreement
Number of Protocol modification
4
Date of Protocol modification
17-Oct-2014
BI Trial number
1200.235
BI Product(s)
Afatinib
Title of protocol
A regulatory requirement post-marketing 
surveillance study to monitor the safety and 
efficacy of GIOTRIF®(afatinib dimaleate, 
20mg, 30mg, 40mg, q.d) in Korean patients 
with locally advanced or metastatic non-small 
cell lung cancer (NSCLC) with Epidermal 
Growth Factor Receptor (EGFR) mutations
To be implemented only after 
approval of the 
IRB/IEC/Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent Authority 
to be notified of change with 
request for approval
Can be implemented without 
IRB/IEC/ Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
Section to be changed
3.3.2 Inclusion Criteria
Description of change

Patients who have been started on 
GIOTRIFP® 
Pin accordance with the 
approved label in Korea

Patients who have signed on the data 
release consent form 
Was changed to: 
•
Patients who have been started on 
GIOTRIF®  in accordance with the 
approved label in Korea 
•
Age ≥ 19 years at enrolment

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BI Trial No.: 1200.235
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•
Patients who have signed on the data 
release consent form
Rationale for change
Request by Korea Authorities (MFDS)
Number of Protocol modification
5
Date of Protocol modification
01-Sep-2017
BI Trial number
1200.235
BI Product(s)
Afatinib
Title of protocol
A regulatory requirement post-marketing 
surveillance study to monitor the safety and 
efficacy of GIOTRIF®(afatinib dimaleate, 
20mg, 30mg, 40mg, q.d) in Korean patients 
with locally advanced or metastatic non-small 
cell lung cancer (NSCLC) with Epidermal 
Growth Factor Receptor (EGFR) mutations or 
patients with locally advanced or metastatic 
NSCLC of squamous histology progressing on 
or after platinum-based chemotherapy
To be implemented only after 
approval of the 
IRB/IEC/Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent Authority 
to be notified of change with 
request for approval
Can be implemented without 
IRB/IEC/ Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
Section to be changed
All pages
Description of change
Doc. No.: c02597942-05
Was changed to: 
Doc. No.: c02597942-06
Rationale for change
Changed document number in the BIRDS
Rationale for change
All pages
Section to be changed
Date : 17 Oct 2014

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Was changed to: 
Date : 01 Sep 2017
Description of change
As per Protocol Amendment
Section to be changed
All pages
Description of change
Version no.: 5
Was changed to: 
Version no.: 6
Rationale for change
As per Protocol Amendment 
Section to be changed
All corresponding pages
Description of change
Change of Title of Protocol 
A regulatory requirement post-marketing 
surveillance study to monitor the safety and 
efficacy of GIOTRIF®(afatinib dimaleate, 
20mg, 30mg, 40mg, q.d) in Korean patients 
with locally advanced or metastatic non-small 
cell lung cancer (NSCLC) with Epidermal 
Growth Factor Receptor (EGFR) mutations
Was changed to: 
A regulatory requirement post-marketing 
surveillance study to monitor the safety and 
efficacy of GIOTRIF®(afatinib dimaleate, 
20mg, 30mg, 40mg, q.d) in Korean patients 
with locally advanced or metastatic non-small 
cell lung cancer (NSCLC) with Epidermal 
Growth Factor Receptor (EGFR) mutations or 
patients with locally advanced or metastatic 
NSCLC of squamous histology progressing on 
or after platinum-based chemotherapy
Rationale for change
Product label updated.
Section to be changed
Cover page
Description of change
Phone: 
   Fax:
Was changed to: 

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Phone: 
   Fax: 
Rationale for change
Change of Trial Clinical Monitor
Section to be changed
All corresponding pages
Description of change
Diagnosis:
-
Patients with locally advanced or 
metastatic non-small cell lung cancer 
(NSCLC) with Epidermal Growth Factor 
Receptor (EGFR) mutation(s)
Was changed to: 
-
Patients with locally advanced or 
metastatic non-small cell lung cancer 
(NSCLC) with Epidermal Growth Factor 
Receptor (EGFR) mutation(s)
-
Patients with locally advanced or 
metastatic NSCLC of squamous histology 
progressing on or after platinum-based 
chemotherapy
Rationale for change
Product label updated.
Section to be changed
All corresponding pages
Description of change
data release consent form
Was changed to: 
patient consent form
Rationale for change
To be consistent with a consent form title in 
use.
Section to be changed
1.2 DRUG PROFILE
Description of change
For the treatment of EGFR TKI-naïve NSCLC 
patients, the recommended dose of afatinib is 
40 mg orally once daily.
Was changed to: 
For the treatment of EGFR TKI-naïve NSCLC 
patients or patients with NSCLC of squamous 
histology progressing on or after platinum-

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based chemotherapy, the recommended dose 
of afatinib is 40 mg orally once daily.
Rationale for change
Product label updated.
Section to be changed
4.1.4 Drug assignment and administration of 
doses for each patient
Description of change
The physicians indicate doses and timing.
Was changed to: 
The physicians indicate doses and timing 
based on the current authorized label in 
Korea..
Rationale for change
As this is a regulatory PMS to report cases 
within approved label, the concerning sentence 
was revised to avoid a confusion.
Section to be changed
Protocol Synopsis
5.1.1 Endpoints of safety
Description of change
All reported adverse events in patients who 
take at least one dose of GIOTRIFP® 
Pwill be 
noted.
Was changed to: 
All reported adverse events in patients who 
take at least one dose of GIOTRIFP®
Pbased on 
the current authorized label in Korea will be 
noted.
Rationale for change
As this is a regulatory PMS to report cases 
within approved label, the concerning sentence 
was revised to avoid a confusion.
Section to be changed
5.1.2.1 Definitions of adverse events
Description of change
Related
a. Certain: An event occurring in a plausible 
time relationship to drug administration and 
that cannot be explained by concurrent disease 
or other drugs or chemicals. The response to 
withdrawal of the drug (dechallenge) should 
be clinically plausible. The event must be 
definitive pharmacologically or 
phenomenologically, using a satisfactory 
rechallenge procedure if necessary.
b. Probable/Likely: An event with a reasonable 
time sequence to administration of the drug, 
unlikely to be attributed to concurrent disease 

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or other drugs or chemicals, and which follows 
a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not 
required to fulfill this definition.
c. Possible: An event with a reasonable time 
sequence to administration of the drug, but 
which could also be explained by concurrent 
disease or other drugs or chemicals. 
Information on drug withdrawal may be 
lacking or unclear.
Was changed to: 
Related
a. Certain: An event occurring in a plausible 
time relationship to drug administration and 
that cannot be explained by concurrent disease 
or other drugs or chemicals. The response to 
withdrawal of the drug (dechallenge) should 
be clinically plausible. The event must be 
definitive pharmacologically or 
phenomenologically, using a satisfactory 
rechallenge procedure if necessary.
b. Probable/Likely: An event with a reasonable 
time sequence to administration of the drug, 
unlikely to be attributed to concurrent disease 
or other drugs or chemicals, and which follows 
a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not 
required to fulfill this definition.
c. Possible: An event with a reasonable time 
sequence to administration of the drug, but 
which could also be explained by concurrent 
disease or other drugs or chemicals. 
Information on drug withdrawal may be 
lacking or unclear.
d. Conditional/Unclassified: Case of requiring 
more data or reviewing the additional data for 
the appropriate assessment
e. Unassessable/Unclassifiable: Case that it 
cannot be judged and complemented or 
confirmed due to the insufficient or 
contradictory information
Rationale for change
As per MFDS guideline on re-examination of 

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new drugs, the 6 categories of AE causality are
included.
Section to be changed
5.4.1.4 Number of cases subject to safety 
evaluation
Description of change
These cases include those who signed the 
informed consent form to participate in this 
study as subject, took GIOTRIF® once at 
least, and were followed by the physician once 
or more.
Was changed to: 
These cases include those who signed the 
informed consent form to participate in this 
study as subject, took GIOTRIF® according to 
the approved label once at least, and were 
followed up via phone/mail/visit by the 
physician once or more.
Rationale for change
As per MFDS guideline on re-examination of 
new drugs, the detailed methods on safety 
follow up are included.
Section to be changed
7.3.1 Safety analyses
Description of change
Safety analyses will be based on all patients
treated, i.e. all patients who received at least
one dose of GIOTRIF®.
Was changed to:
Safety analyses will be based on all patients
treated, i.e. all patients who received at least
one dose of GIOTRIF® based on the current
authorized label in Korea.
Rationale for change
As this is a regulatory PMS to report cases
within approved label, the concerning sentence 
was revised to avoid a confusion.
Number of Protocol modification
6
Date of Protocol modification
20-Nov-2018
BI Trial number
1200.235
BI Product(s)
Afatinib
Title of protocol
A regulatory requirement post-marketing 
surveillance study to monitor the safety and 
efficacy of GIOTRIF®(afatinib dimaleate, 

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20mg, 30mg, 40mg, q.d) in Korean patients 
with locally advanced or metastatic non-small 
cell lung cancer (NSCLC) with Epidermal 
Growth Factor Receptor (EGFR) mutations or 
patients with locally advanced or metastatic 
NSCLC of squamous histology progressing on 
or after platinum-based chemotherapy
To be implemented only after 
approval of the 
IRB/IEC/Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent Authority 
to be notified of change with 
request for approval
Can be implemented without 
IRB/IEC/ Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
Section to be changed
All pages
Description of change
Doc. No.: c02597942-06
Was changed to: 
Doc. No.: c02597942-07
Rationale for change
Changed document number in the BIRDS
Rationale for change
All pages
Section to be changed
Date : 01 Sep 2017
Was changed to: 
Date : 20 Nov 2018
Description of change
As per Protocol Amendment
Section to be changed
All pages
Description of change
Version no.: 6
Was changed to: 
Version no.: 7

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Rationale for change
As per Protocol Amendment 
Section to be changed
40TUTitle page
Description of change
Phone: 
   Fax: 
Was changed to: 
Phone: 
   Fax: 
Rationale for change
Change of Trial Clinical Monitor
Section to be changed
40TUFlow ChartU40T
Description of change
Add: 
Baseline
Platinum-based chemotherapy
Rationale for change
MFDS comment refer to Product label 
updated.
Section to be changed
40TUFlow ChartU40T
Description of change
Add:
Overall survival follow up
Rationale for change
MFDS comment refer to Product label 
updated.
Section to be changed
3.3 SELECTION OF POPULATION
Description of change
A total of 3000 patients
Was changed to : 
A total of 1,149 patients
Rationale for change
No. of patients amendment
Section to be changed
40TU5.2.1 Endpoints of effectivenessU40T
Description of change
Add:

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
Overall Survival (OS), defined as time 
from the date of the first 
administration of afatinib to the date 
of death.
Rationale for change
MFDS comment refer to Product label 
updated.
Section to be changed
5.1.2.2 Adverse event and serious adverse 
event reporting
Description of change
All SAEs must be reported
Swith details of non-
serious AEs occurring at the same time,S within 
24 hours of occurrence via telephone/fax to the 
Local PV Manager (LPVM) of BI Korea using 
the SAE report form (Attachment2).
Rationale for change
Delete
Section to be changed
5.1.2.2 Adverse event and serious adverse 
event reporting
Description of change
Add :
Non-serious ADR must be reported using 
eCRFs and NIS AE form within 7 calendar 
days
Rationale for change
In accordance with NIS protocol SOP
(001-MCS-90-118_RD-01_7.0)
Section to be changed
40TU5.2.2 Assessment of effectivenessU40T
Description of change
Add:
In the case of OS data of the survived subject 
at the end of the study (Visit 4) is not 
available, the information should be collected 
by telephone, letter contact with the patient at 
the end of the PMS study period.
Rationale for change
MFDS comment refer to Product label 
updated.
Section to be changed
40TU6.2.2.1Visit 1 – Baseline VisitU40T
Description of change
•
Demographic data: year of birth(age), 
gender, pregnancy, height, weight, smoking 
statusS, alcohol consumption (units and 
alcoholism diagnosis)
Rationale for change
Delete 

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Section to be changed
40TU6.2.3 End of trial and follow-up periodU40T
Description of change
Add:
The survived subject at the end of the study 
(Visit 4) is not available, the information 
should be collected by telephone, letter contact 
with the patient at the end of the PMS study 
period.
Rationale for change
MFDS comment refer to Product label 
updated.
Section to be changed
40TU7.3.1 Demographics and Baseline 
Characteristics analysesU40T
Description of change
Add:
Data for the demographics and baseline 
characteristics in safety analysis set is 
demonstrated by descriptive statistics. In the 
descriptive statistics, number of subjects, 
mean, standard deviation, median, minimum 
and maximum will be calculated for 
continuous variables, and frequency and 
percentage will be presented for categorical 
variables. 
The following demographics and baseline 
characteristics will be reported.
< Demographic information > 
- Age, Gender, Pregnancy, Height, Weight, 
Smoking status, Pediatric group (Under 19 
years), Geriatric group (65 years or older), 
Other medical history and its classification, 
Kidney disorder, Liver disorder, Subjects 
whose drug administration period of long-term 
(24 weeks or more)
< Medication information > 
- Giotrif administration status (Total 
administration period of Giotrif, Total 
administration dose of Giotrif), Concomitant 
medication and its classification,Reason of 
prematurely study withdrawal.
Rationale for change
MFDS comment - specific analysis plan
Section to be changed
40TU7.3.2 Safety analysesU40T
Description of change
Add:
Each endpoint will be analyzed by each 

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indication (‘locally advanced or metastatic 
non-small cell lung cancer (NSCLC) with 
Epidermal Growth Factor Receptor (EGFR) 
mutation(s)’ or ‘locally advanced or metastatic 
NSCLC of squamous histology progressing on 
or after platinum-based chemotherapy’).
In the safety analysis set, the number of 
subjects with AEs and the number of AEs will 
be calculated. Also, the incidence proportion 
of AEs will be estimated with its 95% 
confidence interval.
Rationale for change
MFDS comment refer to Product label 
updated.
MFDS comment - specific analysis plan
Section to be changed
40TU7.3.2.1 Adverse Events by Demographics and 
Baseline CharacteristicsU40T
Description of change
Add:
For the AE(s) by demographics and baseline 
characteristics in the safety analysis set:
- The number of subjects to whom AE 
occurred and the number of AEs will be 
calculated.
- The incidence proportion of AEs and its 95% 
confidence interval will be estimated. Chi-
square test or Fisher’s exact test will be used 
for comparing between subcategories of each 
demographics and baseline characteristics.
- If necessary, analysis for the impact of the 
safety may be carried out using logistic 
multiple regression analysis. In general, the 
variables corresponding to the baseline 
characteristics listed in section 7.3.1 are used 
as an independent variable. However, as 
considering the structure and characteristics of 
the collected data, the variables used for the 
actual analysis can be added or subtracted.
Rationale for change
MFDS comment - specific analysis plan
Section to be changed
40TU7.3.2.2 Adverse Events by Preferred TermsU40T
Description of change
Add:
All AEs recorded in the CRF will be classified 
by body organs and terms under the 

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classification standard of MedDRA terms, and 
all AEs excluding the AEs where causal 
relationship with Giotrif  is “Unlikely” will be 
treated as AEs which causality cannot be 
excluded (hereafter “Adverse Drug Reaction 
(ADR)”).
For subjects to whom AE occurred, the 
incidence proportion of AEs and the number of 
AEs will be summarized. Details are as 
follows.
①The frequency and percentage of the 
number of AEs according to serious adverse 
event, intensity, outcome of the event, action 
taken, causality, therapy of the event will be 
calculated.
②All AEs will be classified into the preferred 
terms according to serious adverse event, 
intensity, outcome of the event, action taken, 
causality, therapy of the event. The frequency 
and percentage of the number of each AE will 
also be calculated.
③The number of subjects and the number of 
AE/ADR, Serious AE/Serious ADR, 
unexpected AE/ADR, unexpected Serious 
AE/unexpected Serious ADR will be 
calculated according to the preferred terms. In 
this case, the following subgroups are 
presented separately. Also, the incidence 
proportion and its 95% confidence interval will 
be estimated.
④Preferred terms of Serious AE/Serious 
ADR, unexpected AE/ADR will be presented 
respectively according to the proportion of AE 
in the local product document.
⑤For subjects excluded from the safety 
analysis set†, the number of subjects and the 
number of AE/ADR, Serious AE/Serious 
ADR, unexpected AE/ADR, unexpected 
Serious AE/unexpected Serious ADR will be 
calculated according to the preferred terms. 
Also, the incidence proportion and its 95% 
confidence interval will be estimated.
†Subject excluded from safety analysis set: 
‘Subjects who have not taken Giotrif’ and 

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‘Follow-up failure’ of patients excluded from 
safety analysis sets will be excluded 
(Reflecting the Ministry of Food and Drug 
Safety (MFDS) guideline).
Rationale for change
MFDS comment - specific analysis plan
Section to be changed
40TU7.3.3 Main analyses of effectivenessU40T
Description of change
Add:
Effectiveness analysis shall be conducted for 
subjects of the effectiveness analysis set. Each 
endpoint will be analyzed by each indication 
(‘locally advanced or metastatic non-small cell 
lung cancer (NSCLC) with Epidermal Growth 
Factor Receptor (EGFR) mutation(s)’ or 
‘locally advanced or metastatic NSCLC of 
squamous histology progressing on or after 
platinum-based chemotherapy’).
The final effectiveness assessment of 
“Improved” will be classified as “Effective”, 
“Unchanged” will be classified as “No 
changed”, and “Worsening of symptoms due 
to cancer” will be classified as “Worsened”. 
The effectiveness rate and its 95% confidence 
intervals will be estimated with exact method.
Rationale for change
MFDS comment refer to Product label 
updated.
Section to be changed
40TU7.3.3.3 Overall SurvivalU40T
Description of change
Add:
Overall Survival (OS), defined as time from 
the date of the first administration of afatinib 
to the date of death. 
UFor patients with known date of death:
OS [days] = date of death – (date of start of 
treatment) + 1 
UFor patients known not death case:
OS (censored) [days] = date of last contact 
showing no death - (date of start of 
treatment) + 1.
Kaplan-Meier estimates and 95% confidence 
intervals for the 25th, median, and 75th 

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percentiles of the survival distribution will be 
calculated for OS, using Greenwood’s standard 
error estimate. Kaplan-Meier curves will be 
produced without confidence intervals.
Rationale for change
MFDS comment refer to Product label 
updated.
Section to be changed
40TU7.3.3.4 Demographics and Baseline 
Characteristics analyses of effectivenessU40T
Description of change
The effectiveness by factor was classified into 
3 categories of ‘Improved’, ‘Unchanged’, and 
‘Worsened’ based on the evaluation of cancer-
related symptoms at last visit to evaluate the 
improvement rate. 
The improvement rate will be analyzed 
according to the baseline characteristics listed 
in below Chisquare test or Fisher’s exact test 
will be used for comparing between 
subcategories of each baseline characteristic 
and will be estimated with its 95% confidence 
interval.
- Age, Gender, Pregnancy, Height, Weight, 
Smoking status, Pediatric group (Under 19 
years), Geriatric group (65 years or older), 
Other medical history and its classification, 
Kidney disorder, Liver disorder, Subjects 
whose drug administration period of long-term 
(24 weeks or more)
If necessary, analysis for the impact of the 
change from baseline to last visit may be
carried out using multiple regression analysis. 
In general, the variables corresponding to the 
baseline characteristics listed in section 7.3.1 
are used as an independent variable. However, 
as considering the structure and characteristics 
of the collected data, the variables used for the 
actual analysis can be added or subtracted.
The effectiveness rate will be analyzed 
according to the baseline characteristics listed 
in section 7.3.1 Chi-square test or Fisher’s 
exact test will be used for comparing between 
subcategories of each baseline characteristic 

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Non-interventional study protocol                      Protocol revision 
18 May 2020
BI Trial No.: 1200.235
Doc. No.: c02597942-07
Page 63 of 64
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and will be estimated with its 95% confidence 
interval.
Rationale for change
MFDS comment - specific analysis plan
Section to be changed
7.6
DETERMINATION OF SAMPLE 
SIZE
Description of change
Sample size of 3000 patients is based on the 
requirement of the local regulatory authority
(Ministry of Food and Drug Safety). As per 
regulation, long-term surveillance is necessary 
for the indication. Since locally advanced or 
metastatic non-small cell lung cancer 
(NSCLC) is chronic disease, it might be 
restrictive to collect safety and effectiveness data 
in short-term (8±2weeks) period, all patients 
will be enrolled for longer-term (24±2weeks and 
48±2weeks) surveillance. 
Was changed to :
With sample size of 1,149, ADR with an 
incidence of 0.26% can be detected in at least 
one patient with a probability of 95%, including 
interstitial lung disease(ILD, incidence 0.7%) 
listed in Korean FPI for GIOTRIF®
In case of Japan GIOTRIFP® rPMS, planned 
sample size was 1,500. To detect an ADR with 
an incidence of 0.20% (or 0.30%) or greater in at 
least one patient with a probability of 95% (or 
99%), at least 1500 patients needed to be entered 
and have at least one observation after treatment.
The following AEs listed in the Risk 
Management Plan for GIOTRIF®: diarrhoea, 
rash/acne, nail effect and interstitial lung disease 
(include ILD-like event)
Rationale for change
No. of patients amendment, Rationale update
Section to be changed
8.4.1
Time windows
Description of change
Deleted :
Any SAE, whether or not considered related to 
GIOTRIFP®
P tablets, or whether or not
GIOTRIFP®
P tablets has been administered, 
must be reported immediately via eCRF and 

Boehringer Ingelheim
Non-interventional study protocol                      Protocol revision 
18 May 2020
BI Trial No.: 1200.235
Doc. No.: c02597942-07
Page 64 of 64
Proprietary confidential information. 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies.
SAE/Special interest of AE Report Form.
Add : 
All AEs will be reported in accordance with 
5.1.2.2.
Rationale for change
Delete duplication