Real-world Study on Afatinib as First-line Treatment in Patients With Epidermal Growth Factor Receptor (EGFR) Mutation-positive Advanced Non-small Cell Lung Cancer (NSCLC)
Conditions: Non-squamous, Non-Small Cell Lung Cancer
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-118_RD-23 (2.0) / Saved on: 03 Jul 2020
 
Non-interventional Study Protocol
Document Number:
c38958167-01
BI Study Number:
1200-0318
BI Investigational
Product (s):
Giotrif® (afatinib)
Title:
Real-world study on afatinib as first-line treatment in 
patients with epidermal growth factor receptor (EGFR)
mutation-positive advanced non-small cell lung cancer
(NSCLC)
Brief lay title
The study observes afatinib as first-line treatment in 
patients with epidermal growth factor receptor (EGFR)
mutation-positive advanced non-small cell lung cancer 
Protocol version 
identifier:
3.0
Date of last version of 
protocol:
26 Aug 2019 (v2.0)
03 July 2019 (v1.0)
PASS:
No
EU PAS register 
number:
TBD
Active substance:
Afatinib
Antineoplastic agents, tyrosine kinase inhibitors
ATC code: L01XE13
Medicinal product:
Giotrif®, 30 mg and 40 mg tablets
Product reference:
30 mg: EU/1/13/879/004, EU/1/13/879/005, 
EU/1/13/879/006
40 mg: EU/1/13/879/007, EU/1/13/879/008, 
EU/1/13/879/009
Procedure number:
N/A
Joint PASS:
No
Research question and 
objectives:
Primary objective: 
To assess the time on treatment of afatinib as first-line 
therapy in advanced non-small cell lung cancer patients 
with EGFR mutation. Time on treatment (TOT) is defined 
from the start of afatinib treatment until the end of the 
afatinib treatment or death date by any cause.

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Non-interventional Study Protocol                                                            
BI Study Number 1200-0318
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1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 6
3.
RESPONSIBLE PARTIES.................................................................................... 8
4.
ABSTRACT........................................................................................................... 9
4.1
FLOW CHART............................................................................................... 12
5.
AMENDMENTS AND UPDATES..................................................................... 15
6.
MILESTONES..................................................................................................... 18
7.
RATIONALE AND BACKGROUND................................................................ 19
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 21
9.
RESEARCH METHODS .................................................................................... 22
9.1
STUDY DESIGN............................................................................................ 22
9.2
SETTING........................................................................................................ 22
9.2.1
Study population ..................................................................................... 23
9.2.2
Study duration ......................................................................................... 24
9.2.3
Eligibility................................................................................................. 24
9.2.4
Study visits .............................................................................................. 25
9.2.5
Study discontinuation.............................................................................. 25
9.3
VARIABLES .................................................................................................. 26
9.3.1
Exposures ................................................................................................ 27
9.3.2
Outcomes................................................................................................. 27
9.3.2.1
Primary outcomes............................................................................. 27
9.3.2.2
Secondary outcomes......................................................................... 28
9.3.3
Covariates................................................................................................ 28
9.4
DATA SOURCES........................................................................................... 28
9.5
STUDY SIZE.................................................................................................. 29
9.6
DATA MANAGEMENT................................................................................ 29
9.6.1
Electronic data capture system................................................................ 29
9.6.2
Data entry................................................................................................ 29
9.6.3
Statistical software .................................................................................. 29
9.7
DATA ANALYSIS......................................................................................... 29
9.7.1
Main analysis........................................................................................... 30

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Non-interventional Study Protocol                                                            
BI Study Number 1200-0318
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9.7.3
Safety Analysis........................................................................................ 31
9.8
QUALITY CONTROL................................................................................... 31
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 31
9.9.1
Lost to follow-up..................................................................................... 32
9.9.2
Channelling bias...................................................................................... 32
9.9.3
Study Sample Size................................................................................... 32
9.10
OTHER ASPECTS ......................................................................................... 32
9.10.1
Data quality assurance............................................................................. 32
9.10.2
Patient completion................................................................................... 33
9.10.3
Completion of study................................................................................ 33
9.10.4
Study records........................................................................................... 33
9.10.4.1
Source documents ............................................................................ 33
9.10.4.2
Direct access to source data and documents .................................... 33
9.10.5
Protocol deviations.................................................................................. 33
9.10.6
Compensation available to the patient in the event of study related injury33
9.11
BIAS 33
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 34
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...................................................................................................... 34
10.2
STATEMENT OF CONFIDENTIALITY...................................................... 34
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 36
11.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 36
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 37
11.3
REPORTING TO HEALTH AUTHORITIES................................................ 40
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 41
13.
REFERENCES .................................................................................................... 42
13.1
PUBLISHED REFERENCES......................................................................... 42
13.2
UNPUBLISHED REFERENCES................................................................... 45
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 46
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 47
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 48
ANNES 3.1 ECOG PERFORMANCE STATUS....................................................... 48

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Non-interventional Study Protocol                                                            
BI Study Number 1200-0318
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ANNES 3.2 PROPOSED TNM STAGE GROUPINGS............................................ 48
ANNES 3.3 RECIST GUIDELINE, VERSION 1.1................................................... 49
ANNEX 4. REVIEWERS AND APPROVAL SIGNATURES................................... 50

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Non-interventional Study Protocol                                                            
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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event(s)
AESI
Adverse Event of Special interest
ASD
Absolute Standardised Differences
BI
Boehringer Ingelheim
CA
Competent Authority
CI
Confidence Interval
CTL
Clinical Trial Leader
CTM
Clinical Trial Manager
CR
Complete Response
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organisation
CTCAE
Common Terminology Criteria for Adverse Events
CUP
Compassionate Use Programmes
DCR
Disease Control Rate
EAP
Expanded Access Programme 
eCRF
Electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EGFR
Epidermal Growth Factor Receptor
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practice
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator Site File
MAH
Marketing Authorisation Holder
MDRD
Modification of Diet in Renal Disease 
MedDRA
Medical Dictionary for Regulatory Activities
N
Number
NCI
National Cancer Institute
NGS
Next generation sequencing
NIS
Non-Interventional Study
NSCLC
Non-Small Cell Lung Cancer
ORR
Objective Response Rate
OS
Overall Survival
PASS
Post-Authorisation Safety Study
PD
Progressive Disease
PFS
Progression-Free Survival

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Non-interventional Study Protocol                                                            
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001-MCS-90-118_RD-23 (2.0) / Saved on: 03 Jul 2020
PR
Partial Response
PS
Performance score
PT
Preferred Term
RDC
Remote Data Capture
SAE
Serious Adverse Event
SAS
Statistical Analysis Software
SD
Stable Disease
SEAP
Statistical and Epidemiological Analysis Plan
SmPC
Summary of Product Characteristics
SOC
System Organ Classes
SOP
Standard Operating Procedures
SqCC
Squamous Cell Carcinoma
T790M
Thr790Met
TKI
Tyrosine Kinase Inhibitor
TMF
Trial Master File
TOT
Time on treatment
TTF
Time-to-Treatment Failure
US
United States
VEGF
Vascular Endothelial Growth Factor
WHO
World Health Organisation

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Non-interventional Study Protocol                                                            
BI Study Number 1200-0318
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3.
RESPONSIBLE PARTIES
This study is sponsored by Boehringer Ingelheim (BI).
BI appointed a clinical trial leader (CTL) who is responsible for coordinating the activities 
required in this study. CTL will manage the study in accordance with applicable regulations 
and internal standard operating procedures (SOPs). In addition, CTL will instruct the study
team to conduct related procedures in this study, including preparing, conducting and 
reporting, ordering the materials as needed for the study. CTL will ensure that appropriate 
training and information are delivered to internal clinical trial manager (CTM), clinical 
research associates (CRAs) or external contract research organisation (CRO) members (CRO 
Project Managers and/or CRO CRAs), and investigators of participating sites.
The study will be done by a CRO with which the responsibilities and tasks will have been 
agreed and a written contract filed before initiation of the study. Data management and 
statistical evaluation will be performed by a CRO, which is appointed by the sponsor.
Tasks and functions assigned to organise, manage and evaluate the study will be defined 
according to BI SOPs. A list of responsible persons and relevant local information (as
reference in protocol if applicable) are in the investigator site file (ISF) and the trial master
file (TMF) document.
A coordinating investigator and a co-coordinating investigator will be nominated to 
coordinate principal investigators at different sites participating in this multicentre study. 
Tasks and responsibilities for the coordinating investigator will be defined in a contract filed 
before the initiation of the study.
Relevant documentation on the participating (principal) investigators and other important
participants (e.g., their curricula vitae) will be filed in the ISF. An ISF containing all relevant
study related documentation will be maintained according to local regulations and BI SOPs at
each study site. 

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Non-interventional Study Protocol                                                            
BI Study Number 1200-0318
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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Giotrif®
Name of active ingredient:
Afatinib
Protocol 
date:
Study 
number:
Version/Revision:
Version/Revision date:
03 July 2019
1200-0318
3.0
26 Aug 2019 8 Mar 2022
Title of 
study:
Real-world study on afatinib as first-line treatment in Chinese patients 
with EGFR mutation-positive advanced non-small-cell lung cancer
Rationale 
and 
background:
Afatinib, an irreversible ErbB family blocker, is approved in epidermal 
growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) naïve 
patients. Afatinib showed a median progression-free survival (PFS) of 
approximately 11.0 months in previous clinical trials in China (LUX-Lung 
3, LUX-Lung 6) as first-line treatment in patients with EGFR mutation 
positive non-small cell lung cancer (NSCLC) (P13-07382, P14-00758). In
addition, afatinib showed a significant better median PFS and time-to-
treatment failure (TTF) versus geftinib in LUX-Lung 7 (P16-04350). In 
LUX-Lung 3 and LUX-Lung 6 trials, patients with Exon 19 deletion had
more than 12 months [LUX-Lung 3 OS with Del19 patients: 33.3m vs 
21.1m, HR0.54(0.36-0.79), LUX-Lung 6 OS with Del19 patients: 31.4m 
vs 18.4m, HR0.64(0.44-0.94) OS benefit versus platinum-base 
chemotherapy (P15-00344). In addition, in LUX-Lung trials, afatinib 
demonstrated clinical benefit in patients with baseline brain metastases 
and with the uncommon mutations G719X,L861Q, and S768I (P16-
01306,P15-05932). However, resistance developed in most of patients, 
and the most common mechanism of resistance to 1st or 2nd generation 
EGFR TKIs (>50%) was the emergence of a second-site EGFR-mutation, 
thr790met (T790M) (R15-6101, P09-09950).
There are limited real world data with afatinib first-line therapy in EGFR 
mutated, advanced NSCLC Chinese patients who are treatment naive. 
Therefore, this study aims to assess the effectiveness and safety of afatinib
first-line treatment in EGRF mutated, advanced NSCLC Chinese patients 
in routine clinical practice.
Research 
question and 
objectives:
The primary objective of this study is to assess the time on treatment of 
afatinib as first-line therapy in advanced NSCLC patients with EGFR 
mutation. Time on treatment (TOT) is defined from the start of afatinib 
treatment until the end of the afatinib treatment or death date by any 
cause.
The secondary objectives of this study are to assess objective response 

Boehringer Ingelheim
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Non-interventional Study Protocol                                                            
BI Study Number 1200-0318
c38958167-01
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001-MCS-90-118_RD-23 (2.0) / Saved on: 03 Jul 2020
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Giotrif®
Name of active ingredient:
Afatinib
rate, overall survival and safety of afatinib first-line therapy in advanced 
NSCLC patients with EGFR mutation.
The exploratory objective is to collect data on acquired resistance 
mechanism (T790M mutation, etc) to afatinib first-line therapy.
Study 
design:
Non-interventional, prospective, multicentre study based on real-world
data of Chinese EGFR-mutated NSCLC patients treated with afatinib as 
first-line treatment .  
Population:
It is planned that approximately 10 study centres in China will participate
in this non-interventional study (NIS), and 76 eligible patients will be 
enrolled. Every patient who fulfils eligibility criteria and agrees to 
participate in the study will be enrolled in the study. Recruitment of 
patients for this study is competitive.
Inclusion criteria:

Patients who are diagnosed with locally advanced or metastatic 
NSCLC with EGFR sensitive mutation

Patients who will initiate afatinib as first-line treatment for EGFR 
mutation-positive NSCLC

Male or female patients age ≥18 years

Written informed consent per local regulatory requirement
Exclusion criteria: 

Patients who have received previous systemic therapy (previous 
adjuvant or neo-adjuvant therapies are permitted)

Patients with symptomatic brain metastases (patients with brain 
metastases, who were previously treated, are eligible provided 
they have asymptomatic brain metastasis for at least 4 weeks on 
stable doses of medication) at the start of afatinib treatment

Patients with concurrent participation in an interventional 
Oncology clinical trial during the first-line treatment phase or 
within the last 30 days prior to the first-line treatment phase. If 
patients join another interventional study during the period of
second-line treatment or later-line treatment, this patient should 
not be excluded from this study.
Variables:
Primary outcomes
Time on treatment of afatinib (ToT) as first-line therapy in advanced non-
small cell lung cancer patients with EGFR mutation. Time on treatment is 
defined from the start of afatinib treatment until the end of the afatinib 
treatment or death date by any cause. Patients that are lost to follow up or 

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Non-interventional Study Protocol                                                            
BI Study Number 1200-0318
c38958167-01
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001-MCS-90-118_RD-23 (2.0) / Saved on: 03 Jul 2020
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Giotrif®
Name of active ingredient:
Afatinib
withdraw before the end of study will be censored at the time of last 
known contact.
Secondary outcomes
Overall survival (OS) from the start of afatinib until the date of death, loss 
to follow up (including patient withdrawal) or end of study period
Objective response rate (ORR), [objective response is defined as best 
overall response of complete response (CR), partial response (PR)]
according to RECIST 1.1 with afatinib  first-line therapy
Adverse events (AEs), serious adverse events (SAEs), afatinib-related 
AEs (ADRs) as indicated by incidence, seriousness and intensity graded 
according to United States (US) national cancer institute's (NCI) common 
terminology criteria for AEs version 5.0 (CTCAE Version 5.0)
Further outcome
Resistance mechanisms (Type and proportion:T790M,etc) after afatinib 
first-line treatment.
Data 
sources:
Data for this study will be obtained via the following sources:
-
Patient medical information: The investigator or authorized 
medical staff will record clinical and treatment data from patients’ 
medical records into an electronic case report form (eCRF) at 
baseline and at every visit up to end of the follow up period ( refer 
to Section 9.4)
Study size:
76 patients 
Study 
duration:
The duration of data collection for an individual patient will be a 
maximum of approximately 33 months, It is anticipated that all data 
collection for this study started from May 2020(first patient enrolled) and 
will continue until December 2023 (two years after the last patient was 
enrolled)
Data 
analysis:
Time on treatment (TOT) will be analysed using Kaplan-Meier method, 
and the median Time on Treatment (TOT) along with two-sided 90% 
confidence interval (CI) will be calculated. Overall survival (OS) will be 
analysed similarly. 
Objective response rate (ORR) and acquired resistance mutation type, and 
AEs will be summarised descriptively by frequency and proportions.
Milestones:
IRB/IEC Approval: May 2020
First Patient In: May 2020

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Non-interventional Study Protocol                                                            
BI Study Number 1200-0318
c38958167-01
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001-MCS-90-118_RD-23 (2.0) / Saved on: 03 Jul 2020
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Giotrif®
Name of active ingredient:
Afatinib
Last Patient In: Dec 2021
Interim Analysis: Dec 2022
Last Patient Out: Dec 2023
Database Locked: Mar 2024
Final NIS Report: Jun 2024
4.1
FLOW CHART 
Table 1. Patient Flow Chart
Procedure
Baseline
Treatment 
(first-line)
Treatment
(second-line)
Further
subsequent 
treatment(s) 
up to death
End of 
study
(Until Dec 
2023 or  
death)
Observation period 
Before 
initiation of 
afatinib 
Initiation of 
afatinib first-
line 
treatment:
Followed by 
regular visits 
according to 
institution 
standards
Start second-
line treatment 
(first visit ≤1 
months 
followed by 
regular visits
according to 
institution 
standards)
Start further
subsequent
treatment(s) 
followed by 
regular 
visits  
according to 
institution 
standards
Informed consenta
X
Demographics (age, gender, 
height, etc.)
X
Body weight 
X
X
Presence of brain metastases 
X
X
Afatinib dose
X
ECOG Performance Status
X
X
Baseline characteristics

Type of EGFR mutation 
at start of afatinib 
therapy 

Genetic testing
informationb

Disease stage

Comorbidities 
Xa

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BI Study Number 1200-0318
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
Medical history 
Laboratory testing
information c
X
X
Eligibility (I/E criteria)
X
Administration/Concomitant 
therapies
X
X
X
Tumour assessment
according to local 
institutional standardsd
X
X
X
Patient vital status
X
X
X
X
X
Regular follow-up
X
X
Genetic testingb
Xf
Adverse events (AEs)
X
X
Xe
Xe
Xe
a: Written informed consent must be obtained before any screening/baseline data collection
are performed. 
b: Genetic testing report (including PCR, NGS, etc.) will be collected if available
c: Detailed Laboratory tests are included in section 9.3.3. The estimated GFR (glomerular 
filtration rate) using modification of diet in renal disease (MDRD) formula, eGFR = 186 x 
SCr (mg/dL)-1.154 x Age-0.203 x (0.742 if female) (R02-2529).
d: Tumour assessment will only be applied while patients with anti-tumour therapy (first-
line and second-line or later lines). If the treatment finish, the assessment will end.
e: All AEs have to be collected and documented on the eCRF from the day of signing 
informed consent up to 30 days after the last dose of afatinib administration. In addition, all 
ADRs associated with afatinib and AEs with fatal outcome must be collected and 
documented on the eCRF after the end of residual effect period (30 days after the last dose 
of afatinib administration) up to the end of study. Progression of underlying malignancy is 
exempted from reporting as adverse event on the eCRF AE page and on the NIS AE form, 
when considered not related to afatinib, requirements for reporting on NIS AE form are 
included in section 11.2. 
f: Genetic testing is needed according to clinical practice prior to subsequent treatment.

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Below Firure 1 is the study flow chart:
Figure 1:Study Flow Chart
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Non-interventional Study Protocol                                                            
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5.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study 
protocol
Amendment or update
Reason
1.0
03 
Jul 
2019
NA
NA
NA
2.0
26 
Aug
2019
Refer to 
Protocol 
Version 2.0
Refer to Protocol version 2.0
Refer to 
Protocol 
Version 2.0
3.0
8
Mar 
2022
4
Abstract updating per protocol 3.0
Abstract 
updating per 
protocol 3.0
6
Milestone updating per updated study 
timeline
Milestone 
updating per 
updated study 
timeline
7
Adding related information of study
rationale and background：
1. Afatnib clinical benefit in 
uncommon EGFR mutation and 
brain metastases.
2. Limited real world data with 
afatinib first-line treatment in 
EGFR-mutated, advanced non-
small cell lung cancer Chinese 
patients.
Study rationale 
and 
background 
changing
8
Primary objective and secondary 
objective were updated to :
1. The primary objective of this study 
is to assess the time on treatment 
of afatinib as first-line therapy in 
advanced non-small cell lung 
cancer patients with EGFR 
mutation. Time on treatment
(TOT) is defined from the start of 
afatinib treatment until the end of 
the afatinib treatment
2. The secondary objective is to 
assess objective response rate , 
overall survival and safety of 
Research 
question and 
objectives 
updating per 
study rationale 

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Non-interventional Study Protocol                                                            
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001-MCS-90-118_RD-23 (2.0) / Saved on: 03 Jul 2020
afatinib first-line therapy in 
advanced NSCLC patients with 
EGFR mutation. To collect data on 
acquired resistance mechanism 
(T790M mutation, etc) to afatinib 
first-line therapy.
9
Related sessions in research methods 
were updated to:
1. Study design: This NIS will be 
conducted at 10 study sties in 
China and the patients treated 
with first-line afatinib will be 
followed up until death, lost to 
follow-up, withdraw from the 
study, or end of the study for 
other reasons, whichever comes 
first and no later than 2023.
2. Study Setting: 76 patients treated 
with afatinib first line treatment, 
will be enrolled into this 
prospective NIS across multiple 
centres in China. 
3. Study Variables - Outcomes: 
Primary outcome is time on 
treatment of afatinib as first-line 
therapy in advanced non-small 
cell lung cancer patients with 
EGFR mutation. Time on 
Treatment (TOT) is defined from 
the start of afatinib treatment until 
the end of the afatinib treatment.
Patients that are lost to follow up 
or withdraw before the end of 
study will be censored at the time 
of last known contact. Secondary 
outcomes are overall survival, 
Objective response rate, 
Resistance mechanisms and 
safety.
4. Study size: Seventy-six patients 
will be included in this study.
5. Data analysis: We conducted time 
on treatment (TOT) of afatinib
first-line therapy and overall 
survival (OS) for the main 
analysis. Moreover , ORR,
Research 
methods 
updating per 
updated study 
objectives

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resistance mechanism and AEs 
will be for further analysis. If data 
allows, it would also be of 
interest to look at the overall 
survival in patients who had 
different subsequent treatments 
after afatinib.
11
Updating Adverse events reporting 
with Pregnancy
Updating 
Adverse events 
reporting with 
Pregnancy

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6.
MILESTONES
Milestone
Planned Date
IRB/IEC Approval
May 2020
First Patient In
May 2020
Last Patient In
Dec 2021
Interim Analysis
Dec 2022
Last Patient Out
Dec 2023
Database Locked
Mar 2024
Final NIS Report 
Jun 2024

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7.
RATIONALE AND BACKGROUND
Lung cancer is the leading cause of cancer-associated mortality worldwide. In 2018, World 
Health Organisation (WHO) reported approximately 2.1 million new lung cancer cases
annually and 1.8 million deaths which represents 18.4% of the total cancer deaths worldwide
(R18-3308). In China, lung cancer is also considered as a leading cause of death among 
males. A total of 0.73 million new lung cancer cases and 0.61 million deaths (R18-1649). For
NSCLC, it accounts for approximately 85% of all primary lung cancers where most patients 
were presented with advanced and unresectable disease at the time of diagnosis (R18-3355,
R08-2617). 
Current available therapeutic strategy varies depending on the disease stages with some 
combining local treatments (surgery and/or radiotherapy) and systemic treatments 
(chemotherapy and/or targeted therapy). Systemic therapies are the mainstay treatment for 
patients with stage IIIb/IV (unresectable cancers) (P11-07424). These may include 
chemotherapy, vascular endothelial growth factor (VEGF) inhibitor, immunotherapy and
target therapy. Treatment with EGFR-TKI is the preferred option for patients with EGFR 
gene mutation as metastatic EGFR-mutant lung cancers are sensitive to EGFR TKIs (P18-
01881).
Acquired resistance to EGFR-targeted TKIs therapy is inevitable due to tumour evolution. 
Kohsaka and team reported in 2018 that EGFR mutation-positive NSCLC is highly 
heterogeneous at the cellular level, facilitating clonal expansion of resistant tumours via 
multiple molecular mechanisms (P18-10855). To date, the 6 approved EGFR-TKIs can be 
classified into three different generations - 1st generation (erlotinib, gefitinib and icotinib), 
2nd generation (afatinib and dacomitinib) and 3rd generation (osimertinib) (R18-0130, P19-
03609).
Efficacy and safety of TKIs of different generation are widely investigated in WJTOG3405, 
NEJ002, ARCHER 1050, EURTAC, OPTIMAL, NEJ026, LUX-Lung 3, LUX-Lung 6, LUX-
Lung 7, AURA3 and FLAURA(P19-00432). The range of PFS reported with the longest
being 18.9 months was indicated in patients who were with EGFR-mutated advanced NSCLC 
and treated with osimertinib as the first-line (FLAURA) comparing to standard of care (10.2 
months) (either received gefitinib or erlotinib) in EGFR mutant NSCLC treatment naïve 
patients (R18-0130). To date, osimertinib it is the only commercially approved 3rd generation 
EGFR TKI for the treatment of patients with EGFR thr790met (T790M) positive tumour in 
China (P19-00432).
The first marketing authorisation of afatinib was granted on 12 Jul 2013 in the US (trade 
name Gilotrif®) as first-line treatment for patients with metastatic NSCLC and whose 
tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected 
by an FDA-approved test (P13-10659) and the indication was updated in 2018 in US for the 
First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose 
tumours have non-resistant EGFR mutations as detected by an FDA-approved test. In the 
European Union (EU), afatinib was approved on 25 Sep 2013 (trade name Giotrif®) as 
monotherapy for the treatment of EGFR TKI-naïve patients with locally advanced or 
metastatic NSCLC with activating EGFR mutation(s). Furthermore, in US and EMA, afatinib 
is also approved in for squamous cell carcinoma (SqCC) of the lung progressing after 

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platinum-based chemotherapy. In China, afatinib (trade name Giotrif®) was approved on 21 
Feb 2017 for patients with NSCLC with activating EGFR mutation that previously were not 
treated with EGFR TKI and for squamous cell carcinoma (SqCC) of the lung progressing
after platinum-based chemotherapy.
Afatinib showed a median PFS of approximately 11 months in treatment-naïve patients with 
EGFR common and uncommon mutations in LUX-Lung 3 (P13-07382), LUX-Lung 6 (P14-
00758) and LUX-Lung 7 (P16-04350). Furthermore, when comparing with gefitinib, it 
reduced the risk of PFS (HR=0.73 [95% CI 0·57–0·95],) in LUX-Lung 7. In addition, in 
LUX-Lung trials, afatinib demonstrated clinical benefit in patients with baseline brain 
metastases and with the uncommon mutations G719X,L861Q, and S768I (P16-01306,P15-
05932). Nevertheless, most patients (approximately >50%) developed resistance to either 1st 
or 2nd generation EGFR TKIs due to the emergence of a second-site EGFR-mutation, the 
T790M (R15-6101, P09-09950).
There are limited real world data with afatinib first-line therapy in EGFR-mutated, advanced 
non-small cell lung cancer Chinese patients who are treatment naive. Therefore, this study 
aims to assess the effectiveness and safety of afatinib first-line treatment in EGFR mutated, 
advanced non-small cell lung cancer Chinese patients in routine clinical practice.

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Non-interventional Study Protocol                                                            
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8.
RESEARCH QUESTION AND OBJECTIVES
Data from real-world setting will provide information on afatinib first-line treatment in 
Chinese patients diagnosed with advanced EGFR mutation-positive NSCLC.
Primary objective:

The primary objective of this study is to assess the time on treatment of afatinib as
first-line therapy in advanced non-small cell lung cancer patients with EGFR 
mutation. Time on treatment (TOT) is defined from the start of afatinib treatment until 
the end of the afatinib treatment or death date by any cause. Patients that are lost to 
follow up or withdraw before the end of study will be censored at the time of last 
known contact..
Secondary objective: 

To assess objective response rate , overall survival and safety of afatinib first-line 
therapy in advanced NSCLC patients with EGFR mutation. 
Exploratory objective:
To collect data on acquired resistance mechanism (T790M mutation, etc) to afatinib 
first-line therapy.

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Non-interventional Study Protocol                                                            
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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a NIS to be conducted at approximately 10 sites in China where real world data are 
from EGFR mutation positive NSCLC patients who will initiate afatinib as first-line 
treatment and receiving subsequent therapy. All the study sites will need to have afatinib used 
in regular clinical practice. Participating investigators will screen patients for eligibility, 
obtain informed consent, and enrol patients who meet the eligibility criteria. Investigators or 
trained site personnel will then complete the eCRF to capture information on demographic, 
medical history, and treatment information at the time of enrolment.
This study will only include patients who are newly diagnosed and who will receive afatinib 
as first-line treatment, regardless if they will receive 3rd generation or other treatment
subsequently. Data will be collected for the patients who receiving afatinib first-line therapy 
and subsequent therapy. Data of patients’ resistance mechanism after afatinib treatment will 
also be collected. 
Day 0 is the date that the patient sign the  informed consent . Day 1 is the first dose of 
afatinib. We collected the date of initial and metastatic diagnosis. Day 1 is the first dose of 
afatinib therapy (index date). The patients will be followed up by regular visits according to 
institution standards after start of afatinib until death, lost to follow-up, withdraw from the 
study, or end of the study for other reasons, whichever comes first and no later than Dec 
2023. Please refer to Section 4.1 for the visit plan and major information collected during 
each visit.
This study is descriptive only and there are no comparisons between groups. To assess the 
presence of this bias (discussed in Section 9.9), data from 1200.0066 study [where patients 
were diagnosed with locally advanced or metastatic NSCLC harbouring EGFR mutation(s)]
may be used to verify if this study contains potential channelling bias.
9.2
SETTING
76 patients, who are diagnosed with locally advanced or metastatic NSCLC (with activating 
EGFR mutation) and will be treated with afatinib as fist line treatment, are be enrolled into 
this prospective NIS across multiple centres in China. 
Eligibility will be assessed prior to enrolment during a scheduled visit. Patients who fulfil
eligibility criteria as well as agree to participate in the study by signing an informed consent 
(required by local regulation and legal requirement) will be included into the study.
Participation of patients in this study is not intended to change the routine treatment that 
patients receive as determined by their clinicians; all treatment decisions, type and timing of 
disease monitoring are at the discretion of the treating physician. Patients will be followed by 
regular visits according to institution standards after the treatment is initiated. Study sites
Site selection criteria in China:

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
Sites prescribe afatinib on a regular clinic basis to patients with EGFR mutation-
positive NSCLC

Capability of conducting an NIS, including qualification, experience, availability and 
research resource of investigators

A genetic test [(next-generation sequencing (NGS) or polymerase chain reaction, 
(PCR)] is applicable for patients diagnosed with NSCLC
After completing the sites feasibility for this study, 10 study sites participated in this 
prospective observational study.
Table 2. Study Sites
No
City
Site
1
Beijing
2
Chengdu
3
Zhengzhou 
4
Hangzhou 
5
Haikou
6
Zhongshan 
7
Guangzhou
8
Guangzhou
9
Shenyang 
10
Shenzhen 
9.2.1
Study population
Eligible patients will be enrolled in this study and will receive afatinib (first-line) and 
subsequent treatment (second-line) of either 3rd generation EGFR TKI or other treatments. 
Patients who are administrated with afatinib as first-line treatment started from May 2020 ( 
first patient enrolled) and will be followed up until death, lost to follow-up, withdraw from 

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Non-interventional Study Protocol                                                            
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the study, or end of the study for other reasons, whichever comes first and no later than Dec 
2023. 
9.2.2
Study duration 
It is anticipated that all data collection for this study started from May 2020 ( first patient 
enrolled) and will continue until Dec 2023 or the event of OS . The maximum duration of 
data collection for an individual patient will be a maximum of 33 months. this period may be 
truncated due to treatment switching, patient withdrawal from the study, or death or end of 
study for any other reason. 
9.2.3
Eligibility
Patients must meet all of the following inclusion criteria and not meet any of the exclusion 
criteria to be eligible for the study:

Inclusion criteria:
o
Patients who are diagnosed with locally advanced or metastatic NSCLC with EGFR 
sensitive mutation positive
o
Patients who will initiate afatinib as first-line treatment for EGFR mutation-positive 
NSCLC 
o
Male and female patients with age ≥18 years
o
Written informed consent per local regulatory requirement 

Exclusion criteria:
o
Patients who have received previous systemic therapy (previous adjuvant or neo-
adjuvant therapies are permitted)
o
Patients with symptomatic brain metastases (patients with brain metastases, who were 
previously treated, are eligible provided they have asymptomatic brain metastasis for 
at least 4 weeks on stable doses of medication) at the start of afatinib treatment
o
Patients with concurrent participation in an interventional oncology clinical trial 
during the first-line treatment phase or within the last 30 days prior to the first-line
treatment phase. If patients join another interventional study during the period of 
second-line treatment or later-line treatment, this patient should not be excluded from 
this study
All patients who fulfil eligibility criteria and provide written informed consent will be 
enrolled
Patients’ record in the study will be maintained in the ISF at the investigational sites. 

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9.2.4
Study visits
This NIS does not impose a therapy protocol, diagnostic/therapeutic procedure, but a regular 
clinical visit schedule. Patients will be enrolled in the study during a regularly scheduled 
clinic visit prior to initiating their treatment (Day 0). Day 1 is defined as the day that the 
patient initiates afatinib (index date). Patients will be followed by regular visits according to 
institution standards since enrolment. After progression on first-line treatment with afatinib, 
based on the clinical practice, patients may have an appropriate genetic examination (such as 
NGS or PCR) in order to identify the best treatment option based on the testing result.
Lab testing and additional procedures would be based on physician’s judgement and clinical 
practice.
Below Figure 1 list the study flow chart and visits
Figure 1: Study Flow Chart 
9.2.5
Study discontinuation
BI reserves the right to discontinue the study or at a particular study site at any time for the 
following reasons:

Failure to meet expected enrolment goals overall or at a particular study site

Emergence of any efficacy/safety information that could significantly affect the 
continuation of the study, or any other administrative reasons
 
 
 
  
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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
Violation of regulations, the study protocol, or the contract by a study site, disturbing 
the appropriate conduct of the study
The investigator/the study site will be reimbursed for reasonable expenses incurred in the 
event of study termination (except in the event of the third reason).
9.3
VARIABLES
This is a prospective , observational study. Clinical data will being collected and enters data 
directly into the eCRF during or after the patient visit per study protocol. The study protocol 
does not mandate treatments, each participating site provides and documents patient care and 
outcomes according to usual care, physician discretion and local practice standards. Thus, 
study variables may not be available for all patients at all data collection time points per 
routine medical care. All the data will be continuously and directly into the eCRF during or 
after the patient visit in the whole study period. 
The study variables to be collected include:
Date of diagnosis
Demographics: age at the start of afatinib treatment, gender, smoking status
Laboratory test: hematology, biochemistry and urine examinations. List below table 2:
Table 3. Laboratory test
Category
Parameters
Hematology
Hemoglobin, platelet count, white blood cell (WBC), absolute 
neutrophil count (ANC)
Chemistry
Electrolytes:
Sodium and potassium
Liver function tests:
Alkaline phosphatase, aspartate amino transferase (AST/SGOT), 
alanine amino transferase (ALT/SGPT), γ-glutamyltransferase 
(GGT), total bilirubin
Renal function parameters:
Blood urea/Blood Urea Nitrogen (BUN), creatinine 
Other:
Glucose, albumin, phosphorus, lactate dehydrogenase (LDH), total 
protein, 
Urinalysis
pH, protein, glucose, blood/erythrocytes, leucocytes, nitrite; in case 
of clinically significant finding further evaluation should be 
performed and results documented. Dipstick testing is sufficient. 
Stage of disease at the start of afatinib treatment
Tumour histology 

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Type of EGFR mutations at the start of afatinib and subsequent treatment, specifically 
the type of acquired resistance mutation 
Sites of metastases at start of afatinib treatment
Body weight and height at the start of afatinib treatment
Eastern cooperative oncology group (ECOG) performance score (PS) (if available) at 
start of afatinib treatment

Date of start and end of afatinib treatment

Starting dose of afatinib

Afatinib dose modification(s) and date(s) (if applicable)

ECOG PS (if available) at start of subsequent treatment

Sites of metastases at the start of subsequent treatment

Reason for discontinuation of afatinib treatment (e.g., progressive disease (PD), AE)

If subsequent treatment was provided within an expanded access programme 
(EAP)/compassionate use programmes (CUP) or prescribed as clinical practice

Comorbidities (hepatitis B, gastritis, liver cirrhosis, etc.)

Concomitant medications including (PPIetc.)

AEs (leading to dose modification)

Date & Cause of death
9.3.1
Exposures
Afatinib:
Patients will be treated with afatinib 30 mg or 40 mg tablet once daily as indicated in the 
approved labels of afatinib.
3rd generation EGFR TKI or other subsequent treatment:
Patients may be treated with 3rd generation EGFR TKI or other subsequent treatment as 
indicated in the approved labels.
The Summaries of Product Characteristics on Giotrif® is contained in the ISF in the 
“Summary of Product Characteristics” (SmPC) section.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
Time on treatment of afatinib as first-line therapy in advanced non-small cell lung 
cancer patients with EGFR mutation. Time on Treatment (TOT) is defined from the 
start of afatinib treatment until the end of the afatinib treatment. Patients that are lost 
to follow up or withdraw before the end of study will be censored at the time of last 
known contact.

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9.3.2.2
Secondary outcomes

Overall Survival(OS) from the start of afatinib until the end of study, date of death, 
patient withdrawal or loss to follow-up 

ORR [OR is defined as best overall response of CR and PR] according to RECIST 1.1 
by investigator review with afatinib in first-line treatment 

AEs, SAEs, afatinib-related AEs (ADRs) as indicated by incidence seriousness and 
intensity graded according to United States (US) national cancer institute's (NCI)
(CTCAE Version 5.0)
9.3.3
Covariates
As mentioned previously, the data from study 1200-0066 will be used to assess presence of 
potential channelling bias and to put the results into perspective. Therefore, the baseline 
characteristics of patients in 1200-0066 trial will be described. The covariates to be collected 
in the both studies (if applicable) are listed as following.

Baseline demographic: age, gender, height, weight, body mass index, , smoking status 
(former, current, never) 

Clinical characteristics including medical history, surgery history, lab testing 
information (haematology, biochemistry and urine examinations), disease stage, 
tumour histological classification, EGFR mutation at start of afatinib therapy, ECOG 
PS score, brain metastases, afatinib starting dose

Current/Concomitant medications
9.4
DATA SOURCES
Data for this study will be obtained via the following sources:
-
Patient medical information: The investigator or authorised medical staff will record 
clinical and treatment data from patients’ medical records/laboratory tests/physical 
examination into an eCRF at baseline and at every visit up to the end of the follow-up 
period. 
There are no protocol-mandated tests, procedures, or clinic visits for this study. All the data 
will be continuously and directly into the eCRF during or after the patient visit in the whole 
study period. 

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9.5
STUDY SIZE
Seventy-six patients will be included in this study.
Based on LUX-Lung trials, we assume the median time on treatment (TOT) on afatinib to be 
12 months in this study. Assuming that the time on treatment (TOT) follows an exponential 
distribution, it is expected to have 35 events till 2 years after last patient in, given total 
sample size equal to 76, considering a 30% drop out rate. 
9.6
DATA MANAGEMENT
9.6.1
Electronic data capture system
Data will be gathered in the electronic data capture (EDC) system prepared by the sponsor or 
appointed CRO. The details of data management procedures to ensure the quality of the data 
will be described in the statistical and epidemiological analysis plan (SEAP) available in 
eTMF.
9.6.2
Data entry
All the data will be continuously and directly into the eCRF during or after the patient visit in 
the whole study period. All reported data from the enrolled investigator’s site will be entered 
via a secured web-based EDC study database. All site personnel will be fully trained in using 
the EDC system, including eCRF completion guidelines. Site personnel will be provided with 
secure usernames and passwords in order to enter study data into the EDC system. All 
participating sites will only have access to view and enter the data for their patients. A data 
manager will perform concurrent review during the course of the data collection period. Data 
entered in the eCRFs that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study; also current 
medical records must be available. For eCRFs all data must be derived from source 
documents. Data queries generated from the database will be created on an ongoing basis,
queries will be based on the data management system logic deck and database validation for 
adequacy and consistency. The site management team will follow-up to request the 
completion of such queries.
9.6.3
Statistical software
All analyses will be performed using statistical analysis software (SAS) for Microsoft 
Windows operating system statistical software (
) 
version 9.3 or higher, using validated implementations of each application or SAS custom 
programming.
9.7
DATA ANALYSIS
For the purpose of this study, analyses will generally be descriptive in nature and will be
conducted using SAS statistical software (version 9.3 or higher). Descriptive data regarding 
patient demographic and clinical characteristics will be calculated. For categorical measures, 
data will include the frequency (number of cases (n)) and percentage (%) of total study 

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patients observed in each category (N). All variables will be summarised descriptively 
through tabular displays of mean, median, ranges and standard deviations of continuous 
variables and frequency distributions of categorical variables. When necessary, continuous 
variables also will be categorised into intervals, with the distribution of patients (n, N, %) for 
each interval provided.
AEs will be graded in accordance with CTCAE Version 5.0. The safety analyses include 
frequency and intensity of AEs, SAEs and ADRs by System Organ Class (SOC)/Preferred 
Term (PT) using a current medical dictionary for regulatory activities (MedDRA) dictionary. 
In addition, AEs resulting in the discontinuation of treatment will be studied.
To assess the presence of channelling bias, we will use the data from study 1200-0066 to 
assess potential channelling and to put the results into perspective. The baseline 
characteristics of patients in this study and in study 1200-0066 separately. Patient 
characteristics will be compared between the two groups using absolute standardised
differences (ASD), where an ASD of at least 10% will be considered a meaningful difference.
9.7.1
Main analysis
All patients treated with afatinib will be included in the analysis of the primary outcome, 
Time on Treatment (TOT) on afatinib. Time on Treatment (TOT) will be evaluated by 
Kaplan-Meier analysis. Median Time on Treatment (TOT) and two-side 90% CI, and the 
quartiles will be calculated from the Kaplan-Meier curve. Patients who are lost to follow up 
without providing the end date of treatment with afatinib will be censored at the time of last 
known contact.
Overall survival (OS) will be evaluated by Kaplan-Meier analysis. Median overall survival 
(OS) and two-side 90% CI, and the quartiles will be calculated from the Kaplan-Meier curve. 
Patients who are lost to follow up (including patient withdrawal) without providing the end 
date of treatment will be censored at the time of last known contact. Patients who reach the 
end of study period without providing the end date of treatment will be censored at the end of 
study.

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9.7.3
Safety Analysis
All adverse events and adverse drug reactions collected per study protocol will be included 
and summarised in the interim safety analysis and in the final study report.
9.8
QUALITY CONTROL
This NIS will be conducted according to Guidelines for Good Pharmacoepidemiology
SPractice (GPP) and Good Pharmacovigilance Practice (GVP), and also will be conducted 
following the standards of International Council for Harmonisation/Good Clinical Practice 
(ICH/GCP) (7) in accordance with local regulations, particularly regarding ethics, protection 
of patient’s privacy, and processing of data. All necessary related data and documents will be 
made available for inspection.
All entries in the eCRFs will be stored in a database. The structure of the database is based on 
the division into sections and entry fields defined in the eCRFs. To improve and ensure data 
quality, data checks will be performed automatically in the eCRFs directly on electronic entry 
at the study site.
Plausible value ranges for numerical data entries, and logical data and list entries will be filed 
in the eCRFs. The tests for consistency and completeness based on this will be performed 
during entry in the eCRFs. The validity of the recorded data will, therefore, be ensured by the 
validations incorporated in the documentation system, which highlight incorrect or 
implausible entries to the data entry clerk/doctor. 
If corrections are necessary after the data are saved, these will be documented in an audit 
trail. 
For further quality assurance of the documented patient observations, a sample-size based 
source data verification will be performed on about 30% of patients included (not including 
the additional data collected for follow-up analyses). In addition, a risk-based monitoring will 
be taken for critical data and documents of all patients, and 100% of these critical data and 
documents will be verified.
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by independent ethics committees (IECs) or by regulatory authorities. 
The quality assurance auditor will have access to all medical records, the investigator’s study-
related files and correspondence, and the informed consent documentation of this study.
9.9
LIMITATIONS OF THE RESEARCH METHODS
Prospective data collection brings its own challenges. Even with a careful controlled design, 
there may be various sources of bias that can completely distort the results. In this study, 
potential limitations of the study design can be listed as:

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9.9.1
Lost to follow-up
All patients will be followed up until the event of OS. If a patient misses more than 1 clinic 
care visit, the site will attempt to communicate with the patient and document the patient’s 
reason for not returning. Sites will be requested to contact patients at various times of the day 
and evening and on different days of the week. If the patient cannot be contacted after the due 
diligence process, the treating physician will attempt to contact the patient’s designated 
secondary contacts, including the patient’s general practitioner and next-of-kin or out-of-
household contacts to obtain information on the patient’s whereabouts and vital status. If the 
patient’s care has been transferred to another healthcare professional, the treating physician at 
the enrolling site will be responsible for obtaining the required follow-up information from 
the new treating physician. Patients who do not return for at least 2 scheduled visits, and for 
whom no information is available will be considered lost to follow-up and will be censored at 
time of last visit or last known contact with the healthcare provider.. Follow-up information 
collecting could be accepted by phone call if the information is available and complete.
9.9.2
Channelling bias
Channelling bias can occur due to preferential prescribing in relation to different risks for the 
events of interest. For example, if aftinib therapy would be prescribed more often compared 
with other treatments to high risky Chinese patients with EGFR mutation positive NSCLC 
(e.g., patients in this study are more severe than other Chinese EGFR mutation positive 
NSCLC patients or with more comorbidities at baseline). Thus, more incidences of outcome 
events were expected in the group with afatinib therapy (e.g., the incidence rates of 
AEs/ADRs will be affected). Furthermore , all patients who fulfil eligibility criteria and 
provide written informed consent will be enrolled. as patients with severe disease or other 
disabilities (eg those who are likely to have poorer outcomes) may be excluded from the 
study.  This study is descriptive only and there are no comparisons between groups.To assess 
the presence of the bias, we plan to use the data from study 1200-0066 to put the results into 
perspective to compare baseline demographic and clinical characteristics of the NSCLC 
patients. Through this, we can verify that safety or efficacy difference is due to patient 
baseline characteristics or the sequential therapy.
9.9.3
Study Sample Size 
76 patients were enrolled in this study, this is a small sample size which may impact the 
assessment of study outcomes. A sample size of 76 patients is expected to ensure an 80% 
chance to observe the width of the 90% CI of median TOT of afatinib smaller than or equal to 
11 months.
9.10
OTHER ASPECTS
9.10.1
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by IECs or by regulatory authorities. The quality assurance auditor 
will have access to all medical records, the investigator’s study-related files and 
correspondence, and the informed consent documentation of this study.

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9.10.2
Patient completion
The collection of the data of patients will continue until the end of data collection or 
withdrawal of consent (if applicable) which occurs first.
9.10.3
Completion of study
The end of the study will occur when the data is collected from the last patient’s data. No 
further data will be collected afterwards.
9.10.4
Study records
eCRFs for individual patients will be provided by the sponsor via remote data capture. 
9.10.4.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the eCRFs that are transcribed from source documents must be consistent 
with the source documents, or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study; also 
current medical records must be available.
9.10.4.2
Direct access to source data and documents
The investigator/institution will permit study-related monitoring, audits, IEC review, and 
regulatory inspection, providing direct access to all related source data/documents. eCRFs
and all source documents, including progress notes and copies of laboratory and medical test 
results, must be available at all times for review by the sponsor’s clinical study monitor, 
auditor and inspection by health authorities (e.g.,NMPA). The CRA/CTM and auditor may 
review all eCRFs, and written informed consents. The accuracy of the data will be verified by 
reviewing the documents described in Section 9.10.4.1.
9.10.5
Protocol deviations
NA
9.10.6
Compensation available to the patient in the event of study related injury
NA
9.11
BIAS
Methodological efforts have been taken to minimise channelling bias and attrition bias: these 
efforts including using the data from study 1200-0066 to assess potential channelling and to 
put the results into perspective, which will help address this issue. Details of bias can be 
referred to Section 9.9.

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10.
PROTECTION OF HUMAN SUBJECTS
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
GCP (to the extent applicable to the NIS setting and required by local regulations), Good 
Epidemiological Practice (GEP), guidelines for GPP, and relevant BI SOPs. Standard medical 
care (prophylactic, diagnostic and therapeutic procedures) remains in the responsibility of the 
treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol/ICH GCP.
10.1
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 IEC and competent authority (CA) according to national and 
international regulations. The same applies to the implementation of changes introduced by 
amendments.
Prior to patient participation in the study, written informed consent must be obtained from
each patient (or the patient’s legally accepted representative) according to ICH GCP and to
the regulatory and legal requirements. Each signature must be personally dated by each 
signatory and the informed consent and any additional patient information form retained by 
the investigator as part of the study records. A signed copy of the informed consent and any 
additional patient information must be given to each patient or the patient’s legally accepted 
representative.
The patient must be informed that his/her study-related data will be used by BI in accordance 
with the local data protection law. The level of disclosure must also be explained to the 
patient.
The patient must be informed that his/her medical records may be examined by authorized 
monitors (CTM/CRA) or quality medicine auditors appointed by BI, by appropriate IEC 
members, and by inspectors from regulatory authorities.
10.2
STATEMENT OF CONFIDENTIALITY 
Individual patient medical information obtained as a result of this study is considered 
confidential, and disclosure to third parties is prohibited with the exceptions noted below. 
Patient privacy will be ensured by using patient identification code numbers. 
Data protection and data security measures are implemented for the collection, storage, and 
processing of patient data by principle 6 and 12 of the WHO GCP handbook.
Data generated as a result of the study need to be available for inspection on request by the 
participating investigators, the sponsor’s representatives, by the IEC and the regulatory 
authorities.

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Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the
study need to be available for inspection on request by the participating physicians, the
sponsor’s representatives, by the IEC and the regulatory authorities.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
11.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (e.g., an abnormal test finding), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. 
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an AE is at least a reasonable possibility. Adverse reactions may arise from the 
use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorisation include off-
label use, overdose, misuse, abuse, and medication errors.
Serious adverse event
SAE is defined as any AE which
-
results in death
-
is life-threatening 
-
requires in-patient hospitalisation, or prolongation of existing hospitalisation 
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly/birth defect
Life-threatening in this context refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious events, such as important medical events that might not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above.
Examples of such events are intensive treatment in an emergency room or at home for
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation
or development of drug dependency or drug abuse. Any suspected transmission via a 
medicinal product of an infectious agent is also considered a serious adverse reaction
Adverse Event of Special Interest (AESI)
No AESIs have been defined for this study.

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11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files.
Collection of AEs
The study design is of non-interventional nature, and the study is conducted within the 
conditions of the approved marketing authorisation. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
afatinib. For this reason, the following AE collection and reporting requirements have been 
defined.
The following must be collected by the investigator in the eCRF from signing the informed 
consent onwards until the end of the study:

From signing the informed consent onwards until 30 days after the last dose of 
afatinib administration:
o
*All AEs (serious and non-serious)

From the end of the residual effect period (30 days after the last dose of afatinib 
administration) onwards until the individual patient’s end of study:
o
All ADRs (serious and non-serious) associated with afatinib
o
*All AEs with fatal outcome
*Exemption regarding progression of underlying malignancy:
“Progressive Disease (PD) of the malignancy” is the study endpoint and will be recorded 
on the appropriate page of the eCRF.
During the whole study, progression of the malignancy under study (including signs and 
symptoms of progression) should not be reported as adverse event unless the progression is 
considered related to afatinib.
When there is evidence suggesting a causal relationship between afatinib and the progression 
of the underlying malignancy, the event must be reported as an AE on the eCRF and on the 
NIS AE Form.
All AEs that are to be collectedincluding those persisting after study completion, must be 
followed up until they are resolved, have been sufficiently characterised, or no further 
information can be obtained.
Causal relationship of adverse event
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an AE. An adverse reaction, in 
contrast to an AE, is characterised by the fact that a causal relationship between a medicinal 
product and an occurrence is suspected. 

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Medical judgment should be used to determine the relationship, considering all relevant 
factors, including the pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases, and relevant 
history. 
Arguments that may suggest a reasonable causal relationship could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative etiologies that could explain the event (e.g., pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g., Stevens-Johnson syndrome)

An indication of dose-response (i.e., greater effect size if the dose is increased, 
smaller effect size if the dose is diminished)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g., pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g., after 5 half-lives). 
Of note, this criterion may not apply to events whose time course is prolonged despite 
removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g.,
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
Intensity of adverse event
The intensity of AEs should be classified and recorded according to the CTCAE criteria in 
the eCRF.
Pregnancy:
In rare cases, pregnancy might occur in a NIS. Once a patient has been enrolled in the study
and has taken study medication, the investigator must report any drug exposure during
pregnancy in a study participant within 7 days by means of Part A of the Pregnancy
Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male

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trial participant becomes pregnant. This requires a written consent of the pregnant partner.
The ISF will contain the trial specific information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring
Form (Part B).
The ISF will contain the Pregnancy Monitoring Form (Part A and B). As pregnancy itself is
not to be reported as an AE, in the absence of an accompanying serious ADR and/or AESI,
only the Pregnancy Monitoring Form and not the NIS AE form is to be completed. If there is
a serious ADR and/or AESI associated with the pregnancy a NIS AE form must be completed
in addition.
Expedited reporting of AEs and drug exposure during pregnancy
The following must be reported by the investigator on the NIS AE form and/or Pregnancy
Monitoring Form from signing the informed consent onwards until the end of the study and
provide o BI unique entry point:
Table 4: Expedited reporting of AEs and drug exposure during pregnancy
Type of Report
Timeline
All serious ADRs associated with afatinib 
Giotrif®
immediately within 24 hours
All AEs with fatal outcome in patients 
exposed to afatinib Giotrif®
*Exemption applies
immediately within 24 hours
All non-serious ADRs associated with 
afatinib Giotrif®
7 calendar days
Drug exposure during pregnancy
7 calendar days
*Exemption
Death due to disease progression of the underlying malignancy is a study endpoint and the 
natural course of the disease. As such it is exempted from reporting as an SAE. Progression 
of the subject's underlying malignancy will be recorded on the appropriate pages of the 
eCRF only and will not be reported on the NIS AE Form. However, when there is evidence 
suggesting a causal relationship between afatinib and the progression of the underlying 
malignancy, the event must be reported as an SAE on the NIS AE Form and on the eCRF.
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions, the investigator could inform the Sponsor upfront via telephone. 
This does not replace the requirement to complete and fax and/or email the NIS AE form.
Information required
For each reportable AE, the investigator should provide the information requested on the 
appropriate eCRF pages and the NIS AE form (if applicable).

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11.3
REPORTING TO HEALTH AUTHORITIES
AE reporting to regulatory agencies will be done by the Marketing Authorisation Holder
(MAH) according to local and international regulatory requirements. 
Exemptions are described in section 11.2, if applicable.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The rights of the investigator and the sponsor with regard to the publication of the results of 
this study are described in the investigator contract.
The publication for study design is planned for Dec 2019, the interim analysis for the primary 
outcome and some secondary outcomes  is planned for Dec 2022, and the publication kick-
off for primary outcome is planned for Jun 2023 after the interim analysis report is 
completed. The final publication will be written after the final NIS report is completed in Dec 
2024.
BI intends to use data from this study to prepare peer-reviewed publications and other
scientific communications such as abstracts, posters, and podiums presentations.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
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Ramalingam SS, Owonikoko TK, Khuri FR. Lung cancer: new 
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Dungo RT and Keating GM. Afatinib: first global approval. Drugs 
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mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. 
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Niederst MJ, Hu H, Mulvey HE, Lockerman EL, Garcia AR, 
Piotrowska Z, et al.The allelic context of the C797S mutation acquired 
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P15-00344
James Chih-Hsin Yang*, Yi-Long Wu*, Martin Schuler, Martin 
Sebastian, Sanjay Popat, Nobuyuki Yamamoto, Caicun Zhou, et al. 
Afatinib versus cisplatin-based chemotherapy for EGFR
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LUX-Lung 6): analysis of overall survival data from two randomised, 
phase 3 trials. Lancet Oncol 2015; 16: 141-51.
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James C-H Yang*, Lecia V Sequist*, Sarayut Lucien Geater, Chun-
Ming Tsai, Tony Shu Kam Mok,et al. Clinical activity of afatinib in 
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uncommon EGFR mutations: a combined post-hoc analysis of LUX-
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O’Byrne, MD, et al. First-Line Afatinib versus Chemotherapy in 
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P18-11537
Hochmair MJ, Morabito A, Hao D, Yang CT, Soo RA, Yang JCH, et 
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positive advanced NSCLC: a real-world study (GioTag). ESMO Asia 
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(ESMO), Singapore, 23 - 25 Nov 2018 Ann Oncol. 2018. 29 (Suppl 
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Hochmair M, Cufer T, Morabito A, Hao D, Yang C, Soo R, et al. 
Sequential treatment with afatinib and osimertinib in real-world 
patients with EGFR mutation-positive advanced NSCLC: the GioTag 
study. BTOG 2019, 17th Ann Conf of the British Thoracic Oncology 
Group (BTOG), Dublin, 23 - 25 Jan 2019. Lung Cancer (Neth). 2019. 
127 (Suppl 1), S37, Abstr 86.
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Park K, Bennouna J, Boyer M, Hida T, Hirsh V, Kato T, et al. 
Sequencing of therapy following first-line afatinib in patients with 
EGFR mutation-positive non-small cell lung cancer. Lung Cancer 
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Lu S. EGFR-TKI ADR management Chinese expert consensus. 
(Original in Chinese). Chin J Lung Cancer 2019. 22 (2): 57 – 81.
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Bosch JP, Lewis JB, Greene T, Rogers N, Roth D, et. A more accurate 
method to estimate glomerular filtration rate from serum creatinine: a 
new prediction equation. Ann Intern Med 1999. 130(6):461-470
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Arcila ME, Oxnard GR, Nafa K, Riely GJ, Solomon SB, Zakowski 
MF, et al. Rebiopsy of lung cancer patients with acquired resistance to 
EGFR inhibitors and enhanced detection of the T790M mutation 
using a locked nucleic acid-based assay. Clin Cancer Res. 2011. 17 
(5): 1169 – 1180.
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Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, et 
al. Acquired EGFR C797S mutation mediates resistance to AZD9291 
in non-small cell lung cancer harboring EGFR T790M. Nature Med. 
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Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, 
Chewaskulyong B, Lee KH, et al. FLAURA Investigators Osimertinib 
in untreated EGFR-mutated advanced non-small-cell lung cancer. N 
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R18-3355
Brahmer JR, Govindan R, Anders RA, Antonia SJ, Sagorsky S, 
Davies MJ, et al. The Society for Immunotherapy of Cancer 
consensus statement on immunotherapy for the treatment of non-small 
cell lung cancer (NSCLC). J Immunother Cancer 2018. 6 (1): 75.
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Eisenhauer EA,et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1) Eur J Cancer; 2009; 
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13.2
UNPUBLISHED REFERENCES
c01617169-07
Investigator’s Brochure (IB): Afatinib (BIBW 2992), Indication: 
Oral Treatment of Cancer,
1200.P1/1200.P2/1200.P3/1200.P4/1200.P5/1200.P6/1200.P7/1200.
P8/1200.P9/1200.P10/1200.P11/1200.P12/1200.P13/1200.P14 
Version 20, 14 December 2018
c01802941-10
Investigator’s Brochure (IB): Afatinib (BIBW 2992), Indication: 
Oral Treatment of
Cancer,1200.P1/1200.P2/1200.P3/1200.P4/1200.P5/1200.P6/1200.P
7/1200.P8/1200.P9/1200.P10, Version 16, 06 Jul 2015
c14668275-03
Protocol for non-interventional studies: GioTag: Real-world data 
study on sequential therapy with Gi(l)otrif®/afatinib as first-line 
treatment followed by osimertinib in patients with EGFR mutation 
positive advanced non-small cell lung cancer

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Document 
Reference Number
Date
Title
1
NA
3-Sep-2019
Informed consent form
2
NA
26-Dec-2019
Statistical and epidemiological 
analysis plan

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Non-interventional Study Protocol                                                            
BI Study Number 1200-0318
c38958167-01
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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable 

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Non-interventional Study Protocol                                                            
BI Study Number 1200-0318
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ANNEX 3. ADDITIONAL INFORMATION
ANNES 3.1 ECOG PERFORMANCE STATUS 
Grade
Definition
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled, cannot carry on any self-care, totally confined to bed or 
chair
5
Dead
ANNES 3.2 PROPOSED TNM STAGE GROUPINGS
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Non-interventional Study Protocol                                                            
BI Study Number 1200-0318
c38958167-01
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001-MCS-90-118_RD-23 (2.0) / Saved on: 03 Jul 2020
ANNES 3.3 RECIST GUIDELINE, VERSION 1.1
Refer to the Revised RECIST guideline (version 1.1) which was
published in by Eisenhauer EA,et al. New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1)
Eur J Cancer; 2009; 45; 228-247.(R09-0262)
 
 
  
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Non-interventional Study Protocol                                                            
BI Study Number 1200-0318
c38958167-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-23 (2.0) / Saved on: 03 Jul 2020
Study Title: Real-world study afatinib as first-line treatment in patients with epidermal growth 
factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer (NSCLC)Study 
Number: 1200.0318
Protocol Version: V3.0
I here with certify that I agree to the content of the study protocol and to all documents 
referenced in the study protocol.
Position: ________
Name/Date: _______________________
Signature: _______________
Position:
________
Name/Date: _______________________
Signature: _______________
Position: ________
Name/Date: _______________________
Signature: _______________
Position: ________
Name/Date: _______________________
Signature: _______________
Position: ________
Name/Date: _______________________
Signature: _______________
Position: ________
Name/Date: _______________________
Signature: _______________
Position: ________
Name/Date: _______________________
Signature: _______________