Clinical trial NCT01853826
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Boehringer Ingelheim
Start date: 2013-07-17; Completion date: 2024-03-06
Enrollment: 481 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To evaluate the safety and tolerability of afatinib (Giotrif) in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutation(s) and have never been treated with an EGFR-TKI

Detailed description:

Arms: arm 1: Patients diagnosed with EGFR mutation positive non-small cell lung cancer (NSCLC) locally advanced or metastatic who have never been treated with EGFR tyrosine kinase inhibitors (TKI) received a daily dose of 40 milligrams (mg) of afatinib (Giotrif®), in the form of film-coated tablet over a 28 day cycle. Afatinib was taken orally with 250 milliliters (mL) of water at the same time of the day and without eating anything for at least 3 hours. Patients continued on treatment for as long as there was no disease progression or no other trial withdrawal criteria. The dose was reduced to 30 mg or 20 mg once daily when the initial dose was not tolerated by the patient.
Interventions: intervention 1: Afatinib
Intervention descriptions: intervention 1: Patients received a daily dose of 40 milligrams (mg) of afatinib (Giotrif®), in the form of film-coated tablet over a 28 day cycle. Afatinib was taken orally with 250 milliliters (mL) of water at the same time of the day and without eating anything for at least 3 hours. Patients continued on treatment for as long as there was no disease progression or no other trial withdrawal criteria. The dose was reduced to 30 mg or 20 mg once daily when the initial dose was not tolerated by the patient.

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
Doc. No.: c02215411
EudraCT No.:
BI Trial No.:
2009-017661-34
1200.55
BI Investigational
Product(s):
Afatinib (Giotrif®) (BIBW 2992)
Title:
An open label trial of afatinib (Giotrif®) in treatment-naïve (1st line) or 
chemotherapy pre-treated  patients with locally advanced or metastatic 
non-small cell lung cancer (NSCLC) harboring EGFR mutation(s)
Clinical Phase:
IIIb
Clinical Trial 
Leader:
Tel:
Fax:
Co-ordinating 
Investigator:
Phone:
Fax : 
Status:
Final protocol (Revised Protocol (based on global amendment 3))     
Version and Date:
Version:
4
         
Date: 08 Feb 2021
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TITLE PAGE


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
afatinib (BIBW 2992)
Protocol date:
Trial number:
1200.55
Revision date:
08 Feb 2021
13 Mar 2013
Title of trial:
An open label trial of afatinib (Giotrif®) in treatment-naive (1st line) or chemotherapy 
pre-treated  patients with locally advanced or metastatic non-small cell lung cancer 
(NSCLC) harboring EGFR mutation(s)
Co-ordinating 
Investigator:
Trial site(s):
Multi-center trial conducted at up to 200 sites within approximately 11 countries
Clinical phase:
IIIb
Objective(s):
To evaluate the safety, tolerability and efficacy of afatinib (Giotrif®) in patients with 
locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR 
mutation(s) and have never been treated with an EGFR-TKI
Methodology:
Open-label, multi-center, single-arm trial
No. of patients: 
total entered:
481 patients
each treatment:
All entered patients will receive afatinib (Giotrif®)
Diagnosis:
Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC)
harboring EGFR mutation(s) and have never been treated with an EGFR-TKI
Main criteria
for inclusion:
All patients should have locally advanced or metastatic non-small cell lung cancer 
(NSCLC) harboring EGFR mutation(s) and have never been treated with an EGFR-
TKI
Test product(s):
Afatinib (Giotrif®) as 40, 30 and 20 mg film-coated tablets
dose:
40 mg/day or 30 mg/day or 20 mg/day
mode of admin.:
Oral, once daily, continuous
Comparator products:
None.
dose:
mode of admin.:


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
afatinib (BIBW 2992)
Protocol date:
Trial number:
1200.55
Revision date:
08 Feb 2021
13 Mar 2013
Duration of treatment: Continuous treatment in the absence of disease progression or other trial withdrawal 
criteria. The trial is considered concluded when all patients have discontinued trial 
medication and/or have access to Afatinib via options included but not limited to an 
alternative clinical trial, marketed product, an expanded-access program, named 
patient use program, compassionate use protocol or other means based on local 
regulation, and completed the follow up or are lost to follow up.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
afatinib (BIBW 2992)
Protocol date:
Trial number:
1200.55
Revision date:
08 Feb 2021
13 Mar 2013
Criteria for efficacy:
Disease Assessment will be based on the assessment of cancer related symptoms and, 
if available, radiological assessments as per standard of care at the site.
Criteria for safety:
Adverse events according to Common Terminology Criteria (CTCAE) Version 3.0 
(R04 0474).
Statistical methods:
Exploratory descriptive statistics of demographic, efficacy and safety data will be 
presented as appropriate


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FLOW CHART
Procedure
Screening & 
Dispensing*
Treatment and Safety 
evaluation
End of 
Treatment
Follow-up
Visits (V)
V1
V2 onwards***
EOT**/***
FU
Days
Day -1        
(-28 to -1)
Day 28 (-7/+2 days) and 
every 28th day (-7/+2) 
onwards
0-14 Days after 
last trial drug 
intake 
EOT**+ 
28 (-7)
Informed consent
1
X
Demographics
X
Medical history
X
In/Exclusion criteria
X
Physical examination
2
X
X
X
Disease Assessment
X
X
ECG3
X°
Xo
Xo
LVEF assessments3
Xo
Xo
Xo
Safety Laboratory Testing
4
X
Xo
Xo
Urine Examination5
X
Xo
Xo
Pregnancy test
6
X
X
Adverse events
XP(Day15)
X
X
X7
Dispense Trial Medication8
X*D
XD
Compliance
X
X
Termination of Trial Medication
X
Patient Status
X
*
Afatinib (Giotrif®) will be dispensed only after verification that all trial requirements are met.
1
Written informed consent must be obtained before any screening/baseline assessments are performed.
2
Includes vital signs (pulse, blood pressure), temperature, height (cm), weight (kg) and an ECOG performance 
score.
3
ECG/LVEF to be conducted for patients with cardiac risk factors at the discretion of the investigator and in 
accordance to the current standard of care.  In  patients with ejection fraction below the institution’s lower limits of 
normal, cardiac consultation as well as afatinib (Giotrif®) treatment interruption or discontinuation should be 
considered.
4
Safety laboratory testing: haematology, biochemistry and urine examinations (see Section 5.2.3). All laboratory 
tests mentioned in Table 5.2.3: 1 are required to be performed at screening and are recommended to be performed 
at the discretion of the investigator and in accordance to the current standard of care.
5
Urine examinations (see Table 5.2.3: 1) are required to be performed at screening and are recommended to be 
performed at the discretion of the investigator and in accordance to the current standard of care.
6
Beta-Human Chorionic Gonadotropin (β-HCG) testing in urine or serum in women of childbearing potential. A 
negative result is required for inclusion in the trial.
D
Provide a diarrhoea diary with drug supply at cycle 1 and 2. Data on diaries should be checked by the study staff 
against AEs and Appendix 10.1.1.
P
A contact is required 15 (±3) days after the patient’s first dose to assess AEs and dose reductions.
O
Indicates a recommended/optional test or procedure according to patient’s course as required by clinical condition
**
EOT(V): end of treatment (visit) with trial medication. 

FU (V): Follow-up visit (end of observational phase) which should occur 28 days after the end of treatment (EOT) 
visit – This visit can be conducted by a phone call.
7
Within 28 days after last trial drug administration all AEs will be collected and documented. SAEs must always be 
collected, documented, and reported within this 28 day time period. The investigator does not need to actively 
monitor patients for adverse events once the clinical trial has ended. However, if the investigator becomes aware of 
an SAE(s) that occurred after the patient has completed the clinical trial (including any protocol required REP and / 
or follow-up), it should be reported by the investigator to the sponsor if considered relevant by the investigator.


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8
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war), shipment of trial medication 
to patient’s home may be arranged or dispensation of two kits may be done.
***
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war), patient visits may be 
performed remotely.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................5
TABLE OF CONTENTS ...................................................................................7
ABBREVIATIONS.......................................................................................... 11
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................15
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 17
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................17
2.2
TRIAL OBJECTIVES.......................................................................................17
2.3
BENEFIT - RISK ASSESSMENT ...................................................................17
2.4
BENEFIT - RISK ASSESSMENT IN CONTEXT OF COVID-19 
INFECTION.......................................................................................................22
2.4.1
Relevant information on the product in relationship to 
COVID-19..............................................................................................22
2.4.2
Benefits and Risks Conclusions and Recommendations ...................22
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 24
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................24
3.1.1
Administrative structure of the trial...................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................25
3.3
SELECTION OF TRIAL POPULATION ......................................................25
3.3.1
Main diagnosis for study entry............................................................26
3.3.2
Inclusion criteria...................................................................................26
3.3.3
Exclusion criteria ..................................................................................26
3.3.4
Removal of patients from therapy or assessments.............................28
3.3.4.1
Removal of individual patients................................................28
3.3.4.2
Discontinuation of the trial by the sponsor..............................29
4.
TREATMENTS........................................................................................ 30
4.1
TREATMENTS TO BE ADMINISTERED....................................................30
4.1.1
Identity of BI investigational product and comparator 
product(s)...............................................................................................30


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4.1.2
Method of assigning patients to treatment groups ............................30
4.1.3
Selection of doses in the trial................................................................31
4.1.4
Drug assignment and administration of doses for each patient .......31
4.1.4.1
Dose reduction scheme ............................................................32
4.1.5
Blinding and procedures for unblinding ............................................33
4.1.5.1
Blinding....................................................................................33
4.1.6
Packaging, labelling, and re-supply ....................................................34
4.1.7
Storage conditions.................................................................................34
4.1.8
Drug accountability ..............................................................................34
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................35
4.2.1
Rescue medication, emergency procedures, and additional 
treatment(s) ...........................................................................................35
4.2.2
Restrictions............................................................................................36
4.2.2.1
Restrictions regarding concomitant treatment .........................36
4.2.2.2
Restrictions on diet and life style.............................................36
4.2.3
Contraception and pregnancy .............................................................37
4.3
TREATMENT COMPLIANCE.......................................................................38
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 40
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................40
5.1.1
Endpoint(s) of efficacy..........................................................................40
5.1.2
Assessment of efficacy...........................................................................40
5.2
SAFETY..............................................................................................................40
5.2.1
Endpoint(s) of safety.............................................................................40
5.2.2
Assessment of adverse events...............................................................41
5.2.2.1
Definitions of adverse events...................................................41
5.2.2.2
Adverse event and serious adverse event reporting.................42
5.2.3
Assessment of safety laboratory parameters......................................44
5.2.4
Electrocardiogram................................................................................44
5.2.5
Assessment of other safety parameters...............................................44
5.2.5.1
Physical examination ...............................................................44
5.2.5.2
Vital signs ................................................................................45
5.2.5.3
Left ventricular function ..........................................................45
5.3
OTHER...............................................................................................................45
5.3.1
Other endpoint(s)..................................................................................45
5.3.2
Other assessment(s) ..............................................................................45
5.3.2.1
Documentation of diarrhoea ....................................................45
5.3.3
Pharmacogenomic evaluation..............................................................46
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................46


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5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................46
5.6
BIOMARKER....................................................................................................46
5.6.1
Endpoints based on biomarker(s) .......................................................46
5.6.2
Methods of sample collection...............................................................46
5.7
PHARMACODYNAMICS................................................................................46
5.7.1
Pharmacodynamic endpoints...............................................................46
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....47
6.
INVESTIGATIONAL PLAN.................................................................. 48
6.1
VISIT SCHEDULE............................................................................................48
6.1.1
Screening and dispensing visit.............................................................48
6.1.2
Treatment and safety evaluation visits ...............................................48
6.1.3
End of Treatment (EOT) visit..............................................................48
6.1.4
Follow-Up (FU) visit .............................................................................48
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................49
6.2.1
Screening and run-in period(s)............................................................49
6.2.2
Treatment period ..................................................................................52
6.2.3
End of trial and follow-up period........................................................54
6.2.4
Follow-Up...............................................................................................56
7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE......................................................................................... 58
7.1
STATISTICAL DESIGN - MODEL................................................................58
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................58
7.3
PLANNED ANALYSES....................................................................................58
7.3.1
Primary analyses...................................................................................58
7.3.2
Secondary analyses ...............................................................................58
7.3.3
Safety analyses.......................................................................................59
7.3.4
Interim analyses ....................................................................................60
7.4
HANDLING OF MISSING DATA ..................................................................60
7.5
RANDOMISATION ..........................................................................................60
7.6
DETERMINATION OF SAMPLE SIZE ........................................................60
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS ................................................................................................ 61
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................61
8.2
DATA QUALITY ASSURANCE .....................................................................61
8.3
RECORDS..........................................................................................................62


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8.3.1
Source documents .................................................................................62
8.3.2
Direct access to source data and documents.......................................62
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................62
8.4.1
Listedness...............................................................................................62
8.4.2
Expedited reporting to health authorities and IECs/IRBs................62
8.5
STATEMENT OF CONFIDENTIALITY.......................................................63
8.6
COMPLETION OF TRIAL..............................................................................63
9.
REFERENCES......................................................................................... 64
9.1
PUBLISHED REFERENCES...........................................................................64
9.2
UNPUBLISHED REFERENCES.....................................................................66
10. APPENDICES .......................................................................................... 68
10.1
MANAGEMENT OF EXPECTED ADVERSE EVENTS.............................68
10.1.1 Management of diarrhoea and hydration status following 
treatment with afatinib (Giotrif®) ......................................................68
10.1.2 Management recommendations for dermatological AEs 
following treatment with afatinib (Giotrif®)......................................69
10.1.3 Management of mucositis/stomatitis...................................................73
10.2
NEW YORK HEART ASSOCIATION CLASSIFICATION OF HEART 
FAILURE............................................................................................................75
10.3
LIST OF POTENT INHIBITORS AND INDUCERS OF P 
GLYCOPROTEIN (MDR1) .............................................................................76
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 77


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ABBREVIATIONS
ADL
AE
ALT (SGPT)
ANC
AST (SGOT)
Activities of Daily Living
Adverse Event
Alanine Amino Transferase (Serum Glutamate Pyruvate Transaminase)
Absolute Neutrophil Count
Aspartate Amino Transferase (Serum Glutamic Oxaloacetic Transaminase)
AUC
β-HCG
BI
BSA
BSC
BUN
CA
Area under the Curve
Beta-Human Chorionic Gonadotropin
Boehringer Ingelheim
Body Surface Area
Best Supportive Care
Blood Urea Nitrogen
Competent Authority
CI
Confidence Interval
CML
CPK
Clinical Monitor Local
Creatine Phosphokinase
CRA
Clinical Research Associate
CRF
CR
CRO
Case Report Form
Complete Response
Contract Research Organization
CTCAE
CTL
CTM
Common Terminology Criteria for Adverse Events
Clinical Trial Leader
Clinical Trial Manager
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
DCR
Clinical Trial Report
Disease Control Rate
DNA
EC
ECG
ECHO
ECOG
Deoxyribonucleic Acid
Ethics Committee
Electrocardiogram
Echocardiography
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
e.g.
EGFR
EOT
erbB
Exempli gratia
Epidermal Growth Factor Receptor
End of Treatment
Epidermal Growth Factor family of receptors (erB1/EGFR/HER1, 
erB2/HER2, erB3/HER3, erB4/HER4)
EU
EudraCT
European
European Clinical Trials Database
FDA
FU
Food and Drug Administration
Follow-up Visit
GABA
GCP
Gamma-Aminobutryic Acid
Good Clinical Practice
GGT
y-glutamyltransferase


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G-Tube
HDPE
HEPB
HEPC
HER2
HIV
HR
HRQoL
Gastronomy-tube
High-Density Polyethylene
Hepatitis B
Hepatitis C
Human Epidermal Growth Factor Receptor 2
Human Immunodeficiency Virus
Hazard Ratio
Health Related Quality of Life
IB
ICH
Investigator’s Brochure
International Conference on Harmonisation
IEC
ILD
Independent Ethics Committee
Interstitial Lung Disease
IRB
Institutional Review Board
ISF
IUD
Investigator Site File
Intrauterine Device
i.v.
intravenous
IWRS
LDH
LVEF
Interactive Web-based Response System
Lactic Dehydrogenase
Left Ventricular Ejection Fraction
MedDRA
mg
min
mL
Medical Dictionary for Drug Regulatory Activities
miligrams
Minute
Milliliter
MTD
MUGA
NSCLC
NYHA
Maximum Tolerated Dose
Multiple Gated Acquisition scan
Non-small Cell Lung Cancer
New York Heart Association
OPU
OR
ORR
OS
Operative Unit
Objective Response
Overall Response Rate
Overall Survival
PC
Pemetrexed/Cisplatin
PCR
P-gp
PD
PDM
PFS
PK
PR
PSTAT
Polymerase Chain Reaction
P-glycoprotein (P-gp)
Progression Disease
Project Data Manager
Progression Free Survival
Pharmacokinetics
Partial Response
Project Statistician
RDC
REP
RNA
SAE
Remote Data Capture
Residual Effect Period
Ribonucleic acid
Serious Adverse Event
SD
SOC
Stable Disease
Standard Of Care


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SOPs
Standard Operating Procedures
SPF
SUSARs
Sun Protection Factor
Suspected Unexpected Serious Adverse Reactions
TKI
tmax
Tyrosine Kinase Inhibitor
Time of Occurrence for Maximum Peak Drug Concentration
TS
Treated Set
ULN
USA
UVA
UVB
WBC
WOCBP
Upper Limit of Normal
United States of America
Ultraviolet A
Ultraviolet B
White Blood Cell Count
Women of Child-Bearing Potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer-related death globally. 
It has been the most commonly diagnosed cancer each year since 1985 with an estimated 1.36 
million new cases diagnosed and approximately 1.2 million deaths each year worldwide 
(R05-0876, R06-0221). 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 (R05-0876). 
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 (R06-1301, R06-1302). 
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 (R06-1301, R06-1393, 
R06-1394). However, recent clinical experiences with specific EGFR-Tyrosine Kinase 
Inhibitors (TKI) have demonstrated tumour regression in only 10% to 15% of unselected 
NSCLC patients (R05-0867, R06-1301, R06-1306). The frequency of EGFR somatic 
mutations was found to be approximately 10% in NSCLC patients from the US, Europe or 
Australia compared to a mutation rate of up to 30% in patients from Japan and Taiwan 
(R06-1262, R06-1306, R06-1393). 
This is in general agreement with composite data from three retrospective analyses, in which 
the response rates for NSCLC patients harboring EGFR mutations ranged from 65% to 94% 
(R06-1306).
The pre-clinical and clinical data support the clinical testing of irreversible inhibitors of 
EGFR in NSCLC patients who are naïve to previous EGFR-TKI treatment as well as in 
patients who have progressed after treatment with a reversible EGFR-TKIs such as gefitinib 
and erlotinib (R06-1307, R07-1162), for which the only remaining standard treatment option 
is currently Best Supportive Care (BSC).
In preclinical disease models with Epidermal Growth Factor Family of Receptors (ErbB) 
pathway deregulation, afatinib (an irreversible TKI) effectively inhibits ErbB receptor 
signaling resulting in tumour growth inhibition or tumour regression.[U02-1391, U02-1702, 
U02-1703, U02-1660, U02-1614, U07-1338, P08-06904] As a single agent it retains 
significant anti- tumour activity in NSCLC cell lines (in vitro) and tumour models (in vivo, 
xenografts or transgenic models) driven by mutant EGFR isoforms known to be resistant to 
the reversible EGFR TKIs erlotinib and gefitinib.[P08-06904]


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A number of clinical trials with afatinib (Giotrif®) have evaluated treatment of NSCLC 
patients, both those who are EGFR TKI naïve as well as those previously treated with a 
reversible EGFR TKI (see Section 2.3).
First line EGFR TKI naïve patients with EGFR mutation positive tumours showed significant 
and clinically meaningful improvements in Progression Free Survival (PFS) and Overall 
Response Rate (ORR) accompanied by significant delays in time to deterioration of the 
cancer-related symptoms of cough and dyspnoea as compared to patients receiving up to six 
cycles of pemetrexed/cisplatin (LUX-Lung 3/1200.32). In a separate single arm trial, (LUX-
Lung 2/1200.22) [U11-3644-01] enrolling both first and second line TKI naïve patients, high 
ORRs and disease control rates (DCRs) were seen in both groups (61%, and 82%, 
respectively) and were confirmed by independent review.
Lastly, in trial 1200.34 (LUX-Lung 6), afatinib treatment compared to gemcitabine/cisplatin 
as first-line treatment for patients with Stage IIIB or IV adenocarcinoma resulted in a 
prolonged PFS and higher ORR observed in patients treated with afatinib (P13-06250).
1.2
DRUG PROFILE
Afatinib (Giotrif®) is a potent and selective, irreversible ErbB Family Blocker in preclinical
models. It covalently binds to and irreversibly blocks signaling from all homo- and 
heterodimers formed by the ErbB family members EGFR (ErbB1), HER 2(ErbB2), ErbB3, 
ErbB4. [U02-1083, U03-1086, U11-2645-01].
For the latest information on the drug profile of afatinib (Giotrif®), please refer to the current 
Investigator’s Brochure (IB) (U03-3218). All references in this protocol concerning afatinib 
(Giotrif®) refer to the free base compound of afatinib (Giotrif®).
Afatinib (Giotrif®) is moderately rapidly absorbed after oral administration, with median 
Time of Occurrence for Maximum Peak Drug Concentration (tmax values) approximately 3 
hours after drug administration. In general, afatinib gMean maximum plasma concentration 
and exposure increased with increasing doses after a single dose and at steady state. 
However, moderate to high inter- and intra-individual differences in plasma concentration 
were seen. Afatinib (Giotrif®) is highly distributed out of the blood and has a moderate to 
high clearance. The overall gMean terminal half-life at steady state was 37.2 hours in cancer 
patients. The major route of elimination of afatinib (Giotrif®) was via feces. After food 
intake, a decreased systemic exposure was observed compared to administration under fasted 
conditions. The Pharmacokinetics (PK) characteristics in Caucasian cancer patients were 
comparable to those observed in Japanese cancer patients.
Afatinib (Giotrif®) is bound covalently to proteins to a variable extent and covalent protein 
adducts were the major circulating metabolites in the plasma. Afatinib (Giotrif®) did not 
show relevant inhibition or induction of cytochrome P450 isoenzymes, and it appears 
unlikely that drug-drug interactions based on this mechanism will occur. 
Afatinib (Giotrif®) is a substrate of the P-glycoprotein (P-gp) transporter. Concomitant 
administration of the potent P-gp inhibitor ritonavir did not relevantly change the exposure to 


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40 mg afatinib (Giotrif®) when taken simultaneously with or 6 h after afatinib (Giotrif®) but 
increased the bioavailability of afatinib (single dose of 20 mg) by 48% and 39% for AUC0-∞ 
and Cmax when given 1 h before afatinib, respectively. Pretreatment with the potent P-gp 
inducer rifampicin decreased the plasma exposure of 40 mg afatinib by 34 % afatinib (AUC0-
∞) and 22 % (Cmax), respectively. If P-gp inhibitors need to be taken, they should be 
administered simultaneously with afatinib (see Section 4.2.2.1) [U12-1170-01].
In pre-clinical trials afatinib is not irritant to intact skin but an ocular irritant. Afatinib 
(Giotrif®) is mutagenic in a single bacteria strain, but did not show genotoxic potential in 
vivo when tested up to overt toxic/lethal doses. Studies on embryo-foetal development in rats 
and rabbits up to life-threatening doses have revealed no indication of teratogenicity.
Two Phase I open label dose-escalation trials (U07-3128-02, U08-1023-03) each determined 
a Maximum Tolerated Dose (MTD) with continuous dosing of afatinib (Giotrif®) as 40 mg 
and 50 mg daily, respectively. Adverse Events (AEs) observed with afatinib are consistent 
with those reported for EGFR and dual EGFR/ Human Epidermal Growth Factor Receptor 2 
(HER2) inhibitors. The most frequent drug-related toxicities were associated with 
gastrointestinal disorders (including diarrhoea, nausea, vomiting, and mucositis/stomatitis), 
skin and subcutaneous tissue disorders (including rash, pruritus, acneiform rash, acne, 
paronychia), general disorders (including fatigue and mucosal inflammation), respiratory 
disorders (including epistaxis), and metabolism and nutritional disorders (including anorexia, 
dehydration). Early and proactive management of diarrhoea, skin rash, and stomatitis together 
with treatment interruptions and dose reductions is recommended in line with recent 
guidelines in the management of common toxicities of EGFR and EGFR/HER2 TKIs and 
monoclonal antibodies (R07-4077, P07-11507, R07-4078, R11-0826).
Afatinib has been approved as monotherapy to treat patients with advanced or metastatic non-
small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor 
(EGFR) mutations.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
This trial will evaluate the safety, tolerability and efficacy of afatinib (Giotrif®) in patients 
with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR 
mutation(s) and have never been treated with an EGFR-TKI.
2.2
TRIAL OBJECTIVES
To evaluate the safety, tolerability and efficacy of afatinib (Giotrif®) in patients with locally 
advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutation(s) 
and have never been treated with an EGFR-TKI.
See Section 5 for trial endpoints.
2.3
BENEFIT - RISK ASSESSMENT
The benefits of providing afatinib (Giotrif®) to patients via enrollment in this trial are based 
on the results obtained in two prior studies in patients with pathologic confirmation of 
stage IIIB or stage IV NSCLC. These trials were afatinib (Giotrif®) monotherapy trials and 
were either Phase III or large (>100 patients) Phase II trials with particular relevance for the 
proposed population for this trial in that they included NSCLC patients with confirmed 
EGFR mutations. Both trials enrolled EGFR TKI-naïve patients (1200.32 and 1200.22).
In addition, data from a third study, a Phase III open label, randomized trial in Asian patients 
with EGFR mutation-positive advanced adenocarcinoma of the lung, confirmed these results.
An overview of the characteristics of these trials is provided in Table 2.3: 1. 
Table 2.3: 1
Study characteristics of LUX-Lung 2, 3 and 6
Trial 
Regions
EGFR 
mutation 
status
Line of 
treatment
Prior 
EGFR 
TKI
Afatinib 
starting 
dose
Comparator Patients per 
treatment group 
1200.32
LUX-Lung 3
Asia, Europe, 
North America, 
South America
Positive
First
No
40 mg
Chemo 1
Afatinib:230
Chemo: 115
1200.22
LUX-Lung 2
Taiwan, USA
Positive
First or 
second
No
40 mg or 
50 mg
None
129 (40 mg: 30; 
50 mg: 99)
1200.34
LUX-Lung 6
China, South 
Korea, Thailand
Positive
First
No
40 mg
Chemo2
Afatinib: 242
Chemo: 122
1 Chemotherapy with pemetrexed/cisplatin
2 Chemotherapy with gemcitabine/cisplatin
EGFR TKI Naïve Patients


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1200.32 (LUX-Lung 3)
The study was a randomised, open-label, phase III study of afatinib (Giotrif®) versus 
chemotherapy as first-line treatment for patients with Stage IIIB or IV adenocarcinoma of the 
lung harboring an EGFR activating mutation who were not eligible for standard curative-
intent treatment with surgery or chemo-radiotherapy and who had received no prior systemic 
treatment for locally advanced, recurrent or metastatic NSCLC. The primary objective of the 
study was to assess the efficacy of afatinib (Giotrif®) as defined by progression-free survival 
(PFS) by central independent review. Secondary endpoints included ORR and Health Related 
Quality of Life (HRQoL) including NSCLC specific symptom control. A central test for 
EGFR mutations was carried out using the companion diagnostic TheraScreen® EGFR RGQ 
PCR kit. Three hundred forty five (345) patients were randomised in a 2:1 ratio to receive 
either afatinib (n=230) 40 mg daily continuous treatment in the absence of disease 
progression or adverse events or Pemetrexed/Cisplatin (PC) (n=115) 500 mg/m2 + 75 mg/m2 
q21 days up to 6 cycles. Baseline characteristics were well balanced between arms: overall 
the median age was 61 years, 65% of patients were female, 72% were Asian, 68% were 
never-smokers and 89% had Stage IV disease. Regarding EGFR mutation status, 49% had 
deletions in exon 19 (Del19), 40% had the L858R mutation and 11% had a variety of other 
less common mutations.
As assessed by central independent review, treatment with afatinib (Giotrif®) resulted in a 
significantly prolonged PFS as compared to treatment with PC (median 11.1 vs 6.9 months, 
HR 0.58; 0.43–0.78; p=0.0004). In patients with common EGFR mutations (Del19/L858R), 
the median PFS for afatinib (Giotrif®) treated patients was 13.6 months as compared to 6.9 
months for patients receiving PC (HR=0.47; 0.34-0.65; p<0.0001). The ORR for patients 
treated with afatinib (Giotrif®) (56%) was significantly higher than that for patients treated 
with PC (23%) (p<0.0001). The prolonged PFS and higher ORR observed in patients treated 
with afatinib (Giotrif®) were accompanied by significant delays (as compared to patients 
treated with PC) in time to deterioration of the cancer-related symptoms of cough (HR=0.60, 
p=0.0072) and dyspnoea (HR=0.68, p=0.0145). The pre-specified number of events 
necessary to evaluate Overall Survival (OS) has not yet been reached.
In the afatinib (Giotrif®) arm, the highest CTCAE Grade of AEs was Grade 3 in 51.1%, 
Grade 4 in 3.9%, and Grade 5 in 5.7% of patients. In the chemotherapy arm, the highest 
CTCAE Grade of AEs was Grade 3 in 44.1%, Grade 4 in 9.9%, and Grade 5 in 2.7% of 
patients. The incidence of patients with AEs leading to dose reduction was 57.2% (afatinib) 
and 16.2% (chemotherapy). The incidence of AEs leading to treatment discontinuation was 
14.0% (afatinib) and 15.3% (chemotherapy). Drug-related AEs leading to treatment 
discontinuation were experienced by 7.9% (afatinib) and 11.7% of patients (chemotherapy).  
SAEs were reported in 28.8% (afatinib) and 22.5% (chemotherapy) of patients, 14.4% of 
patients in each treatment arm experienced drug-related SAEs. The most frequent SAEs 
related to treatment with afatinib (Giotrif®) were diarrhoea (6.6%) and vomiting (3.5%). The 
most frequent SAEs related to chemotherapy were vomiting (2.7%) and fatigue (2.7%). There 
were 13 deaths (5.7%) reported due to on-treatment AEs in the afatinib (Giotrif®) arm, with 
4 of them (sepsis, dyspnoea, acute respiratory distress syndrome, and death) considered 
related to afatinib (Giotrif®) by the investigator. Three deaths (2.7%) were reported due to 


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on-treatment AEs in the chemotherapy group; none of them were considered related to 
chemotherapy by the investigator.[U12-1199-01]
1200.22 (LUX-Lung 2)
Further evidence of the benefits of afatinib (Giotrif®) in EGFR TKI-naïve patients with 
NSCLC was obtained in trial 1200.22, an exploratory open-label single arm Phase II trial of 
afatinib (Giotrif®) as first- or second-line treatment. The primary objective of the study was 
to assess the efficacy of afatinib (Giotrif®) as defined by the objective response rate (ORR). 
Patients were screened for EGFR mutations determined centrally by sequencing and/or using 
a Genzyme assay consisting of PCR amplification followed by direct sequencing performed 
bidirectionally. Secondary endpoints included PFS by both independent and investigator 
assessments, clinical benefit (CR, PR, SD) and OS.
The study enrolled and treated a total of 129 patients including 61 first-line patients (23 who 
received a starting dose of 40 mg and 38 who received a starting dose of 50 mg) and 68 
second-line patients (7 who received a starting dose of 40 mg and 61 who received a starting 
dose of 50 mg). Of the patients, 41.9% were male, 58.1% were female, the median age was 
61 years, 96.9% had a baseline ECOG performance status of 0 or 1, 12.4% were Caucasian 
and 86.8% were Asian. 
In the first-line setting, confirmed objective responses were noted in 66% of 61 patients with 
a median PFS of 12.0 months by independent review and 15.6 months by investigator 
assessment. DCR was 87%. Efficacy was similarly high in the group of patients who had 
received prior first-line chemotherapy (N=68; ORR 57%; PFS by independent review 8 
months and by investigator assessment 10.5 months; DCR 78%). Median OS was not reached 
in the first line population. Median OS in second line patients was 23.3 months (95 % CI 
18.5-38). 
Similar high rates of response of between 57% and 69% by independent review were seen 
across subgroups divided by lines of treatment (first and second line), by starting dose (50 
and 40 mg), by gender (men and women), by country (Taiwan and USA), by race (Asians 
and Caucasians), and by the type of the two most common EGFR mutations (Del19 and 
L858R). 
The most common AEs were diarrhoea (94.6%), rash/acne (93.8%), nail effect (85.3%), 
stomatitis (81.4%) and pruritus (57.4%). Diarrhoea was reported by 96.7% of patients in the 
40 mg starting dose group and 93.9% in the 50 mg starting dose group. For 20.2% of patients 
that started on either the 40mg or 50 mg dose, diarrhoea was reported as Grade 3 at the 
highest during the course of the event, with no Grade 4 or 5 diarrhoea reported. Diarrhoea
was reported as an SAE for 1.6% of patients (2/129); both of whom received a starting dose 
of 50 mg. While 24.8% of patients had their dose reduced due to diarrhoea, no patients 
discontinued from the study due to diarrhoea. Rash/acne was reported in 90.0% of patients in 
the 40 mg starting dose group and 94.9% in the 50 mg starting dose group. Overall, 23.3% of 
patients developed Grade 3 rash/acne, with 28/30 of these patients in the 50 mg starting dose 
group. No Grade 4 or 5 rash/acne was reported. Rash/acne was reported as an SAE for 3.9% 
of patients, all of whom received a starting dose of 50 mg. Overall, 26.4% of patients had 


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their dose reduced due to rash/acne but only 2 (1.6%) discontinued treatment due to 
rash/acne.[U11-3644-01] 
1200.34 (LUX-Lung 6)
More recent evidence of the benefits of afatinib (Giotrif®) versus chemotherapy in EGFR 
TKI-naïve asian patients with NSCLC was obtained in trial 1200.34, an open-label, 
randomized,  Phase III trial of afatinib (Giotrif®) versus chemotherapy as first-line treatment 
for patients with Stage IIIB or IV adenocarcinoma of the lung harboring an EGFR activating 
mutation who had received no prior chemotherapy or EGFR-targeting drugs for  advanced 
NSCLC. The primary objective of the study was to assess the efficacy of afatinib (Giotrif®) 
as defined by progression-free survival (PFS) by central independent review and determined 
by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints included 
ORR, disease control rate (DCR), duration of response, tumor shrinkage, overal survival 
(OS), patient-reported outcomes (PRO), and safety and pharmicokinetics of afatinib
(Giotrif®). A central test for EGFR mutations was carried out using the companion diagnostic 
TheraScreen® EGFR RGQ PCR kit. Three hundred and sixty four (364) patients were 
randomised in a 2:1 ratio to receive either afatinib (n=242) 40 mg daily continuous treatment 
in the absence of disease progression or adverse events, or Gemcitabine/Cisplatin (GC) 
(n=122), with Gemcitabine 1000 mg/m2 on Day 1 and Day 8, with cycplatin 75 mg/m2 every 
21 days up to 6 cycles. Baseline characteristics were well balanced between arms: overall the 
median age was 58 years, 65% of patients were female, 77% were never-smokers and 94% 
had Stage IV disease. Regarding EGFR mutation status, 51% had deletions in exon 19 
(Del19), 38% had the L858R mutation and 11% had a variety of other less common 
mutations.
As assessed by central independent review, treatment with afatinib(Giotrif®) resulted in a 
significantly prolonged PFS as compared to treatment with GC (median 11.0 vs. 5.6 months, 
HR 0.28, p<0.0001). The ORR for patients treated with afatinib (66.9%) was significantly 
higher than that for patients treated with GC (23%) (p<0.0001). The prolonged PFS and 
higher ORR observed in patients treated with afatinib (Giotrif®) were accompanied by 
significant delays (as compared to patients treated with GC) in time to deterioration of the 
cancer-related symptoms of cough (HR=0.45, p=0.0001) and dyspnoea (HR=0.54, 
p<0.0001). The pre-specified number of events necessary to Overall Survival (OS) has not 
yet been reached.
The incidence of patients with AEs leading to dose reduction was 32.2% in the afatinib 
(Giotrif®) arm and 26.5% in the chemotherapy arm. In the afatinib (Giotrif®) arm, drug-
related AEs leading to treatment discontinuation were experienced by 5.9% of the patients as 
compared to 39.8% of the patients in the chemotherapy arm.  The most frequent reported 
afatinib-related AEs were diarrhoea, rash/acne and stomatitis. The most frequent reported 
chemotherapy-related AEs were nausea/vomiting , fatigue, and bone-marrow suppresion. 
There were 14 deaths (5.9%) reported due to on-treatment AEs in the afatinib (Giotrif®) arm, 
and three deaths (2.7%) were reported due to on-treatment AEs in the chemotherapy group.  
Significant differences between the proportion of patients with improvements in lung cancer 
symptoms  of cough, dyspnoea, and pain were observed with patient in afatinib (Giotrif®) 


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arm compared to chemotherapy ( P13-06250). Taken together, these results support the 
efficacy data and conclusions of LUX-Lung 3.
Risks
Most diarrhoea and rash/acne was adequately managed by a combination of pausing 
treatment, reducing the dose, and supportive treatment with loperamide for diarrhoea and 
topical antibiotics for rash. Dose reduction was required to manage common AEs in 
approximately half of patients treated with afatinib (Giotrif®). Treatment related AEs that led 
to discontinuation occurred in 8% of afatinib (Giotrif®) treated patients in study 1200.32, and 
9% in study 1200.22. The frequency of discontinuation due to diarrhoea was <5% for afatinib 
(Giotrif®) treated patients in each of the aforementioned studies.
The low rates of discontinuation due to diarrhoea and rash/acne compared with the incidence 
of these events suggested that the protocol-defined dose reduction scheme and recommended 
medical management were effective and allowed patients to continue treatment with afatinib
(Giotrif®) for as long as there was clinical benefit. In study 1200.32 in which patients were 
randomised between treatment with afatinib (Giotrif®) and chemotherapy, overall treatment-
related AEs led to discontinuation of therapy in 8% of patients receiving afatinib (Giotrif®) 
as compared to 12% of patients receiving pemetrexed/cisplatin in spite of the fact that the 
afatinib (Giotrif®) treatment patients remained on treatment for a significantly longer period.
In a pooled analysis of patients taking the 40 mg dose in monotherapy trials, the frequency of 
patients with serious adverse events were: diarrhoea (3.2%), vomiting (2.6%), dyspnoea 
(1.6%), metastases to central nervous system (1.4%), fatigue (1.0), pneumonia (1.0), and 
respiratory failure; all others occurred at a rate less than 1% (U12-1482-01).
Interstitial Lung Disease (ILD) or ILD-like events are a known and infrequent risk associated 
with EGFR inhibitor therapy and encompass a variety of clinical entities. Diagnosis is often 
made on clinical and/or radiographic findings and at times is difficult to distinguish from 
pulmonary processes, such as infection or malignancy. In afatinib (Giotrif®) monotherapy 
and combination therapy trials, adverse events identified as potential ILD or ILD-like, were 
reported infrequently (unadjudicated frequency 1.5%; investigator assigned drug related 
frequency 0.7%). The frequency of these events is similar to that observed with other EGFR 
inhibitors. [U03-3218] As this is a known class effect of other EGFR/HER2 inhibitors, 
patients with known ILD will be excluded from this trial and careful monitoring of 
pulmonary symptoms with sudden onset is warranted in patients treated with afatinib
(Giotrif®).
Overall these findings demonstrate that for patients with EGFR mutation positive NSCLC the 
benefits of treatment with afatinib (Giotrif®) outweigh the associated risks. These patients
experienced significant improvements in time to disease progression that were accompanied 
by significant and clinically meaningful improvements in disease related symptoms. Adverse 
events observed following treatment with afatinib (Giotrif®) have been of a nature and 
severity expected for EGFR inhibitors. Dose reduction was frequently required to manage 
common AEs, but the dose reduction scheme and the proposed supportive care described for 


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common AEs allowed the vast majority of patients to remain on treatment for as long as there 
was clinical benefit.
Gastrointestinal perforation, including fatalities, has been reported during treatment with 
afatinib in 0.2% of patients across all randomized controlled clinical trials. In the majority of 
cases, gastrointestinal perforation was associated with other known risk factors, including 
concomitant medications such as corticosteroids, NSAIDs, or anti-angiogenic agents, an 
underlying history of gastrointestinal ulceration, underlying diverticular disease, age, or 
bowel metastases at sites of perforation. In patients who develop gastrointestinal perforation 
while taking afatinib, treatment should be permanently discontinued.
2.4
BENEFIT - RISK ASSESSMENT IN CONTEXT OF COVID-19 INFECTION
2.4.1
Relevant information on the product in relationship to COVID-19
Relevant mechanism of action, clinical pharmacology aspects, relevant non-clinical and 
clinical data are described in the current afatinib Investigator’s Brochure [c01617169-11] and
the current afatinib drug label. There is no non-clinical nor clinical data on how afatinib may 
affect COVID-19 viral infections. Gastrointestinal effects of afatinib like stomatitis or 
diarrhea or skin toxicities may enhance susceptibility for viral infections thus effective 
management of these side effects is important. There is no non-clinical nor clinical data to 
suggest that afatinib may directly alleviate nor exacerbate viral infections like COVID-19, 
and based on the mechanism of action (specific inhibition of the tyrosine kinases of the ErbB 
family), there would be no expectation of such direct interaction to affect COVID-19 disease.
Recent afatinib trials have implemented mitigations in order to reduce the patient risk of 
contracting COVID-19 due to the local COVID situation. Depending on the local COVID 
situation, protocol-defined trial procedures requiring travel to the study site may impose a 
potential COVID risk and therefore should be appropriately mitigated with measures, if these 
are deemed necessary by investigator.
2.4.2
Benefits and Risks Conclusions and Recommendations
Patients in clinical trials with afatinib have advanced late stage cancer with limited treatment
options. Given the life threatening nature of the underlying disease, the approach 
recommended by professional oncology organizations (e.g. ASCO, ESMO) remains to treat
patients with cancer as under normal circumstances. No consensus on recommendations exist
regarding holding or delaying treatment in cancer patients with no signs of a COVID-19
infection. Withdrawing treatment in a cancer patient who may have few or any alternative
treatment options requires a careful, individual evaluation.
There is no evidence/indication that based on the pharmacological mechanism and existing
non-clinical and clinical data that afatinib may increase the risk of progression of COVID-19
infection.


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To date, there is no evidence suggesting a link between susceptibility to COVID-19
infections and the inhibition of ErbB family of tyrosine kinases targeted by afatinib.
Available non-clinical and clinical data from completed clinical trials have not shown an
increased risk of infections with afatinib. 
Considering the limited and sparse data on immune activation and the role of inflammation as
well as other underlying factors that may increase the severity and mortality from COVID-19
infection [R20-0918; R20-0916] , there may be some factors representing the risk for using 
ErbB tyrosine kinases that are currently still unknown. The information about the risk factors, 
the severity and the activity of immune response in patients with COVID-19 infections will 
be constantly monitored as it evolves.
All up-to-date information about the investigational compounds (preclinical, clinical, clinical
pharmacology) is included in the trial documentation, including IB, clinical trial protocol for
the guidance of the investigator. The latter also outlines the measures for management of 
associated AEs, required dose reductions etc. The risk mitigation measures currently in place 
within the clinical trial protocols  are a sufficient safeguard, as patients are frequently 
monitored with comprehensive safety evaluations. Based on laboratory data and any adverse
event that may occur, clinical trial protocols include guidance for the continuation, 
interruption, dose reduction, and discontinuation of study drugs.
Therefore, assuming the protocol-defined requirements for continued study drug
administration are met, the decision about concomitant use of experimental anti-cancer
therapy with afatinib with COVID-19 treatment in case of contracted COVID-19 infection
will be left to the investigator’s benefit-risk assessment on a case-by-case basis.
The investigators will take the totality of information related to each single patient and the
local COVID-19 situation into consideration when performing the individual benefit-risk
assessment on a case-by-case basis. Considering all aspects, the investigator will decide upon
each patient’s continued participation in the trial. BI as the sponsor, recommend to
adhere to the trial protocol as much as possible and where required, will support the
investigator in their decision finding. It is acknowledged that the investigator may decide to
implement protocol deviations where this protects the safety, wellbeing and/or is in the best
interest of the patient. BI has provided guidance to investigators on how to manage these
situations if they occur.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
This trial will evaluate the safety, tolerability and efficacy of the investigational drug afatinib
(Giotrif®) in patients with locally advanced or metastatic non-small cell lung cancer 
(NSCLC) harboring EGFR mutation(s) and have never been treated with an EGFR-TKI. 
EGFR mutation positivity of all patients needs to be established and documented prior to 
enrolment into the trial. Treated patients will visit the investigator at regular intervals as 
specified in the Flow chart. 
All entered patients (i.e., patients that have been treated with the trial medication) will receive 
continuous treatment of afatinib (Giotrif®) in the absence of disease progression or meeting 
any other trial withdrawal criteria (see Section 3.3.4). The trial is considered concluded when 
all patients have discontinued trial medication and/or have access to Afatinib via options 
included but not limited to an alternative clinical trial, marketed product, an expanded-access 
program, named patient use program, compassionate use protocol or other means based on 
local regulation and completed the follow up or are lost to follow up.
Enrolment of new patients into the trial will end once enrolment goal in the trial has been met  
and/or if any of the criteria in Section 3.3.4.2 are met.
All patients will visit the investigator at regular intervals for assessment of safety as outlined 
in the Flow chart. Disease Assessment will be performed at each visit (i.e., every 28 days) 
until disease progression or withdrawal for another reason. Disease Assessment will be based 
on the assessment of cancer related symptoms and, if available, radiologic assessments as per 
standard of care (SOC) at the site. The investigator is not obligated to perform any radiologic 
scans as part of this trial. However, if such scans were performed as part of standard of care 
this information should be recorded on the Disease Assessment case report form.
Participation will be open to physicians experienced in treating patients with NSCLC and 
who can complete the site qualification and initiation process.
3.1
OVERALL TRIAL DESIGN AND PLAN
3.1.1
Administrative structure of the trial
This trial is sponsored by Boehringer Ingelheim (BI).
Boehringer Ingelheim (BI) will appoint a Clinical Trial Leader (CTL), responsible for 
coordinating the activities required in order to manage the trial in accordance with applicable 
regulations and internal Standard Operating Procedures (SOPs), directing the clinical trial 
team in the preparation, conduct, and reporting of the trial, ordering the materials as needed 
for the trial, ensuring appropriate training and information of a local Clinical Trial Manager 
(CTM), Clinical Research Associates (CRAs), and investigator.
Data Management and Statistical evaluation will be performed by BI and/or a Contract 
Research Organization (CRO) according to BI SOPs. A BI: Project Data Manager (PDM),  
Project Statistician (PSTAT) and Project Programmer will provide oversight for these 
activities.


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Tasks and functions assigned in order to organize, manage, and evaluate the trial will be 
defined according to BI SOPs. A list of responsible persons will be provided in the Clinical 
Trial Master File (CTMF) document.
The organization of the trial will be done by the respective local BI-organization Operating 
Unit (OPU) or by a CRO with which the responsibilities and tasks will have been agreed and 
a written contract filed before initiation of the clinical trial. A CTM will be appointed and 
will be responsible for coordinating the activities required in order to manage the trial in 
accordance with applicable regulations and internal SOPs.
The coordinating investigator is a investigator participating in the trial that has experience of 
this type of trial and investigations. The coordinating investigator has been designated by BI 
and will sign the Clinical Trial Report (CTR). Since this trial will not require any blinding or 
randomisation there will be no steering committee or data monitoring committee needed for 
this trial.
The trial will be performed by investigators specialized in the treatment of lung cancer.
Documents on the coordinating investigator and other important participants, especially their 
curricula vitae, will be filed in the CTMF. 
Details on handling of the trial supplies including responsible institutions are given in Section 
4 of this protocol.
Boehringer Ingelheim will appoint CROs to be responsible for special services, such as: trial 
medication logistics and data management activities (eCRF and discrepancy management).
All relevant trial documentation will be stored in the CTMF at BI. In addition each site will 
have an Investigator Site File (ISF) containing all trial documents relevant for the site, as 
required by local regulation and BI SOP.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
Because of the exploratory nature of this trial there will be no control group. 
3.3
SELECTION OF TRIAL POPULATION
A log of all patients screened/enrolled into the trial (i.e., patients who provided consent) will 
be maintained in the ISF at the investigator’s site regardless of whether they have been 
treated with the investigational drug or not. This trial will accommodate up to 500 patients at 
up to 200 sites within Europe, in Australia and in Israel.
Participation in this trial will be available to patients with advanced NSCLC who meet all the 
eligibility requirements specified in Sections 3.3.2 and 3.3.3 (i.e., inclusion and exclusion 
criteria).


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3.3.1
Main diagnosis for study entry
All patients should have locally advanced or metastatic NSCLC harboring EGFR mutation(s) 
and have never been treated with an EGFR-TKI.
3.3.2
Inclusion criteria
Patients with:
1) locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) 
2) Epidermal Growth Factor Receptor (EGFR) mutation-positive result per the 
institution’s testing methodology. 
3) male or female patients age ≥18 years
4) Adequate organ function, defined as all of the following:
a.
Absolute Neutrophil Count (ANC) > 1500/mm3. (ANC >1000/mm3 may be 
considered in special circumstances such as benign cyclical neutropenia as 
judged by the investigator and in discussion with the sponsor).
b. Platelet count >75,000/mm3
c.
Serum creatinine 1.5 times of the upper limit of normal
d. Total Bilirubin < 1.5 times upper limit of (institutional) normal (Patients with 
Gilbert’s syndrome total bilirubin must be <4 times institutional upper limit of 
normal).
e.
Aspartate Amino Transferase (AST) or Alanine Amino Transferase (ALT) < 
three times the upper limit of (institutional) normal (ULN) (if related to liver 
metastases < five times ULN). 
5) ECOG score between 0 - 2
6) written informed consent by patient or guardian prior to admission into the trial that is 
consistent with International Conference on Harmonisation (ICH)- Good Clinical 
Practice (GCP) guidelines and local law.
3.3.3
Exclusion criteria
Patients who or with:
1) prior treatment with an EGFR tyrosine kinase inhibitor (TKI)
2) anti-cancer treatment within 2 weeks prior to start of trial treatment (continued use of 
anti-androgens and/or gonadorelin analogues for treatment of prostate cancer 
permitted) 


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3) radiotherapy within 14 days prior to drug administration, except as follows:
a.
Palliative radiation to organs other than chest may be allowed up to 2 weeks 
prior to drug administration, and
b. Single dose palliative treatment for symptomatic metastasis outside above 
allowance to be discussed with sponsor prior to enrolling.
4) major surgery within 4 weeks before starting trial treatment or scheduled for surgery 
during the projected course of the trial
5) known hypersensitivity to afatinib (Giotrif®) or any of its excipients (see Section 
4.1.1)
6) history or presence of clinically relevant cardiovascular abnormalities such as 
uncontrolled hypertension, congestive heart failure New York Heart Association 
(NYHA) classification of 3 (Refer to Appendix 10.2), unstable angina or poorly 
controlled arrhythmia as determined by the investigator. Myocardial infarction within 
6 months prior to starting trial treatment.
7) are Women of Child-Bearing Potential (WOCBP) and men who are able to father a 
child, unwilling to use adequate contraception prior to trial entry, for the duration of 
trial participation and for at least 28 days after treatment has ended. Adequate 
methods of contraception and Women of Child-Bearing Potential described in Section 
4.2.3.
8) are WOCBP childbearing potential (see Section 4.2.3) who are nursing or are 
pregnant or do not agree to submit to pregnancy testing required by this protocol
9) any history of or concomitant condition that, in the opinion of the investigator, would 
compromise the patient’s ability to comply with the trial or interfere with the 
evaluation of safety for the trial drug
10) previous or concomitant malignancies at other sites, except effectively treated non-
melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or 
effectively treated malignancy that has been in remission for more than 3 years and is 
considered to be cured.
11) requiring treatment with any of the prohibited concomitant medications listed in 
Section 4.2.2 that can not be stopped for the duration of trial participation
12) known pre-existing interstitial lung disease
13) presence of poorly controlled gastrointestinal disorders that could affect the 
absorption of the trial drug (e.g. Crohn’s disease, ulcerative colitis, malabsorption, or 
CTC grade ≥2 diarrhoea of any aetiology) based on investigator assessment.


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14) active hepatitis B infection (defined as presence of Hepatitis B (HepB) sAg and/or 
HepB DNA), active Hepatitis C (HEP C) infection (defined as presence of Hep C
RNA) and/or known Human Immunodeficiency Virus (HIV) carrier.
15) meningeal carcinomatosis
16) symptomatic brain metastases (patients with asymptomatic brain metastases, who 
were previously treated, are eligible provided they have had Stable Disease (SD) for 
at least 4 weeks on stable doses of medication) 
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
The investigator or patient themselves may stop trial treatment at any time for safety or 
personal reasons.
If a patient is entered in violation of inclusion/exclusion criteria, the sponsor, in discussion 
with the investigator, will determine the medical risk/benefit on a patient-by-patient basis and 
can require such a patient be discontinued from the trial treatment.
The investigator or the sponsor may permanently discontinue a patient’s participation at any 
time for any of the following reasons:

patient withdraws consent, without the need to justify the decision

unequivocal disease progression. Study treatment can be continued beyond 
radiological progression only (without symptomatic progression) until clinical 
progression if it is deemed in the patient’s benefit following a careful risk benefit 
assessment and confirmation of clinical benefit by the investigator. Each case must be 
discussed in details and agreed between the investigator and the Sponsor, and only 
after sponsor approval, the trial treatment can continue.

patient fails to follow protocol requirements/directions and represent a safety issue for 
the patient

eligibility criteria are violated and represent a safety issue for the patient

patient requires concomitant medication which may interfere with the trial medication 
(see Section 4.2.2)

patient is no longer able to participate for other medical reasons (e.g., surgery, adverse 
events or other diseases)

adverse events that can not be managed by dose reduction

further dose reductions considered necessary but not allowed according to the 
protocol (see Section 4.1.4.1)

patient is found to be pregnant during trial participation (please refer to Table 4.2.3: 1) 

is diagnosed with ILD

is diagnosed with gastrointestinal perforations

change in the patient’s status creating an unfavourable risk/benefit in favour to stop 
trial treatment

termination of the trial


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The sponsor may remove patients from the study if the patient has access to afatinib via 
options included but not limited to an alternative clinical trial, marketed product, an 
expanded-access program, named patient use program, compassionate use protocol or other 
means based on local regulation. This may mean a change in packaging and labelling. The 
cost of any ongoing supply of study medication will be incurred by the sponsor until 
progression occurs. If a patient is removed from the study treatment, an end of treatment 0-14 
days later and a follow up visit 28 days later will be performed to ensure all adverse events 
are followed up and then the patient will be considered to have completed the trial.
When discontinuation is due to a SAE the investigator must follow the event until it is 
resolved, becomes chronic, or remains stable with no resolution expected. Data on these 
events must be collected in the electronic case report form (eCRF). For guidelines in the 
management of class expected adverse events, refer to Appendix 10.1.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Emergence of any efficacy/safety information that could significantly affect 
continuation of the trial
2. Violation of GCP, the Clinical Trial Protocol (CTP), or the contract by a trial site staff 
or investigator, disturbing the appropriate conduct of the trial.
3. Discontinuation or modification of the clinical development program with afatinib
(Giotrif®) for any reason
4. At the discretion of the sponsor. Drug supply will be arranged for ongoing patients if 
Sponsor decides to terminate the trial. 


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
Boehringer Ingelheim will provide the investigational product afatinib (Giotrif®).
4.1.1
Identity of BI investigational product and comparator product(s)
Substance (INN):
afatinib (Giotrif®)
Pharmaceutical form:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
40, 30, and 20 mg film-coated tablets (the dose of afatinib in 
the film-coated tablets is related to the free base equivalent of 
afatinib) 
Daily dose:
40 mg with an option to reduce the dose based on individual 
tolerability (see Section 4.1.4.1). 
Duration of use:
Continuous daily dosing, one cycle consists of 28 days. 
Patients are eligible for repeated treatment cycles in the 
absence of disease progression or other trial withdrawal 
criteria.
Route of administration:
Oral (swallowed)
Posology:
Once daily
Excipients
Core Tablet: Lactose monohydrate, Microcrystalline 
cellulose, Colloidal silicon dioxide, Crospovidone, and 
Magnesium stearate. Film-coat: Hypromellose 2910, 
Polyethylene glycol 400, Titanium dioxide, Talc, FD&C 
Blue No. 2 11-14% (may not be included in 20 mg tablet), 
and Polysorbate 80.
4.1.2 
Method of assigning patients to treatment groups
When a patient is qualified for entry into the treatment period, treatment                   
assignment will be by means of a third-party web-based system. This will involve the use of 
an Interactive Web Response System (IWRS). The instructions will be provided in the ISF. 
Investigators and site staff will receive unique user IDs and passwords; and a manual 
describing how to access and use the IWRS.
Patients who meet all eligibility criteria will be entered into the trial. Enrolment of new 
patients into the trial will end once enrollment goal in the trial has been met and/or if any of 
the criteria in Section 3.3.4.2 are met. 
There is no comparator group in this trial.  


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4.1.3
Selection of doses in the trial
The dose for patients is 40 mg daily, continuously. This dose was selected based on the 
results from the LUX-Lung 2/1200.22 (P12-03681) [U11-3644-01] study (see Section 1.1
and the current version of the Investigator's Brochure, U03-3218) as well as the results of the 
LUX-Lung 3 (1200.32) study. At the discretion of the treating physician patients can have 
their dose decreased based on the on the criteria mentioned in Section 4.1.4.1.
4.1.4
Drug assignment and administration of doses for each patient
Medication will be dispensed in bottles containing 30 tablets at the beginning of each 
treatment cycle. For administrative purposes treatment will be divided into treatment cycles, 
which are each 4 weeks (28 days) in duration. Patients will take a single oral dose of afatinib
(Giotrif®) each day. Treatment will stop when the patient is diagnosed with disease 
progression or any other reason listed in Section 3.3.4.1. Trial drug will be prescribed by the 
investigator and may be dispensed either by the investigator, site staff or affiliated pharmacy.
The dose of afatinib (Giotrif®) for this trial is 40 mg. All dose reductions will be based on 
individual tolerability (see Section 4.1.4.1). 
The medication should be taken at approximately the same time each day. Food should not be 
ingested for at least three hours before and at least one hour after taking afatinib (Giotrif®)
film-coated tablets.
If the patient does not meet any of the criteria on Table 4.1.4.1: 1 then the dose of afatinib 
(Giotrif®) should remain on the 40 mg dose (unless dose reduction is necessary - see 
Section 4.1.4.1). Dose escalation is prohibited.
Patients will take a single oral dose of afatinib (Giotrif®) daily. The tablet should be 
swallowed with a glass of water (~250 Milliliter (mL)). Afatinib (Giotrif®) tablets are film-
coated and therefore should not be chewed or crushed, but may be administered after 
dispersing the afatinib (Giotrif®) tablets according to the following procedure: 
If dosing of whole tablets is not possible, afatinib (Giotrif®) tablets can also be dispersed in 
approximately 100 ml of non-carbonated drinking water. No other liquids should be used. 
The tablet should be dropped in the water, without crushing it, and occasionally stirred for up 
to 15 Minutes (min) until the tablet is broken up into very small particles. The dispersion 
should be drunk immediately. The glass should be rinsed with approximately 100 ml of water 
which should also be drunk. The dispersion can also be administered through a gastronomy 
tube (G-tube).
If a dose of afatinib (Giotrif®) is missed, it should be taken during the same day as soon as 
the patient remembers. However, if the next scheduled dose is due within eight hours then the 
missed dose must be skipped.
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war), physical 
patient visits to the sites may not be feasible or may need to be restricted to ensure patient 
safety. Based on a thorough assessment of the benefits and risks, the investigator may still 


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decide to continue trial treatment. Where permitted by local law and regulations, trial 
medication may be shipped directly to the patients’ home or two bottles of trial medication 
may be dispensed at the beginning of a treatment cycle, so that the next visit can be 
performed remotely.
4.1.4.1
Dose reduction scheme
Treatment related adverse events will be managed by treatment pauses and subsequent dose 
reductions of afatinib (Giotrif®) according to the schedule described in Table 4.1.4.1: 1.
Dose reductions will apply to individual patients only. Once the dose has been reduced, it 
cannot be increased later.
The investigator is responsible for determining the necessity and frequency of any 
additional/unscheduled visits as well as the extent of the evaluation (e.g., physical 
examination, laboratory testing, adverse events, etc.) performed at these visits. At a minimum 
the investigator should note in the patient’s chart when an additional/unscheduled visit occurs 
and make relevant entries on the AE and medication dispensing eCRFs. 
To prevent the development of more severe adverse events, treatment related diarrhoea, 
nausea and vomiting or rash should be managed early and proactively as described in 
Appendix 10.1.


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Table 4.1.4.1: 1
Dose reduction scheme
AE type and CTC-AE*Grade
Action
Dose Reduction Scheme
Events related to trial drug:
Diarrhoea
Grade 2 persisting for 2 or more 
consecutive days (48 hours) 
despite adequate anti-diarrhoeal 
medication/hydration 
Reduced renal function
to ≥ Grade 2 as measured by serum 
creatinine, proteinuria or decrease 
in glomerular filtration rate of more 
than 50% from baseline
Any drug related AE Grade ≥3
Pause treatment until 
patient has recovered 
to Grade ≤1 or 
baseline1.
Resume treatment at a 
reduced dose 
according to the Dose 
Reduction Column.
If patient has not 
recovered to Grade ≤1 
or baseline1 within 6 
weeks trial treatment 
must be permanently 
discontinued2.
Resume with dose reduction by 10mg 
decrements.
If patient cannot tolerate 20mg/day, 
permanent discontinuation of afatinib 
(Giotrif®) should be considered.
Acute onset and/or unexplained 
worsening of pulmonary systems 
(dyspnoea, cough, fever)
Pause afatinib while 
clinical assessment to 
exclude ILD is 
completed.
If ILD is ruled out as a cause of 
symptoms, grade symptoms and 
relatedness and report as AEs.  If AEs 
are not related, resume afatinib 
(Giotrif®) at current dose. If AEs are 
drug related, follow directions in row 
above. 
If ILD is confirmed, discontinue afatinib
(Giotrif®). 
Gastrointestinal perforations
Permanently 
discontinue afatinib 
(Giotrif®).
NA
* The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v 3.0 
(CTC-AE)
1 Baseline is defined as the CTCAE Grade at the start of treatment
2 In the event that the patient is deriving obvious clinical benefit according to the investigator’s judgment, further 
treatment with afatinib (Giotrif®) will be decided by the investigator.
After treatment pause due to adverse events, treatment at a reduced dose (i.e., with a new 
bottle of medication) will restart at the predefined schedule/cycle (i.e., 28 days (-7/+2 days) 
on the new dose).
In the event of any unrelated adverse events, the investigator may choose to pause the 
medication for up to 14 days, but no dose reduction should occur. If the medication is paused 
for more than 14 days, the decision to continue with afatinib (Giotrif®) will be made by the 
investigator. Patients should be discontinued from the trial if they have been off trial
medication for more than 6 weeks.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Not applicable since this is an open-label trial.


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4.1.6
Packaging, labelling, and re-supply
Afatinib (Giotrif®) will be supplied by BI (or a designated 3rd party drug distribution 
vendor) as film-coated tablets. Available dosage strengths will be 40 mg, 30 mg and 20 mg.
Tablets will be supplied in child-resistant, tamper-evident bottles. Each bottle will contain 30 
tablets of identical dosage strength. 
Each bottle will be labelled according to dosage strength and will also include the trial 
number, medication number, expiry (‘use by’) dates, and instructions for use. Examples of 
the labelling of the bottles are found in the ISF. Adequate supply of afatinib (Giotrif®) 
bottles will be dispensed at each visit to last until the next scheduled visit. Afatinib (Giotrif®) 
must be dispensed in the original bottles. Patients should be instructed to keep the bottles 
tightly closed to protect from moisture.
4.1.7
Storage conditions
Afatinib (Giotrif®) bottles must be kept in a secure, limited access storage area (to authorized 
people) under storage conditions defined below until supplied/administered to patient. 
Temperature logs must be maintained to make certain that the afatinib (Giotrif®) supplies are 
stored at the correct temperature. In the event that the temperature would be out of range, this 
has to be documented in the ISF and reported to the sponsor.
Afatinib (Giotrif®) must be stored in the original package in order to protect from light. 
Film-coated tablets are humidity sensitive, therefore bottles must be kept tightly closed to 
protect from moisture. Tablets must be stored according to the storage instructions on the 
bottle label and in the ISF. 
Patients should be instructed to keep the bottles tightly closed to protect from moisture.
4.1.8
Drug accountability
The investigator, pharmacist, or investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor or designee when the following requirements 
are provided/fulfilled:

approval of the clinical trial protocol by the Institutional Review Board (IRB)/Ethics 
Committee (EC), 

availability of a signed and dated clinical trial contract between the sponsor and the 
investigator /institution,

approval/notification of the regulatory authority, e.g. competent authority,

availability of the curriculum vitae of the principal investigator,

availability of a signed and dated clinical trial protocol, or immediately imminent signing 
of the clinical trial protocol

all other local requirements are met.
The investigator, pharmacist, or investigational drug storage manager must maintain records 
of the product’s delivery to the trial site, the inventory at the site, the use by each patient, and 
the return to the sponsor or alternative disposition of unused product(s). 


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These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers (i.e., medication numbers) assigned to the investigational product(s) 
and trial patients. The investigator, pharmacist, or investigational drug storage manager will 
maintain records that document adequately that the patients were provided the doses specified 
by the CTP and reconcile all investigational product(s) received from the sponsor. At the time 
of return to the sponsor and/or appointed CRO the investigator /pharmacist/investigational 
drug storage manager must verify that all unused or partially used drug supplies have been 
returned by the clinical trial patient and that no remaining supplies are in the investigator’s 
possession.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
Rescue medication
Rescue medications to reverse the action of afatinib (Giotrif®) are not available. Potential 
adverse events should be treated symptomatically. The current version of the Investigator 
Brochure (IB) lists the AEs expected with afatinib (Giotrif®) (U03-3218). Common adverse 
events of treatment with afatinib (Giotrif®) with specified management recommendations 
and/or requirements include diarrhoea, and rash/acne. To improve tolerability and the 
probability of clinical benefit, patients should receive prompt and appropriate supportive care 
at the first signs of symptoms. Suggested treatments for AEs are described in Appendix 10.1.
Symptomatic treatments of side effects or tumour -associated symptoms are allowed.
Emergency procedures
Careful assessment of all patients with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude Interstitial 
Lung Disease (ILD). Trial drug should be paused pending investigation of these symptoms. If 
interstitial lung disease is diagnosed, trial drug must be permanently discontinued and 
appropriate treatment instituted as necessary.
Patients who present with symptoms of keratitis, such as acute or worsening eye 
inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be 
referred promptly to an ophthalmic specialist. If a diagnosis of ulcerative keratitis is 
confirmed, treatment with afatinib should be interrupted or discontinued. If keratitis is 
diagnosed, the benefits and risks of continuing treatment with afatinib should be carefully 
considered. Afatinib should be used with caution in patients with a history of keratitis, 
ulcerative keratitis or severe dry eye. Contact lens use is a risk factor for keratitis and
ulceration.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In this trial supportive treatments will be defined as the best care available judged by the 
investigator, according to the institutional standards for each center. Concomitant 
medications (or therapy) to provide adequate care, may be given as clinically necessary.
For symptom control, palliative radiation therapy is allowed provided that the reason for the 
radiotherapy does not reflect treatment of progressive disease on afatinib (Giotrif®). After 
trial enrolment, palliative radiotherapy may be given for bone pain or for other reasons (e.g. 
bronchial obstruction, skin lesions), provided that the total dose delivered is in a palliative 
range according to institutional standards. During palliative radiotherapy, trial treatment 
should be delayed and may be resumed once the patient has recovered from any radiation 
associated toxicity. If medication is paused for more than 14 days, the decision to continue 
will be made by the investigator. Continuous interruption of > 6 weeks due to palliative 
radiotherapy will not be allowed.
All concomitant therapy, including anaesthetic agents, vitamins, homeopathic/herbal 
remedies, nutritional supplements, must be recorded in the patient’s chart during the 
screening and treatment period, starting from the date of signature of informed consent, and 
ending at the Follow-Up Visit (FU). 
In case of major surgery (as judged by the investigator), it is recommended to stop treatment 
with afatinib (Giotrif®) around one week prior to the surgery, and to restart treatment after 
complete wound healing, provided that complete wound healing occurs ≤ 6 weeks (patients 
should be discontinued from the trial if they have been off trial medication for more than 6 
weeks).
Additional experimental anti-cancer treatment and/or standard chemo-, immunotherapy, 
hormone treatment (with the exception of megestrol acetate and use of anti-androgens and/or 
gonadorelin analogues for treatment of prostate cancer), or radiotherapy (other than palliative 
radiotherapy for symptom control) is not allowed concomitantly with the administration of 
trial treatment.
Afatinib is a substrate of the P-gp transporter. Caution should be exercised when combining 
afatinib (Giotrif®) with P-gp modulators. For a list of potent P-gp inhibitors and inducers see 
Appendix 10.3. As the information on potent inhibitors and inducers of P-glycoprotein may 
evolve, it is important for the treating physician to assess such status on concomitant 
therapies.
4.2.2.2
Restrictions on diet and life style
Patients should be advised to avoid any foods known to aggravate diarrhoea (see 
Appendix 10.1.1).


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To prevent skin related adverse events it is recommended to avoid long exposure to sunlight 
and intense exposure to UV light and/or harsh detergents (pH5 neutral), see also 
Appendix 10.1.2.
4.2.3
Contraception and pregnancy
Female patients must have a negative pregnancy test (β-HCG test in urine or serum) prior to 
commencing trial treatment.
Females will be considered to be of childbearing potential unless surgically sterilized by 
hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two 
years. Women of childbearing potential who are sexually active and not using an acceptable 
method of birth control during the trial and for at least 28 days after the end of active therapy 
are not allowed to participate in the trial.
Acceptable methods of contraception for females include hormonal contraception and double 
barrier method. Double barrier method of contraception is defined as two barrier methods 
used simultaneously each time the patient has intercourse. Accepted barrier methods include 
diaphragm, female condom, cervical cap, male condom and Intrauterine Device (IUD) (the 
diaphragm and cervical cap must be used in conjunction with spermicidal jelly/cream). If 
hormonal contraceptives are used, at least one barrier method should also be used. Partner 
vasectomy, natural 'rhythm' and spermicidal jelly/cream are not acceptable as methods of 
contraception. 
Female patients who are not of childbearing potential due to being postmenopausal (2 years 
without menses) or surgical sterilization (oophorectomy, hysterectomy and/or tubal ligation) 
do not need to use contraception.
Male patients should use adequate contraception (e.g., condom and spermicidal jelly) during 
the trial and for at least 28 days after the end of active therapy.
If a woman becomes pregnant during the treatment period this must be reported as a drug 
exposure during pregnancy case, even if no event occurred. For cases of paternal exposure to 
the BI product during the trial, the pregnancy (mother is not a participant in the trial) has also 
to be reported to BI, if the father (participant in the trial) voluntarily reports it to the 
investigator.
In both cases the pregnant woman has to be followed up until birth of the baby; then it has to 
be reported whether the woman had a normal delivery or not and whether the newborn 
showed any pathological findings. 
If pregnancy is associated with a SAE, both, SAE form and pregnancy monitoring form must 
be completed.


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Table 4.2.3: 1
Pregnancy reporting
Timing of pregnancy
Action
Prior to commencing 
trial medication
Patient should be withdrawn from the trial immediately, as 
per exclusion criteria #7. No reporting necessary.
During trial treatment
Treatment must be stopped immediately and the pregnancy 
should be reported to the sponsor immediately using the 
pregnancy monitoring form (Part A). If the investigator 
wishes to give any further treatment with trial medication, 
this must be discussed and agreed upon with the BI clinical 
monitor. If trial medication is continued despite pregnancy, a 
risk/benefit analysis should be documented. 
The pregnancy should be followed up to final outcome and 
the outcome, including the health status of the newborn 
and/or any premature termination should be reported to the 
sponsor on the pregnancy monitoring form (Part B) (refer to 
Section 5.2.2.2).
If a pregnancy is accompanied by an SAE, an SAE form 
must also be completed. In addition, any event leading to the 
termination of pregnancy (i.e. spontaneous, accidental, or 
induced abortion; as well as miscarriage, intrauterine foetal 
demise/death and congenital malformation/anomaly) must be 
reported as an SAE.
End of Treatment 
(EOT) though Follow-
up visit/end of 
observational phase
The pregnancy should be reported to the sponsor 
immediately using the pregnancy monitoring form (Part A).
The pregnancy should be followed up to final outcome and 
the outcome, including the health status of the newborn 
and/or any premature termination should be reported to the 
sponsor on the pregnancy monitoring form (Part B).
If a pregnancy is accompanied by an SAE, an SAE form 
must also be completed. In addition, any event leading to the 
termination of pregnancy (i.e. spontaneous, accidental, or 
induced abortion; as well as miscarriage, intrauterine foetal 
demise/death) must be reported as an SAE.
4.3
TREATMENT COMPLIANCE
The trial medication will be given to the patient in accordance with the protocol and the 
instructions of the treating physician. The treating physician is responsible for assessing 
patient compliance. Patients will be asked to return all unused trial medication at each visit. 
Tablet counts must be reviewed by the treating physician (or designee) in order to assess 


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compliance with trial medication. Patients will be encouraged to strictly comply with drug 
administration procedures.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
The primary endpoint of this study is the safety assessment, refer to Section 5.2.1 for a 
description of safety endpoints. No specific schedule or type of tumour measurements or 
assessments are required in this trial. 
5.1.1
Endpoint(s) of efficacy
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:

Time to symptomatic progression (TTSP) is defined as the time from first 
administration of afatinib (Giotrif®) to the date of first documented clinically 
significant symptomatic progression that required change in or stopping anti-cancer 
treatment according to investigator’s assessment.
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 (Giotrif®) to the date of progression or to the date of death, 
whichever occurs first.
No specific tumour measurements are required per trial protocol. 
5.1.2
Assessment of efficacy
See Section 5.1.1.
5.2
SAFETY
5.2.1
Endpoint(s) of safety
Safety will primarily be assessed by adverse events according to Common Terminology 
Criteria (CTCAE Version 3) in a descriptive fashion.
No confirmatory safety analysis is planned.
Please refer to Section 5.2.2.2 for details on the collection and reporting of adverse events 
and SAEs.


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5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Safety assessments will consist of monitoring and recording all adverse events (AEs) and 
serious adverse events (SAEs) and includes daily record of diarrhea status as reported by the 
patient for the first two cycles. In addition, the investigator does not need to actively monitor 
patients for adverse events once the clinical trial has ended. However, if the investigator 
becomes aware of an SAE(s) that occurred after the patient has completed the clinical trial 
(including any protocol required REP and / or follow-up), it should be reported by the 
investigator to the sponsor if considered relevant by the investigator.
Adverse 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.
Serious 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 
with the hospitalization:

Hospitalizations for respite care 

Hospitalization planned prior to informed consent (where the condition requiring the 
hospitalization has not changed post trial drug administration)
Intensity of adverse event
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 3.0 in the eCRF.
Causal relationship of adverse event
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms.


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Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE.
Worsening 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 eCRF.
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 (grade 5, outcome fatal).” 
Changes 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 investigator.
Expected Adverse Events
For expected (listed) AEs of afatinib (Giotrif®), see the current version of the IB (U03-3218). 
5.2.2.2
Adverse event and serious adverse event reporting
The residual effect period (REP) for this trial is defined as 28 days after last intake of study 
drug.
Table 5.2.2.2:1 AE/SAE reporting requirements
Time period
Reporting requirements
From signing of informed consent to ≤28 
days after last trial drug administration
Report all AEs and SAEs regardless of 
relatedness or whether the trial drug was 
administered. This includes all deaths.


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Table 5.2.2.2:1 (continued) AE/SAE reporting requirements
Post-treatment (>28 days after last trial drug 
administration)
The investigator does not need to actively 
monitor patients for adverse events once the 
clinical trial has ended. However, if the 
investigator becomes aware of an SAE(s) that 
occurred after the patient has completed the 
clinical trial (including any protocol required 
REP and / or follow-up), it should be 
reported by the investigator to the sponsor if 
considered relevant by the investigator.
BI has set up a list of AEs which are defined to be always serious. In order to support the 
investigator with the identification of these “always serious adverse events”, if a non serious 
AE is identified to be serious per BI 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 
following the same procedure as above. The list of these adverse events can be found via the 
RDC-system.
The investigator must report the following events using the SAE form immediately (within 
24 hours) to the sponsor: SAEs, non-serious AEs relevant to a reported SAE, adverse events 
of special interest. Further details regarding AE reporting procedure are provided in the ISF.
Pregnancy
Pregnancy is an exclusion criterion in this trial.
In rare cases, pregnancy might occur in clinical trials and observational trials. In such cases 
the actions delineated in Table 4.2.3: 1 should be followed. 
Once a female subject has been entered into the clinical trial, after having taken trial
medication, the investigator must report immediately any drug exposure during pregnancy to 
the sponsor. Drug exposure during pregnancy has to be reported immediately (within 24 
hours) to the defined unique entry point for SAE forms of the respective BI OPU (country-
specific contact details will be provided in the Investigator Site File). The outcome of the 
pregnancy associated with the drug exposure during pregnancy must be followed up. In the 
absence of an (S)AE, only the Pregnancy Monitoring Form for Clinical Trials and not the 
SAE form is to be completed. The ISF will contain the Pregnancy Monitoring Form for 
Clinical Trials (Part A and Part B). In the presence of an (S)AE, both the Pregnancy 
Monitoring Form for Clinical Trials and the SAE form must be completed (see Table 4.2.3: 
1).


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5.2.3
Assessment of safety laboratory parameters
Safety laboratory samples will be analyzed at the investigator’s local laboratory. Safety 
laboratory examinations will include haematology, biochemistry and urine examinations. All 
laboratory tests mentioned in Table 5.2.3: 1 should be performed at screening (Visit 1). All 
post screening laboratory testing is optional and should be performed at the discretion of the 
investigator and in accordance to the current standard of care. The recommended safety 
laboratory examinations laboratory tests can also be found in Table 5.2.3: 1.
Table 5.2.3: 1
Clinical laboratory tests
Category
Parameters
Haematology
Haemoglobin, platelet count, and White Blood Cell (WBC)
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, and 
Creatine Phosphokinase (CPK); in case of pathological CPK further evaluation (e.g., 
by determination of isoenzymes, troponin assays, ECG exam) should be performed as 
clinically indicated.
Urinalysis
pH, protein, glucose, blood/erythrocytes, leucocytes, nitrite; in case of pathological 
finding further evaluation should be performed and results documented
Pregnancy 
test
β-HCG testing in urine or serum in Women Of Child-Bearing Potential (WOCBP) 
(see Section 4.2.3)
5.2.4
Electrocardiogram
Twelve-lead ECGs will only be performed locally at the trial sites at the discretion of the 
investigator in accordance to local current standard of care for patients (see Flow chart). 
When performed, the investigator will review the ECG recording at the time of the visit and 
record any ECG abnormality that meets AE criteria.
5.2.5
Assessment of other safety parameters
5.2.5.1
Physical examination 
A general physical examination (which includes measurement of height (in cm) and body 
weight (in kg)) will be performed at screening and at the time points specified in the 
Flow chart. The evaluation of the ECOG performance score will be performed only at Visit 1.


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5.2.5.2
Vital signs
Vital signs (blood pressure and pulse rate after two minutes rest) and temperature (preferably 
oral and/or tympanic: if other locations are used the same location should be used at each 
time point when body temperature is measured) will be recorded at the time points specified 
in the Flow chart.
5.2.5.3
Left ventricular function
Left Ventricular Ejection Fraction (LVEF) as measured by Echocardiography (ECHO) or 
Multiple Gated Acquisition scan (MUGA) will be assessed if clinically indicated. The testing 
of this function and cardiac monitoring  should be considered  in patients that develop 
relevant cardiac signs/symptoms during treatment. In patients with an ejection fraction below 
the institution’s lower limit of normal, cardiac consultation as well as afatinib treatment 
interruption or discontinuation should be considered.
5.3
OTHER
5.3.1
Other endpoint(s)
Not applicable.
5.3.2
Other assessment(s)
5.3.2.1
Documentation of diarrhoea
Patients will receive a diarrhoea diary for the first 2 cycles of Afatinib (Giotrif®) treatment. 
Patients will receive instructions on how to record daily diarrhoea events.  A copy of the 
instructions and the diary will be provided in the ISF.
All data on diaries will be reviewed at visit 2 and 3 and will be checked against the reported 
AEs and adherence to the instructions in Section 10.1.1 (Management of diarrhoea and 
hydration status following treatment with afatinib). 
Use of a daily recording diary will capture quantitatively diarrhea data  (number of bowel 
movements and consistency of diarrhea). 
The diary will be used as a tool for investigators in order to get more granular information on 
the severity and duration of diarrhoea and whether patients followed recommendations in 
terms of anti-diarrheal concomitant medication and sufficient hydration. The diary is also a 
tool for the patient which reminds to contact the investigator in case high number of bowel 
movements are present over some days or in case of any concerns.
Accurate and constant assessment of diarrhoea symptoms, timely initiation of anti-diarrheal 
medication at first signs of diarrhoea, appropriate anti-diarrheal medication dose 
modifications based on the daily diarrhea symptoms, and non-pharmacologic interventions 
will facilitate early and appropriate interventions to minimize the duration and severity of 
dose limiting afatinib-induced diarrhea.


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5.3.3
Pharmacogenomic evaluation
Not applicable.
5.4
APPROPRIATENESS OF MEASUREMENTS
CTCAE criteria are used in the assessment of adverse events in cancer patients. Although an 
updated version is published, in the present trial CTCAE version 3.0 will be used. As several 
pivotal oncology trials are currently ongoing with the investigational product that utilize 
CTCAE version 3.0, it is considered more appropriate to continue to collect safety data using 
the same criteria applicable.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Not applicable since no pharmacokinetic data will be collected or analyzed in this trial.
5.6
BIOMARKER
5.6.1
Endpoints based on biomarker(s)
EGFR – Mutation analysis
As per Section 1.1, there is a strong rationale to identify predictive markers which are 
features at baseline that may predict responsiveness to ErbB TKI in this population. 
Enrolment
The presence of an EGFR mutation is mandatory for trial enrolment. Hence, the EGFR 
mutation analysis must be performed prior to enrolment into the trial (i.e., before a patient is 
consented). Any EGFR mutation-positive result must be documented and the analysis can be 
performed using the institution’s local testing methodology.  
5.6.2
Methods of sample collection
Not applicable since no samples are being collected within the trial.
. 
5.7
PHARMACODYNAMICS
Not applicable since no pharmacodynamic data will be collected or analyzed in this trial.
5.7.1
Pharmacodynamic endpoints
Not applicable since no pharmacokinetic or pharmacodynamic data will be collected or 
analyzed in this trial.


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5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
Not applicable since no pharmacokinetic or pharmacodynamic data will be collected or 
analyzed in this trial.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
6.1.1
Screening and dispensing visit
Patients considered for this trial will undergo an eligibility evaluation (see Flow Chart). If 
patients meet all eligibility requirements they will be dispensed drug for the first 28 day 
treatment cycle.
A contact is required 15 (± 3) days after the patient’s first dose to assess any AEs.
6.1.2
Treatment and safety evaluation visits
Safety evaluation visits are to be conducted after afatinib (Giotrif®) administration, at Day 
28 (-7/+2)/Visit 2, and every 28 (-7/+2) days onwards. Please refer to the required and 
optional procedures to be performed at these visits in the Flow Chart and in Section 6.2.1. 
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war,) patients 
visits may be performed remotely to collect/report study data such as adverse events, 
concomitant therapies, clinical evaluation of tumour by symptoms and study medication 
compliance check. Where permitted by local law and regulations, trial medication may be 
shipped directly to the patients’ home or two bottles of trial medication may be dispensed at 
the beginning of a treatment cycle, so that the next visit can be performed remotely.
The investigator is responsible for determining the necessity and frequency of any 
additional/unscheduled visits as well as the extent of the evaluation (e.g., physical 
examination, laboratory testing, adverse events, etc.) performed at these visits. At a minimum 
the investigator should note in the patient’s chart when an additional/unscheduled visit occurs 
and make relevant entries on the AE and medication dispensing eCRFs. 
A treatment cycle is defined as 28 days.
6.1.3
End of Treatment (EOT) visit
All patients should be evaluated at the end of their trial treatment. This visit should be 
completed on the day of the patient’s last dose on trial medication or up to 14 days later. 
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war,) patient 
visit may be performed remotely to collect/report study data such as adverse events, 
concomitant therapies, clinical evaluation of tumour by symptoms and study medication 
compliance check. 
6.1.4
Follow-Up (FU) visit
Patients should be contacted 28 (-7) days after the EOT visit to follow-up on their general 
condition and any adverse events which were not yet recovered at the EOT visit or any AEs 


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that started since then. In addition, information regarding patients’ status will be collected at 
this visit. This information can be obtained by a phone call.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The trial procedures are summarized in the Flow Chart. 
6.2.1
Screening and run-in period(s)
Visit 1/Day -1 – Screening and dispensing visit
Informed consent must be obtained prior to any trial related procedures taking place.
Tests for which results are not already available as part of the patient’s standard of care, may 
be ordered after the patient signs informed consent.
Prior to determining eligibility the investigator should: 1) review all information obtained at 
this visit, 2) review the inclusion/exclusion criteria and 3) confirm that the patient has 
discontinued all prohibited therapy or medications (see Sections 4.2.2 and 4.2.2.1) and an 
adequate washout period has passed.
Table 6.2.1: 1
Visit 1 /Day -1 – Screening and dispensing visit
The following must be performed and 
information recorded in the patient’s chart
What to include in eCRF
Informed Consent
Written informed consent must be obtained 
prior to any trial related procedures taking 
place.
Date of informed consent
Demographics
Obtain the following demographic data: 
sex, birth date, race, smoking and alcohol 
history
Sex, birth date, race, ethnicity, and 
smoking history


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The following must be performed and 
information recorded in the patient’s chart
What to include in eCRF
Medical history
Oncological and relevant non-oncological 
history including details of previous 
treatment for NSCLC (including pathology)
History of NSCLC:
Oncological and relevant non-oncological 
history including details of any previous 
treatment for NSCLC
The date of first histological diagnosis, 
the primary tumour site, the number and 
location of metastatic sites (bone, brain, 
liver, pleural effusion, other)
Tumour assessment/stage at the time of 
diagnosis according to the 
TNM-classification
Previous surgeries for NSCLC
Previously administered chemo-, 
immuno-, hormone therapy will be 
reported including start and end dates, the 
treatment regimen with the number of 
courses (chemo-immunotherapy), the best 
response obtained (complete response, 
partial response, stable disease, 
progressive disease, unknown), and 
progression date.
Previous radiotherapy - the total radiation 
dose and radiation field will be recorded
Inclusion and 
Exclusion criteria 
Assessment of eligibility according to 
inclusion and exclusion criteria should be 
performed. 
Verify that the patient has met all the 
inclusion and exclusion criteria.
Physical 
examination
Physical examination results (see Flow 
Chart). The evaluation of the ECOG 
performance score will be performed.
Verify that this physical examination was 
performed and record results (see 
Flow Chart). 


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Table 6.2.1: 1 (continued)
Visit 1/Day -1 – Screening and dispensing visit (Page 2 of 3)
The following must be performed and 
information recorded in the patient’s chart
What to include in eCRF
ECG
12-lead resting ECG  may be performed at 
the discretion of the investigator.
Verify if an ECG was performed. 
Any abnormal results are reported on 
baseline conditions form.
LVEF (Left 
Ventricular 
Ejection Fraction)
Cardiac left ventricular function assessment 
by either ECHO (or MUGA) only for 
patients with cardiac risk factors and those
with condition that can affect LVEF, at the 
discretion of the investigator and in 
accordance to the current standard of care. 
Verify if an ECHO (or MUGA) was 
performed.
Safety Laboratory 
Testing
Hematology, and Biochemistry 
examination. See Section 5.2.3 for 
recommended safety laboratory evaluations.
Blood samples may be collected to perform 
the following:
- Retest for missing laboratory test results 
required to establish eligibility
- Safety laboratory testing as deemed 
necessary by the investigator 
Verify that all recommended safety 
laboratory testing were performed and that 
values met eligibility criteria according to 
the protocol.
No lab values are to be recorded on the 
CRF.
Urine 
Examination 
Urine examination. (see Section 5.2.3)
Verify if all recommended urine testing 
was performed. 
No lab values are to be recorded on the 
CRF.
Pregnancy test
β-HCG testing in urine or serum will be 
performed in females of childbearing 
potential (see Section 5.2.3). A negative 
result is required for enrolment in the trial.
Verify that β-HCG testing in urine or serum 
was performed and that patient is not 
pregnant. 


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Table 6.2.1: 1 (continued)
Visit 1/Day -1 – Screening and dispensing visit (Page 3 of 3)
The following must be performed and 
information recorded in the patient’s chart
What to include in eCRF
Adverse events
Patients should be asked to report any 
hospitalizations, emergency treatments, or 
new medications as well as any general 
health issues that may have surfaced since 
signing the informed consent form. All the 
information collected should be recorded in 
the patient’s chart. Refer to Sections: 5.2.2
and 5.2.2.2 for protocol specific 
requirements regarding the collection and 
reporting of adverse event information.
All relevant AEs and all SAEs.
Concomitant 
Medications
Patients should be asked to report any 
concomitant drug use (including, but not 
limited to,: non-prescription medications, 
anaesthetic agents, homeopathic/herbal 
remedies and dietary supplement 
preparations).
No concomitant medications will be 
recorded on eCRFs.
Dispense Trial 
Medication
Dispense 1 bottle of afatinib (Giotrif®) for 
the 28 day treatment cycle (see Section 
4.1.4.)
Record: dose dispensed, amount of bottles 
dispensed, all medication numbers and date 
of first dose administration
6.2.2
Treatment period
Safety evaluation visits are to be conducted after the initiation of afatinib (Giotrif®), at Day 
28 (-7/+2)/Visit 2 and every 28 (-7/+2) days onwards. Additional safety evaluation visits may 
be conducted as necessary, at the investigator’s discretion. The investigator is responsible for 
determining the necessity and frequency of the additional safety visits as well as the extent of 
the evaluation (physical examination, laboratory testing, etc.) at each visit. 


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Table 6.2.2: 1 
Visit 2/Day 28 (-7/+2) and every 28 (-7/+2) days onwards - treatment 
and safety evaluation 
The following must be performed and information 
recorded in the patient’s chart
What to include in eCRF
Physical 
examination
Physical examination results (see Flow Chart). The 
evaluation of the ECOG performance score will be 
performed.
Verify that this physical examination 
was performed and record results 
(see Flow Chart).
Disease 
Assessment
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.
Disease Assessment to be included 
on CRF.
ECG
ECGs may be performed at the discretion of the 
investigator.
Verify if an ECG was performed 
prior to or during any safety 
evaluation.
LVEF (Left 
Ventricular 
Ejection Fraction)
Cardiac left ventricular function assessment by 
either ECHO or MUGA only for patients with 
cardiac risk factors and those with condition that 
can affect LVEF, at the discretion of the 
investigator and in accordance to the current 
standard of care.
Verify if an ECHO (or MUGA) was 
performed prior to or during this 
visit.
Verify that LVEF has not 
deteriorated to CTCAE Grade ≥3. If 
CTCAE Grade ≥3, see Section 
4.1.4.1
Safety Laboratory 
Testing – Optional
Hematology, and Biochemistry examination. See 
Section 5.2.3 for recommended safety laboratory 
evaluations.
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.
Refer to Section 5.2.3 for a list of recommended 
safety laboratory tests. If performed as part of a 
safety evaluation visit, the test results must be filed 
or recorded in the patient’s chart.
Verify if all recommended safety 
laboratory testing was performed 
and that values were acceptable 
according to the protocol. If not, see 
Sections: 4.1.4.1 and 5.2.2.1
No lab values are to be recorded on 
the CRF.
Urine 
Examination –
Optional
Urine examination. See Section 5.2.3 for 
recommended urine examinations.
Urine Examination is optional at this visit and may 
be performed at the discretion of the investigator 
and in accordance to the current standard of care.
Verify if all recommended urine 
testing was performed. 
No values from the urine 
examination are to be recorded on 
the CRF.


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Table 6.2.2: 1 (continued)
Visit 2/Day 28 and every 28 (-7/+2) days onwards - treatment 
and safety evaluation (Page 2 of 2) 
The following must be performed and information 
recorded in the patient’s chart
What to include in eCRF
Adverse events
Patients should be asked to report any 
hospitalizations, emergency treatments, or new 
medications as well as any general health issues 
that may have surfaced since their last visit. All the 
information collected should be recorded in the 
patient’s chart. Refer to Sections: 5.2.2 and 5.2.2.2
for protocol specific requirements regarding the 
collection and reporting of adverse event 
information.
All relevant AEs and all SAEs.
Compliance
Check number of tablets remaining and that trial 
medication was taken correctly, collect any used 
bottles of afatinib (Giotrif®).
Record if the patient is taking the 
medication according to the 
protocol.
Concomitant 
Medications
Patients should be asked to report any concomitant 
drug use (including, but not limited to,: non-
prescription medications, anaesthetic agents, 
homeopathic/herbal remedies and dietary 
supplement preparations)
No concomitant medications will be 
recorded on eCRFs.
Dispense Trial 
Medication
Dispense sufficient medication for the next cycle 
of treatment (see Section 4.1.4).
Record: dose dispensed, medication 
numbers of bottles dispensed, and 
only the start date of any dose 
changes (if applicable).
Contact
A contact is required 15 (±3) days after the 
patient’s first dose to assess AEs and dose 
reductions.
Record when this contact took place.
6.2.3
End of trial and follow-up period
The End of Treatment (EOT) visit marks the end of the patient’s treatment in the trial, and 
should be conducted as soon as the patient discontinues trial medication (afatinib), and may 
occur at any time during the trial. The investigator may discontinue patients due to any of the 
reasons presented in Section 3.3.4.1.


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Table 6.2.3: 1
End of Treatment (EOT) Visit
The following must be performed and information 
recorded in the patient’s chart
What to include in eCRF
Physical 
examination
Physical examination results (see Flow Chart). The 
evaluation of the ECOG performance score will be 
performed.
Verify that this physical examination 
was performed and record results 
(see Flow Chart).
Disease 
Assessment
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.
Disease Assessment to be included 
on CRF.
ECG
An ECG may be performed at the discretion of the 
investigator.
Verify if an ECG was performed. 
LVEF (Left 
Ventricular 
Ejection Fraction)
Cardiac left ventricular function assessment by 
either ECHO or (MUGA) only for patients with 
cardiac risk factors and those with condition that 
can affect LVEF, at the discretion of the 
investigator and in accordance to the current 
standard of care.
Verify if an ECHO (or MUGA) was 
performed.
Safety Laboratory 
Testing – Optional
Hematology, and Biochemistry examination. See 
Section 5.2.3 for recommended safety laboratory 
evaluations.
Laboratory testing is optional at this visit and may 
be performed at the discretion of investigator and 
in accordance to the current standard of care. Refer 
to Section 5.2.3 for a list of recommended safety 
laboratory tests. If performed as part of a safety 
evaluation visit, the test results must be filed or 
recorded in the patient’s chart.
Verify if all recommended safety 
laboratory testing was performed 
and that values were acceptable 
according to the protocol. If not, see 
Section 5.2.2.1
No lab values are to be recorded on 
the CRF.
Urine 
Examination –
Optional
Urine examination. (see Section 5.2.3 for 
recommended urine examinations).
Urine 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.
Verify if all recommended safety 
Urine testing was performed. 
No values from the urine 
examination are to be recorded on 
the CRF.
Pregnancy test
β-HCG testing in urine or serum will be performed 
in females of childbearing potential.
Verify that β-HCG testing in urine 
or serum was performed and that 
patient is not pregnant.
Adverse events
Patients should be asked to report any 
hospitalizations, emergency treatments, or new 
medications as well as any general health issues 
that may have surfaced since their last visit. All the 
information collected should be recorded in the 
patient’s chart. Refer to Sections: 5.2.2 and 5.2.2.2
for protocol specific requirements regarding the 
collection and reporting of adverse event 
information.
All relevant AEs and all SAEs.


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Table 6.2.3: 1 (continued) 
End of Treatment (EOT) Visit (Page 2 of 2)
The following must be performed and information 
recorded in the patient’s chart
What to include in eCRF
Compliance
Collect all unused or partially used and empty 
bottles of afatinib (Giotrif®) from the patient.
Check number of tablets remaining and check that 
trial medication taken correctly.
Record if the patient took the 
medication according to the 
protocol. This information should be 
captured on the Termination of Trial 
Medication eCRF.
Concomitant 
Medications
Patients should be asked to report any concomitant 
drug use (including, but not limited to,: non-
prescription medications, anaesthetic agents, 
homeopathic/herbal remedies and dietary 
supplement preparations).
No concomitant medications will be 
recorded on eCRFs.
Termination of 
Trial Medication
Document any information regarding the patient’s 
last dose of trial drug and why it was stopped. 
(e.g., date of withdrawal of consent, lost to follow-
up, disease progression)
When applicable, every effort should be taken to 
collect and document information on date of death.
Note: any AE which results in death* is considered 
an SAE.
Date when the last dose of trial 
medication was ingested.
Reason for discontinuation.
* The term “Death” should not be reported as the SAE, it is the outcome of an AE.
6.2.4
Follow-Up
The Follow-up (FU) visit should occur 28 (-7) days after the EOT visit.
Follow-up visits should be scheduled for patients who met the trial withdrawal criteria (see 
Section 3.3.4). This visit marks the end of the patient’s participation in the trial. Patients will 
not be required to attend the clinic for this visit. The clinic staff will contact the patients or 
their caregivers by telephone and inquire about any adverse events that might have occurred 
since the last visit and if applicable follow up on any unforeseen pregnancy during the trial. 
All concomitant medication should be added to the patient’s chart. The Patient Status eCRF 
will be completed at this time.
Any additional (unscheduled) follow-up visits should be scheduled for patients with 
unresolved SAEs, AEs, or laboratory abnormalities who have discontinued trial participation. 
These events must be followed until resolution or until agreement is reached between the 
local medical monitor and the investigator that further follow-up is no longer required. 


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Table 6.2.4: 1 
Follow-up (FU) Visit/EOT + 28 Days (-7)
What to Include in the Patient’s Chart
What to include in eCRF
Adverse events
Patients should be asked to report any 
hospitalizations, emergency treatments, or new 
medications as well as any general health issues 
that may have surfaced since their last visit. All the 
information collected should be recorded in the 
patient’s chart. Refer to Sections: 5.2.2 and 5.2.2.2
for protocol specific requirements regarding the 
collection and reporting of adverse event 
information.
All relevant AEs and all SAEs.
Concomitant 
Medications
Patients should be asked to report any concomitant 
drug use (including, but not limited to,: non-
prescription medications, anaesthetic agents, 
homeopathic/herbal remedies and dietary 
supplement preparations).
No concomitant medications will be 
recorded on eCRFs.
Patient Status
Document any information regarding the patient’s 
status during the planned observation time (i.e., 28 
days after the patient’s last dose of medication).
When applicable, every effort should be taken to 
collect and document information on date of death.
Note: any AE which results in death is considered 
an SAE.
Any new anti-cancer medication that 
the patient has taken since EOT 
visit.
Date when the patient completed the 
planned observation time.
Date of death
Patient’s status


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
Exploratory descriptive statistics of demographic, efficacy and safety data will be presented.
7.1
STATISTICAL DESIGN - MODEL
This is an open-label, multi-centre, non-randomised, uncontrolled, single arm trial designed 
to evaluate the safety, tolerability and efficacy of the investigational drug afatinib (Giotrif®) 
in a particular patient population. After the initial screening visit, patients will enter the open-
label treatment period with safety visits at approximately every 28 days until the end of the 
trial. 
7.2
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses with regard to the endpoints described in 
Section 7.3.2 confirmatory sense since the objective of this trial is to describe the safety of 
long term use of afatinib (Giotrif®) in this patient population in an uncontrolled manner.
7.3
PLANNED ANALYSES
All analyses will be based on the Treated Set (TS) which includes all patients who were 
dispensed trial medication and have taken at least one dose of investigational treatment 
(afatinib).
7.3.1
Primary analyses
Refer to Section 7.3.3 for a description of the analysis of safety and tolerability, the primary 
objectives of this trial.
7.3.2
Secondary analyses
Progression-free survival
Progression-free survival is the time from start of treatment to the date of disease 
progression or death, whichever comes first.
For patients with known date of progression:
Progression-free survival [days] = date of progression (or of death if no earlier 
progression) – (date of start of treatment) + 1 
For 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 Section 7.4 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, 


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using Greenwood’s standard error estimate. Kaplan-Meier curves will be produced 
without confidence intervals.
Tumour response according to investigator’s assessment
Each patient will be assigned to one of the following categories:
1. Complete response
2. Partial response
3. Stable disease
4. Progressive disease
5. Not evaluable for response, reasons to be specified (e.g. early death, tumour 
assessments incomplete, etc.)
In the case that the tumour assessment was not based on radiological tumour imaging the 
categories 'complete response' and 'partial response' will be grouped together. Objective 
Response (OR) is defined as complete and partial responses according to investigator's 
assessment.
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).
7.3.3
Safety analyses
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between first drug intake until 
28 days (inclusive) after last treatment administration will be considered 
‘treatment-emergent’. Adverse events that start before first drug intake and deteriorate under 
treatment will also be considered as ‘treatment-emergent’.


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Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA).
Adverse events will be graded according to CTCAE, Version 3.0 (R04-0474).
CTC grades will be applied to laboratory parameters using the current BI oncology standard 
as detailed in the document ‘Conversion of laboratory parameters to CTCAE grades within 
BI.’
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.3.4
Interim analyses
This is a single-arm open label study. The interim analysis may be done after recruitment has 
been completed. The analyses will include the assessment of safety and efficacy if conducted. 
The result from the interim analysis may be presented at professional conferences and 
published in articles after stop of recruitment.
7.4
HANDLING OF MISSING DATA
Missing or incomplete AE dates are imputed according to BI standards.

For PFS:
o
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.
o
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
No randomisation is required since all patients will be treated with afatinib (Giotrif®). 
7.6
DETERMINATION OF SAMPLE SIZE
The number of patients included into this trial is not based on sample size calculations.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial 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 
Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (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.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in the investigator contract. As a general rule, no trial results should be 
published prior to finalisation of the Clinical Trial Report.
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial 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 personal trial-related data will be used by 
Boehringer Ingelheim 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 authorised 
monitors (CTM/CRA) or Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.


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8.3
RECORDS
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via remote 
data capture. Since this is an open label trial emergency code breaks will not be necessary. 
For drug accountability, refer to Section 4.1.8.
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 are filed at the investigator’s site.
Data reported on Electronic Case Report Forms (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 trial; also current medical records must be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. 
CRFs/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 trial 
monitor, auditor and inspection by health authorities (e.g., Food and Drug Administration 
(FDA). The Clinical Research Associate (CRA)/on site monitor and auditor may review all 
CRFs/eCRFs, and written informed consents. The accuracy of the data will be verified by 
reviewing the documents described in Section 8.3.1.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfill the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e., is a known side effect of the drug or not. 
Therefore a unique reference document for the evaluation of listedness needs to be provided. 
For the BI investigational product (afatinib) this is the current version of the Investigator’s 
Brochure (U03-3218). The current version of this reference document is provided in the ISF.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
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 local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File.


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8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
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 trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities.
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last patient/patient out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial. 


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P07-11507
Moy B, Goss PE Lapatinib-associated toxicity and practical management 
recommendations.Oncologist 12 (7), 756 - 765 (2007).
P08-06904
Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, et al. 
BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in 
preclinical lung cancer models. Oncogene. 2008; 27(34), 4702 - 4711.
P11-09424
Porta C, Osanto S, Ravaud A, Climent MA, Vaishampayan U, White DA, et 
al. Management of adverse events associated with the use of everolimus in 
patients with advanced renal cell carcinoma. Eur J Cancer 47, 1287 - 1298 
(2011).
P12-03681
Yang JCH, Shih JY, Su WC, Hsia TC, Tsai CM, Ou SHI, et al. Afatinib for 
patients with lung adenocarcinoma and epidermal growth factor receptor 
mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncology, Published Online 
March 26, 2012, doi:10.1016/S1470-2045(12)70086-4 Lancet Oncol 2012.
P13-06250      Wu YL, Zhou C, Hu CP, Feng JF, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee 
KY, Massey D, Shi Y, Chen J, Zazulina V, Geater SL.   LUX-Lung 6: a 
randomized, open-label, phase III study of afatinib (A) vs emcitabine/cisplatin 
(GC) as first-line treatment for Asian patients (pts) with EGFR mutation-
positive (EGFR M+) advanced adenocarcinoma of the lung.   49th Ann Mtg of 
the American Society of Clinical Oncology (ASCO), Chicago, 31 May - 4 Jun 
2013 J Clin Oncol 31 (Suppl), (2013)
R04-0474
Common terminology criteria for adverse events v3.0 (CTCAE) (publish date: 
December 12, 2003). Website: ctep.cancer.gov/forms/CTCAEv3.pdf ; Cancer 
Therapy Evaluation Program, Common Terminology Criteria for Adverse 
Events, Version 3.0, DCTD, NCI, NIH, DHHS, 31 March 2003, Publish Date: 
12 December 2003 (2003).P13
R05-0867
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, 
Thongprasert S, et al,National Cancer Institute of Canada Clinical Trials 
GroupErlotinib in previously treated non-small-cell lung cancer.
N Engl J Med 353 (2), 123 - 132 (2005) .
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.
R06-1262
Pao W, Miller VA. Epidermal growth factor receptor mutations, small 
molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge 
and future directions. J Clin Oncol. 2005; 23: 2556-2568.


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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. 
3rd 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. 3rd 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.
R06-1307
Heymach JV, Nilsson M, Blumenschein G, Papadimitrakopoulou V, Herbst R. 
Epidermal growth factor receptor inhibitors in development for the treatment
of non-small cell lung cancer. 3rd 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.): 4441-4445.
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.
R07-1162
Sequist LV. Second generation epidermal growth factor receptor tyrosine 
kinase inhibitors in non-small cell lung cancer. Oncologist. 2007; 12: 325-330.
R07-4077
Giaccone G, Melosky B, Reck M. Epidermal growth factor receptor inhibitor 
(EGFRI)-associated rash: a suggested novel management paradigm. A 
consensus position from the EGFRI dermatologic toxicity forum.ECCO 14, 
14th Eur Cancer Conf, Barcelona, 23 - 27 Sep 2007 (Poster).
R07-4078
Lynch TJ, Kim ES, Eaby B, Garey J, West DP, Lacouture ME. Epidermal 
growth factor receptor inhibitor-associated cutaneous toxicities: an evolving 
paradigm in clinical management. Oncologist 12 (5), 610 - 621 (2007).
R11-0826
Potthoff K, Hofheinz R, Hassel JC, Volkenandt M, Lordick F, Hartmann JT, et 
al. Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a 
German expert opinion. Ann Oncol 22 (3), 524 - 535 (2011).


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R06-0221
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA 
2005;55(2)74-108.
R20-0916
Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and
potential vaccines: lessons learned from SARS and MERS epidemic. Asian 
Pac J Allergy Immunol 2020 ; 38(1) ; 1-9.
R20-0918
Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, et al. 
Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung
inflammation by coronavirus-19 (CoV-19 or SARS- CoV-2): anti-
inflammatory strategies. Journal of Biological Regulators & Homeostatic 
Agents, epub ahead of print, doi: 10.23812/CONTI-E; 2020.
9.2
UNPUBLISHED REFERENCES
U02-1083
 Study of BIBW 2992BS, BIBW 3022BS, and BIBW 3049BS in 
various receptor binding assays. 03-02 8810241. 30January 2002.
U02-1391
 Effects of BIBW 2992 on endogenous EGFR and HER2 
phosphorylation states and on proliferation in various cell lines. 22-02 23.
June 2002.
U02-1614
 Anti-tumour activity of the combined EGFR and HER2 inhibitor 
BIBW 2992 BS in nude mouse xenografts derived from the human gastric 
carcinoma cell NCI-N87. 25-02. 16 October 2002.
U02-1660
 Anti-tumour activity of the combined EGFR and HER2 inhibitor 
BIBW 2992 BS in nude mouse xenografts derived from the human ovarian 
carcinoma cell line SKOV-3. 26-02 4 November 2002 
U02-1702
 Minimum effective dose of the epidermal growth factor receptor 
(EGFR) inhibitor BIBW 2992 BS in nude mouse xenografts derived from the 
EGFR-overexpressing human epidermoid carcinoma cell line A431. 32-02. 
25 November 2002.
U02-1703
 Anti-tumour activity of the combined EGFR and HER2 inhibitor 
BIBW 2992 BS in nude mouse xenografts derived from human breast 
carcinoma cell line MDA-MB-453. 31-02 25 November 2002.
c01617169-11Investigator’s Brochure Afatinib (BIBW 2992)
U03-1086
. Inactivation of the EGF signaling pathway by BIBW 2992: 
A time course analysis.28-02 30November 2002.
U07-1338
: BIBW 2992, an irreversible dual EGFR/HER2 kinase 
inhibitor, shows activity on L858R- and L858R/T790M-EGFR mutants, 
07-06. 11 June 2007.


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U07-3128-02
 A phase I open- label dose escalation study of 
continuous once-daily oral treatment with BIBW 2992 in patients with 
advanced solid tumours. 30-March-2007. Revised 23-April-2010.
U08-1023-03
   A phase I open- label dose escalation study of 
continuous once-daily oral treatment with BIBW 2992 in patients with 
advanced solid tumours. 30-January-2008. Revised 25-October-2011.
U11-2645-01
 Potency of BIBW 2992 in HER4 kinase assays in vitro. 
23 November 2011.
U11-3644-01
LUX Lung 2: A phase II single-
arm trial of BIBW 2992 in non-small cell lung cancer patients with EGFR 
activating mutations. 06 December 2011.
U12-1170-01
 Relative bioavailability of a 
single oral dose of 40 mg afatinib given alone compared to concomitant and 
timed administration of multiple oral doses of ritonavir - an open-label, 
randomised, three-way crossover trial in healthy male volunteers.16-May-
2012.
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.
U12-1482-01
Clinical Summary: Afatinib film-coated tablets, 
20mg, 30 mg, 40 mg, 50 mg. 25-Jul-2012.


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10.
APPENDICES
10.1
MANAGEMENT OF EXPECTED ADVERSE EVENTS
Dermatologic adverse events and diarrhoea are the most common side-effects associated with 
treatment with afatinib (Giotrif®). Treatment of these side-effects should be proactive and 
should be started as early as possible after onset of symptoms.
10.1.1
Management of diarrhoea and hydration status following treatment with 
afatinib (Giotrif®)
Patients should be advised to avoid foods known to aggravate diarrhoea, such as: spicy, 
greasy, or fried foods, raw vegetables, fresh fruit or whole grain bread.
Diarrhoea occurs at a high frequency and generally begins within 2 weeks of exposure to 
afatinib (Giotrif®). Although usually mild to moderate, diarrhoea may lead to dehydration 
and compel treatment modification or discontinuation, so early management is essential 
(Table 10.1.1: 1). At the time of initiation of treatment with afatinib (Giotrif®) patients 
should be given a supply of loperamide to keep with them at all times and should be 
counselled on the appropriate use. Patients should be advised to start taking loperamide with 
the onset of diarrhoea.
Patients must be advised to drink an adequate amount of fluids to make up for the fluid lost 
through diarrhoea. A daily fluid intake of approximately ≥2 liters is recommended to avoid 
dehydration; some fluids should contain sugar or salt to avoid hyponatremia and hypokalemia 
caused by electrolyte loss.


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Table 10.1.1: 1
Grade specific treatment recommendations for afatinib (Giotrif®)
related diarrhoea
Severity               
(CTCAE Grading)
Description
Intervention 
concerning afatinib 
(Giotrif®) treatment 
Specific intervention 
Mild (Grade 1)
Increase of < 4 stools per day 
over baseline; mild increase 
in ostomy output compared 
with baseline
Continue same dose
Stop laxatives and advise 
patient to drink at least 8-10 
glasses of water or  clear 
fluids per day; 4 mg (2 
tablets) of loperamide to be 
taken immediately, followed 
by 2 mg (1 tablet) after each 
loose stool (up to 16 mg/day) 
until bowel movements cease 
for 12 hours. However it is 
advised to consult regional 
prescribing reccomandations.
Moderate (Grade 2)
Increase of 4-6 stools per 
day over baseline; i.v. fluids 
indicated < 24 hours; 
moderate increase in ostomy 
output compared with 
baseline; not interfering with 
Activities of Daily Living 
(ADL)
Continue same dose 
unless Grade 2 
diarrhoea continues for 
≥ 2 days (48 hours) in 
which case treatment 
must be paused until 
recovered to ≤ Grade 1 
followed by dose 
reduction
See Grade 1; continue 
loperamide; assess for 
dehydration and electrolyte 
imbalance; consider 
intravenous fluids and 
electrolyte replacement.
Severe (Grade 3)
Increase of ≥ 7 stools per day 
over baseline; incontinence; 
IV fluids > 24 hours; 
hospitalization; severe 
increase in ostomy output 
compared with baseline; 
interfering with ADL
Pause dose until 
recovered to ≤Grade 1 
followed by dose 
reduction*
See Grade 2; plus: an 
infectious process should be 
ruled out with stool cultures; 
aggressive iv fluid 
replacement ≥ 24 hours; 
hospitalization to monitor 
progress; consider 
prophylactic antibiotics if 
patient is also neutropenic;
Life threatening 
(Grade 4)
Life-threatening 
consequences (e.g. 
haemodynamic collapse)
Pause dose until 
recovered to ≤Grade 1 
followed by dose 
reduction*
See Grade 3
* If despite optimal supportive care and a treatment pause, diarrhoea does not resolve to CTCAE Grade ≤1 or 
baseline (CTCAE Grade at the start of treatment) within 6 weeks, treatment with afatinib (Giotrif®) must be 
permanently discontinued. In the event that the patient is deriving obvious clinical benefit according to the 
investigator’s judgment, further treatment with afatinib will be decided by the investigator.
10.1.2
Management recommendations for dermatological AEs following treatment 
with afatinib (Giotrif®)
Dermatologic AEs of afatinib include rash, acne, dermatitis acneiform, and dry skin. General 
recommendations for prophylaxis are summarized in Table 10.1.2: 1 and grade-specific 
treatment recommendations are summarized in Table 10.1.2: 2. For dose adjustment of 
afatinib (Giotrif®) refer to Table 4.1.4.1: 1.


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Specific interventions should be reassessed at least after 2 weeks or at any worsening of 
symptoms, in which case the specific intervention should be adjusted and, depending on own 
clinical experience, early involvement of a dermatologist should be considered. (Adapted 
from R11-0826)
Patients with an intolerable NCI-CTCAE grade 2 or who develop a grade 3 or higher 
dermatological event should be referred to a dermatologist, with prior experience of treating 
patients who have received EGFR therapy, for a more appropriate dermatologic treatment 
option.
Table 10.1.2: 1
General recommendations for prophylaxis while receiving afatinib
(Giotrif®)
Personal hygiene
Use of gentle soaps and shampoos for the body, e.g. pH5 neutral bath and 
shower formulations and tepid water.
Use of very mild shampoos for hair wash.
Only clean and smooth towels are recommended because of potential risk of 
infection. The skin should be patted dry after a shower, whereas rubbing the skin 
dry should be avoided.
Fine cotton clothes should be worn instead of synthetic material.
Shaving has to be done very carefully.
Manicure, i.e. cutting of nails, should be done straight across until the nails no 
longer extend over the fingers or toes. Cuticles are not allowed to be trimmed 
because this procedure increases the risk of nail bed infections.
Sun protection
Sunscreen should be applied daily to exposed skin areas regardless of season. 
Hypoallergenic sunscreen with a high SPF (at least SPF30, PAPA free, 
UVA/UVB protection), preferably broad spectrum containing zinc oxide or 
titanium dioxide are recommended.
Patients should be encouraged to consequently stay out of the sun.
Protective clothing for sun protection and wearing a hat should be recommended.
Moisturizer treatment
It is important to moisturize the skin as soon as anti-EGFR therapy is started.
Hypoallergenic moisturizing creams, ointments and emollients should be used 
once daily to smooth the skin and to prevent and alleviate skin dryness.
Note: avoid greasy creams (e.g. petrolatum, soft paraffin, mineral oil based) and 
topical acne medications.
Prevention of paronychia 
Patients should keep their hands dry and out of water if ever possible.
They should avoid friction and pressure on the nail fold as well as picking or 
manipulating the nail.
Topical application of petrolatum is recommended around the nails due to its 
lubricant and smoothing effect on the skin.


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Table 10.1.2: 2
Grade specific treatment recommendations of skin reactions to 
afatinib (Giotrif®)
Severity 
(CTCAE Grading)
Description
Specific intervention
ACNEIFORM RASH
Mild (Grade 1)
Macular or papular eruptions or 
erythema without associated 
symptoms
Topical steroids (e.g., moderate/low 
strength: triamcinolone acetonide 0.025%, 
desonide 0.05%, alclometasone 0.05%, 
fluticasone propionate 0.05%, 
hydrocortisone acetate 1%) or tacrolimus 
ointment alternative.
Consider topical antibiotics (b.i.d) e.g.: 
clindamycin 1-2%, or topical erythromycin 
1-2% cream of metronidazole 1% or topical 
nadifloxacin 1%;                                
Isolated scattered lesion: cream preferred 
Multiple scattered areas: lotion preferred
Moderate (Grade 2)
Macular or papular eruptions with 
pruritus or other associated 
symptoms; localized desquamation 
or other lesions covering <50% of 
BSA 
Topical steroid treatment as for Grade 1 
oral antibiotic (for 6 weeks) e.g., 
Doxycycline 100 mg b.i.d, Minocycline 
hydrochloride 100mg b.i.d. or, if available, 
oxytetracycline 500 mg b.i.d; stop topical 
antibiotic if being used.
Severe (Grade 3)
Severe, generalized erythroderma or 
macular, popular or vesicular 
eruption; desquamation covering ≥ 
50% of BSA; associated with pain, 
disfigurement, ulceration or 
desquamation 
Topical and systemic treatment as for 
Grade 2. 
If infection suspected (yellow crusts, 
purulent discharge, painful skin/nares):

Switch to oral antibiotic to broad 
spectrum/gram negative cover

Consider skin swab for bacterial 
culture 
Life threatening 
(Grade 4)
Generalized exfoliative, ulcerative, 
or bullous dermatitis 
See Grade 3 


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Table 10.1.2: 2 (continued)
Grade specific treatment recommendations of skin reactions to 
afatinib (Giotrif®) (Page 2 of 3)
Severity 
(CTCAE Grading)
Description
Specific intervention
EARLY AND LATE XEROTIC SKIN REACTIONS - PRURITUS
Mild (Grade 1)
Mild or localized 
Topical steroid moderate strength OR 
topical anti-pruritics (pramoxine 1%, 
doxepin 5% cream) applied b.i.d
Moderate (Grade 2)
Intense or widespread 
See Grade 1 plus oral antihistamines (e.g: 
levocetirizine 5 mg qd, desloratadine 5 mg 
qd, diphenhydramine 25–50 mg t.i.d, 
hydroxyzine 25 mg t.i.d, fexofenadine 60 
mg t.i.d)
Severe (Grade 3)
Intense or widespread and interfering 
with ADL 
Oral antihistamines (e.g: 
levocetirizine 5 mg qd, desloratadine 5 mg 
qd, diphenhydramine 25–50 mg t.i.d, 
hydroxizine 25 mg t.i.d, fexofenadine 60 
mg t.i.d) AND GABA agonists (e.g.: (adjust 
if renal impairment): gabapentin 300 mg 
every 8 hours, pregabalin 50–75 mg every 
8 hours) OR tricyclics: (e.g.: doxepin 
25–50 mg every 8 hours)
XEROSIS (DRY SKIN)
Mild (Grade 1)
Asymptomatic 
Over-the-counter moisturizing cream or 
ointment to face b.i.d AND ammonium 
lactate 12% cream to body b.i.d.
Moderate (Grade 2)
Symptomatic, not interfering with 
ADL 
Over-the-counter moisturizing cream or 
ointment to face b.i.d AND ammonium 
lactate 12% cream to body b.i.d. OR 
salicyclic acid 6% cream to body b.i.d. 
Severe (Grade 3)
Symptomatic, 
interfering with ADL 
See Grade 2. 
Topical steroids of higher potency (e.g. 
prednicarbate, mometasone furoate) 
Consider oral antibiotics 
Over-the-counter moisturizing cream or 
ointment to face b.i.d AND ammonium 
lactate 12% cream to body b.i.d. OR 
salicyclic acid 6% cream to body b.i.d. 
AND topical steroid (moderate/low 
strength; e.g.: triamcinolone acetonide 
0.025%, desonide 0.05%, alclometasone 
0.05%, fluticasone propionate 0.05%) to 
eczematous area b.i.d


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Table 10.1.2: 2 (continued)
Grade specific treatment recommendations of skin reactions to 
afatinib (Giotrif®) (Page 3 of 3)
Severity 
(CTCAE Grading)
Description
Specific intervention
FISSURES
Mild (Grade 1)
Asymptomatic 
Petroleum jelly, Vaseline® or Aquaphor for 
30 minutes under plastic occlusion every 
night followed by application of 
hydrocolloid dressing; antiseptic baths; or 
topical applications.
Moderate (Grade 2)
Symptomatic, not interfering with 
ADL 
See Grade 1. 
Consider oral antibiotics. 
Severe (Grade 3)
Symptomatic, 
Interfering with ADL 
See Grade 2. 
If Grade 2 rash persists for ≥7 days despite treatment and is poorly tolerated by the patient, the investigator 
may choose to pause treatment up to 14 days followed by a reduction in the dose of afatinib (Giotrif®) 
according to the dose reduction scheme in Table 4.1.4.1: 1
10.1.3
Management of mucositis/stomatitis
General and grade specific recommendations are described in Table 10.1.3: 1. For dose 
adjustment refer to Section 4.1.4.1 and for restrictions on concomitant therapies refer to 
Sections 4.2.2.
Treatment is supportive and aimed at symptom control. These may include atraumatic 
cleansing and rinsing with non-alcoholic solutions such as normal saline, diluted salt and 
baking soda solution (e.g. one-half teaspoonful of salt and one teaspoon of baking soda in one 
quart of water every four hours); avoidance of agents containing iodine, thyme derivatives 
and prolonged use of hydrogen peroxide; dietary maneuvers such as promotion of soft, non 
irritating foods like ice-creams, mashed/cooked vegetables, potatoes and avoidance of spicy, 
acidic or irritating foods such as peppers, curries, chilies, nuts and alcohol. If the patient is 
unable to swallow foods or liquids, parenteral fluid and/or nutritional support may be needed. 
Examples of some of the agents suggested in Table 10.1.3: 1 include: topical analgesics –
viscous lidocaine 2%; mucosal coating agents - topical kaolin/pectin; oral antacids, 
maltodextrin, sucralfate; topical antifungals – nystatin suspension. (Adapted from 
P11-09424)


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Table 10.1.3: 1
Grade specific treatment recommendations for afatinib (Giotrif®) 
related mucositis/stomatitis
Severity               
(CTCAE Grading)
Description
Treatment 
recommendations 
Intervention concerning 
afatinib (Giotrif®) 
treatment/dose 
modification 
Mild (Grade 1)
Minimal symptoms; 
normal diet 
Oral rinses with agents 
such as non-alcoholic 
mouth wash, normal 
saline, diluted salt and 
baking soda solution. 
No change. 
Moderate (Grade 2)
Symptomatic, but 
can eat and swallow 
modified diet 
Addition of topical 
analgesic mouth 
treatments, topical 
corticosteroids, antiviral 
therapy if herpetic 
infection confirmed, 
antifungal therapy 
preferably topical on a 
case by case basis. 
Maintain dose if tolerable; 
Hold dose if intolerable 
until recovery to grade ≤1, 
then restart at the same 
dose. 
Severe (Grade 3)
Symptomatic and 
unable to adequately 
aliment or hydrate 
orally 
Same as for Grade 2; 
institute additional 
symptomatic therapy 
(topical or systemic) as 
clinically indicated. 
Hold dose until recovery to 
grade ≤1 or baseline, then 
restart at the reduced dose 
according to 
Section 4.1.4.1. 
Life threatening 
(Grade 4)
Symptoms 
associated with life-
threatening 
consequences 
Same as for Grade 2; 
institute additional 
symptomatic therapy 
(topical or systemic) as 
clinically indicated. 
Hold dose until recovery to 
grade ≤1 or baseline, then 
restart at the reduced dose 
according to 
Section 4.1.4.1. 


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10.2
NEW YORK HEART ASSOCIATION CLASSIFICATION OF HEART 
FAILURE
Class
Patient Symptoms
Class I (Mild)
No limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, or dyspnoea (shortness of 
breath)
Class II (Mild)
Slight limitation of physical activity. Comfortable at rest, but 
ordinary physical activity results in fatigue, palpitation, or dyspnoea.
Class III 
(Moderate)
Marked limitation of physical activity. Comfortable at rest, but less 
than ordinary activity causes fatigue, palpitation, or dyspnoea.
Class IV (Severe)
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical activity is 
undertaken, discomfort is increased.


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10.3
LIST OF POTENT INHIBITORS AND INDUCERS OF P GLYCOPROTEIN 
(MDR1)
Inhibitors
Inducers
Amiodarone
Azithromycin
Captopril
Carvedilol
Clarithromycin 
Conivaptan
Cyclosporine 
Diltiazem
Dronedarone
Erythromycin
Felodipine
Itraconazole
Ketoconazole
Lopinavir
Nelfinavir
Ritonavir
Quinidine
Ranolazine
Saquinavir
Tacrolimus
Ticagrelor
Verapamil
Carbamazepine
Phenytoin
Rifampicin
St John’s Wort
Phenobarbital Salt
Tipranavir
Ritonavir
As the information on potent inhibitors and inducers of P-glycoprotein may evolve, it is 
important for the investigator to assess such status on concomitant therapies and in case of 
questions contact BI clinical monitor.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
5 November 2013
EudraCT number
2009-017661-34
BI Trial number
1200.55
BI Investigational Product(s)
Afatinib (BIBW 2992)
Title of protocol
An open label trial of afatinib (Giotrif®) in 
treatment-naïve (1st line) or chemotherapy pre-
treated  patients with locally advanced or 
metastatic non-small cell lung cancer (NSCLC) 
harboring EGFR mutation(s)
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
X
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
Description of change
Added: Giotrif®
Rationale for change
Approved name of the marketed drug
Section to be changed
Page 1
Description of change


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Phone:
   Fax :
Was changed to: 
Phone: 
Fax : 
Rationale for change
International coordinator moves to another 
hospital.
Section to be changed
Flowchart,  3.3.2 Inclusion criteria, 3.3.4 
Removal of patients from therapy or assessments, 
4.1.4.1 Dose reduction scheme, Section 5.2.4 
Electrocardiogram, 5.2.5.3 Left ventricular 
function, Table 6.2.1:1 Visit 1 /Day -1 –
Screening and dispensing visit, Table 6.2.2:1
Visit 2/Day 28 (-7/+2) and every 28 (-7/+2) days 
onwards - treatment and safety evaluation, Table 
6.2.3:1 End of Treatment (EOT) Visit
Description of change
Flowchart, Note 3 “To be conducted at screening 
and at every 12 weeks thereafter by either ECHO 
or MUGA scans. For LVEF evaluations, the 
assessment can occur ±7 days of the scheduled 
Day 1 of the corresponding cycle”
Was changed to:
“ECG/LVEF to be conducted for patients with 
cardiac risk factors at the discretion of the 
investigator and in accordance to the current 
standard of care.  In  patients with ejection 
fraction below the institution’s lower limits of 
normal, cardiac consultation as well as afatinib 
(Giotrif®) treatment interruption or 
discontinuation should be considered.”
Deleted: note 8 in the Flowchart.


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Section 3.3.2, Deleted: Inclusion criterion 4a 
“Left Ventricular Ejection Fraction (LVEF) > 
50% or within institution normal values.”
Section 3.3.4, Deleted: “deterioration in left 
ventricular cardiac function (LVEF) to CTCAE 
Grade ≥3.”
Section 4.1.4.1, Deleted: “Patients will 
discontinue treatment if they experience 
deterioration in left ventricular cardiac function 
(LVEF) to CTCAE Grade ≥3.”
In section 5.2.4, “A 12-lead ECGs will be 
performed at Screening visit (see Flow chart). All 
post screening ECGs are optional and should be 
performed at the discretion of the investigator and 
in accordance to local current standard of care.
ECGs will be completed locally at the trial sites. 
ECG machines used for this trial should be able to 
indicate QTc interval. The investigator will 
review the ECG recording at the time of the visit 
and record any ECG abnormality that meets AE 
criteria.”
Was changed to:
“Twelve-lead ECGs will only be performed 
locally at the trial sites at the discretion of the 
investigator in accordance to local current 
standard of care for patients (see Flow chart). 
When performed, the investigator will review the 
ECG recording at the time of the visit and record 
any ECG abnormality that meets AE criteria.” 
In section 5.2.5.3 “Left Ventricular Ejection 
Fraction (LVEF) as measured by 
Echocardiography (ECHO) or Multiple Gated 
Acquisition scan (MUGA) will be assessed at: 
Screening visit, every 12 weeks thereafter and at 
EOT visit (see Flow chart). The same method of 
measurement must be used throughout the trial. 
LVEF at EOT does not need to be performed if 
assessment was already done within previous 8 
weeks. Requirement for EOT-LVEF assessment 
may be waived for patients meeting all the 
following criteria: 1) too sick from their disease 


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or disease related symptoms to travel in the 
opinion of the investigator, 2) have evidence of 
stable LVEF on the most recent on-treatment 
assessment, and 3) have no evidence of 
cardiovascular disease”
Was changed to
“Left Ventricular Ejection Fraction (LVEF) as 
measured by Echocardiography (ECHO) or 
Multiple Gated Acquisition scan (MUGA) will be 
assessed if clinically indicated. The testing of this 
function  and cardiac monitoring  should be 
considered  in patients that develop relevant
cardiac signs/symptoms during treatment. In 
patients with an ejection fraction below the 
institution’s lower limit of normal, cardiac 
consultation as well as afatinib treatment 
interruption or discontinuation should be 
considered. “
In Table 6.2.1:1, “12-lead resting ECG will be 
performed at the discretion of the investigator.”
and “Verify that this ECG was performed”.
Were changed to:
“12-lead resting ECG may be performed at the 
discretion of the investigator.” and “Verify if an 
ECG was performed.”
In Table 6.2.1:1, 6.2.2:1 and 6.2.3:1, Added:
“only for patients with cardiac risk factors and 
those with condition that can affect LVEF, at the 
discretion of the investigator and in accordance to 
the current standard of care.”
In Table 6.2.1:1 and 6.2.3:1, “Verify that an 
ECHO (or MUGA) was performed.”
Was changed to:
“Verify if  an ECHO (or MUGA) was 
performed.”
In Table 6.2.1:1, Deleted: “Verify that LVEF > 
50% or within institutional normal values.”
Rationale for change
ECG/LFEV assessments to be performed only if 
clinically indicated.
Left ventricular dysfunction has been associated 
with HER2 inhibition. Based on the available 


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clinical trial data, there is no suggestion that 
afatinib causes an adverse effect on cardiac 
contractility. However, afatinib has not been 
studied in patients with abnormal left ventricular 
ejection fraction (LVEF) or those with significant 
cardiac history. In patients with cardiac risk 
factors and those with conditions that can affect 
LVEF, cardiac monitoring, including an 
assessment of LVEF at baseline and during 
afatinib treatment, should be considered. In 
patients that develop relevant cardiac 
signs/symptoms during treatment, cardiac 
monitoring including LVEF assessment should be 
considered.
Section to be changed
Flowchart, 5.2.2.1 Definitions of adverse events
Description of change
Flowchart, Note D, Added: At cycle 1 and 2
Section 5.2.2.1, Added: for the first two cycles
Rationale for change
Clarification on when dispensing the diary
Section to be changed
Flowchart, 6.1.1 Screening & dispensing visit, 
Table 6.2.2:1
Description of change
Flowchart, Note P “A phone call is required”
Was changed to:
“A contact is required”
Section 6.1.1 “A phone call is required 15 (± 3) 
days after the patient’s first dose to assess any 
AEs.” 
Was changed to:
“A contact is required 15 (± 3) days after the 
patient’s first dose to assess any AEs.” 
In Table 6.2.2:1, “phone call” 
Was changed to:
“contact”
Rationale for change
Clarification on procedures.
Section to be changed
Flowchart, 5.2.2.1 Definitions of adverse events, 
5.2.2.2 Adverse event and serious adverse event 
reporting, Table 5.2.2.2:1 AE/SAE reporting 
requirements, Appendix 10.3 Adverse 


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event/Serious Adverse Event Reporting
Description of change
In the flowchart “In addition, any SAE that the 
treating physician becomes aware of after this 
period should also be reported”
Was changed to:
“The investigator does not need to actively 
monitor patients for adverse events once the 
clinical trial has ended. However, if the 
investigator becomes aware of an SAE(s) that 
occurred after the patient has completed the 
clinical trial (including any protocol required REP 
and / or follow-up), it should be reported by the 
investigator to the sponsor if considered relevant 
by the investigator.”
In section 5.2.2.1 “In addition, any SAE that the 
treating physician becomes aware of after this 
period should also be reported”
Was changed to
“The investigator does not need to actively 
monitor patients for adverse events once the 
clinical trial has ended. However, if the 
investigator becomes aware of an SAE(s) that 
occurred after the patient has completed the 
clinical trial (including any protocol required REP 
and / or follow-up), it should be reported by the 
investigator to the sponsor if considered relevant 
by the investigator.”
In table 5.2.2.2:1 “Report any SAE that the 
treating physician becomes aware of. This 
includes all deaths.”
Was changed to
“The investigator does not need to actively 
monitor patients for adverse events once the 
clinical trial has ended. However, if the 
investigator becomes aware of an SAE(s) that 
occurred after the patient has completed the 
clinical trial (including any protocol required REP 
and / or follow-up), it should be reported by the 
investigator to the sponsor if considered relevant 
by the investigator.”
In section 5.2.2.2, deleted: “A diagram of the 
Adverse Event/Serious Adverse Event reporting 
requirements is provided in Appendix 10.3.“


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Appendix 10.3 has been deleted.
Rationale for change
Variation on SAEs reporting after FU period.
Section to be changed
1.1 Medical background, 2.3 Benefit – Risk 
Assessment
Description of change
In section 1.1, Added: “Lastly, in trial 1200.34
(LUX-Lung 6), afatinib treatment compared to 
gemcitabine/cisplatin as first-line treatment for 
patients with Stage IIIB or IV adenocarcinoma 
resulted in a prolonged PFS and higher ORR 
observed in patients treated with afatinib (P13-
06250).”
In section 2.3, Added: “In addition, data from a 
third study, a Phase III open label, randomized 
trial in Asian patients with EGFR mutation-
positive advanced adenocarcinoma of the lung, 
confirmed these results.”
and added:
“1200.34 (LUX-Lung 6)
More recent evidence of the benefits of afatinib 
(Giotrif®) versus chemotherapy in EGFR TKI-
naïve asian patients with NSCLC was obtained in 
trial 1200.34, an open-label, randomized,  Phase 
III trial of afatinib (Giotrif®) versus 
chemotherapy as first-line treatment for patients 
with Stage IIIB or IV adenocarcinoma of the lung 
harboring an EGFR activating mutation who had 
received no prior chemotherapy or EGFR-
targeting drugs for  advanced NSCLC. The 
primary objective of the study was to assess the 
efficacy of afatinib (Giotrif®) as defined by 
progression-free survival (PFS) by central 
independent review and determined by Response 
Evaluation Criteria in Solid Tumors (RECIST). 
Secondary endpoints included ORR, disease 
control rate (DCR), duration of response, tumor 
shrinkage, overal survival (OS), patient-reported 
outcomes (PRO), and safety and pharmicokinetics 
of afatinib (Giotrif®). A central test for EGFR 
mutations was carried out using the companion 
diagnostic TheraScreen® EGFR RGQ PCR kit. 
Three hundred and sixty four (364) patients were 
randomised in a 2:1 ratio to receive either afatinib 
(n=242) 40 mg daily continuous treatment in the 
absence of disease progression or adverse events, 


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or Gemcitabine/Cisplatin (GC) (n=122), with 
Gemcitabine 1000 mg/m2 on Day 1 and Day 8, 
with cycplatin 75 mg/m2 every 21 days up to 6 
cycles. Baseline characteristics were well 
balanced between arms: overall the median age 
was 58 years, 65% of patients were female, 77% 
were never-smokers and 94% had Stage IV 
disease. Regarding EGFR mutation status, 51% 
had deletions in exon 19 (Del19), 38% had the 
L858R mutation and 11% had a variety of other 
less common mutations.
As assessed by central independent review, 
treatment with afatinib (Giotrif®) resulted in a 
significantly prolonged PFS as compared to 
treatment with GC (median 11.0 vs. 5.6 months, 
HR 0.28, p<0.0001). The ORR for patients treated 
with afatinib (66.9%) was significantly higher 
than that for patients treated with GC (23%) 
(p<0.0001). The prolonged PFS and higher ORR 
observed in patients treated with afatinib 
(Giotrif®) were accompanied by significant 
delays (as compared to patients treated with GC) 
in time to deterioration of the cancer-related 
symptoms of cough (HR=0.45, p=0.0001) and 
dyspnoea (HR=0.54, p<0.0001). The pre-
specified number of events necessary to Overall 
Survival (OS) has not yet been reached.
The incidence of patients with AEs leading to 
dose reduction was 32.2% in the afatinib 
(Giotrif®) arm and 26.5% in the chemotherapy 
arm. In the afatinib (Giotrif®)  arm, drug-related 
AEs leading to treatment discontinuation were 
experienced by 5.9% of the patients as compared 
to 39.8% of the patients in the chemotherapy arm.  
The most frequent reported afatinib-related AEs 
were diarrhoea, rash/acne and stomatitis. The 
most frequent reported chemotherapy-related AEs 
were nausea/vomiting , fatigue, and bone-marrow 
suppresion. There were 14 deaths (5.9%) reported 
due to on-treatment AEs in the afatinib (Giotrif®)  
arm, and three deaths (2.7%) were reported due to 
on-treatment AEs in the chemotherapy group.  
Significant differences between the proportion of 
patients with improvements in lung cancer 
symptoms  of cough, dyspnoea, and pain were 


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observed with patient in afatinib (Giotrif®) arm 
compared to chemotherapy ( P13-06250). Taken 
together, these results support the efficacy data 
and conclusions of LUX-Lung 3.”
In Table 2.3:1, added data on 1200.43.
Rationale for change
Data on trial 1200.34 available
Section to be changed
3.3 Selection of trial population
Description of change
The statement “A log of all patients included into 
the study (i.e. having given informed consent) 
will be maintained in the ISF at the 
investigational site irrespective of whether they 
have been treated with investigational drug or 
not” was reported twice, and one has been deleted
Rationale for change
Typo
Section to be changed
4.1.1 Identity of BI investigational product and 
comparator products; 4.1.6 Packaging, labelling, 
and re-supply
Description of change
In section 4.1.1, “Core Tablet: Lactose 
monohydrate, Microcrystalline cellulose, 
Colloidal silicon dioxide, Crospovidone, and 
Magnesium stearate. Film-coat: Hypromellose 
2910, Polyethylene glycol 400, Titanium dioxide, 
Talc, FD&C Blue No. 2 11-14% (not included in 
20 mg tablet), and Polysorbate 80.”
Was changed to:
Core Tablet: Lactose monohydrate,
Microcrystalline cellulose, Colloidal silicon 
dioxide, Crospovidone, and Magnesium stearate. 
Film-coat: Hypromellose 2910, Polyethylene 
glycol 400, Titanium dioxide, Talc, FD&C Blue 
No. 2 11-14% (may not be included in 20 mg 
tablet), and Polysorbate 80.
In section 4.1.6 “Afatinib (Giotrif®) will be 
supplied by BI (or a designated 3rd party drug 
distribution vendor) as film-coated tablets in 
High-Density Polyethylene (HDPE), child-
resistant, tamper-evident bottles. Available 
dosage strengths will be 40 mg, 30 mg and 20 mg. 
Each plastic bottle will contain 30 tablets of 


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identical dosage strength.”
Was changed to:
“Afatinib (Giotrif®) will be supplied by BI (or a 
designated 3rd party drug distribution vendor) as 
film-coated tablets. Available dosage strengths 
will be 40 mg, 30 mg and 20 mg. Tablets will be 
supplied in child-resistant, tamper-evident bottles. 
Each bottle will contain 30 tablets of identical 
dosage strength.”
Rationale for change
Possible change in image tablets and bottles.
Section to be changed
4.2.1 Rescue medication, emergency procedures, 
and additional treatment(s)
Description of change
Added: Patients who present with symptoms of 
keratitis, such as acute or worsening eye 
inflammation, lacrimation, light sensitivity, 
blurred vision, eye pain and/or red eye should be 
referred promptly to an ophthalmic specialist. If a 
diagnosis of ulcerative keratitis is confirmed, 
treatment with afatinib should be interrupted or 
discontinued. If keratitis is diagnosed, the benefits 
and risks of continuing treatment with afatinib 
should be carefully considered. Afatinib should 
be used with caution in patients with a history of 
keratitis, ulcerative keratitis or severe dry eye. 
Contact lens use is a risk factor for keratitis and 
ulceration.
Rationale for change
New information.
Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment, Appendix 10.3 List of potent inhibitors 
and inducers of P glycoprotein (MDR1)
Description of change
“Strong inhibitors of P-gp (including: 
Amiodarone, Azithromycin, Captopril, 
Carvedilol, Clarithromycin, Conivaptan, 
Cyclosporine, Diltiazem, Dronedarone, 
Erythromycin, Felodipine, Itraconazole, 
Ketoconazole, Lopinavir, Nelfinavir, Ritonavir, 
Quinidine, Ranolazine, Saquinavir, Tacrolimus, 
Ticagrelor, Verapamil) if administered prior to 
afatinib may lead to increased exposure to 
afatinib and therefore should be used with 


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caution. If P-gp inhibitors (including: 
Carbamazepine, Phenytoin, Rifampicin, St John’s 
Wort, Phenobarbital Salt, Tipranavir, Ritonavir) 
need to be taken, they should be administered 
simultaneously with or after afatinib. 
Concomitant treatment with strong inducers of P-
gp may decrease exposure to afatinib (U12-1482-
01).”
Was changed to:
“Caution should be exercised when combining 
afatinib (Giotrif®) with P-gp modulators.  For a 
list of potent P-gp inhibitors and inducers see 
Appendix 10.3.”
Added: Appendix 10.3
Rationale for change
Updated information.
Section to be changed
3.3.3 Exclusion criteria, 4.2.3 Contraception and 
pregnancy
Description of change
Section 3.3.3, exclusion criterion n. 7 “are 
Women of Child-Bearing Potential (WOCBP) 
and men who are able to father a child, unwilling 
to use adequate contraception prior to trial entry, 
for the duration of trial participation and for at 
least 2 weeks after treatment has ended.”
Was changed to:
“are Women of Child-Bearing Potential 
(WOCBP) and men who are able to father a child, 
unwilling to use adequate contraception prior to 
trial entry, for the duration of trial participation 
and for at least 28 days after treatment has 
ended.”
Section 4.2.3, “Women of childbearing potential 
who are sexually active and not using an 
acceptable method of birth control during the trial 
and for at least 14 days after the end of active 
therapy are not allowed to participate in the trial.”
Was changed to:
“Women of childbearing potential who are 
sexually active and not using an acceptable 
method of birth control during the trial and for at 


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least 28 days after the end of active therapy are 
not allowed to participate in the trial.”
“Male patients should use adequate contraception 
(e.g., condom and spermicidal jelly) during the 
trial and for at least 14 days after the end of active 
therapy.”
Was changed to:
“Male patients should use adequate contraception 
(e.g., condom and spermicidal jelly) during the 
trial and for at least 28 days after the end of active 
therapy.”
Rationale for change
Acceptable methods of birth control should be 
used for at least 28 days after the end of active 
therapy to align to the SPC.
Section to be changed
4.2.3 Contraception and pregnancy
Description of change
Deleted: Abstinence is not an acceptable method 
of birth control for this trial.
Rationale for change
The method is acceptable
Section to be changed
Table 4.2.3: 1 Pregnancy reporting
Description of change
Added: “and congenital malformation/anomaly”
Rationale for change
Also congenital malformation/anomaly must be 
reported as SAE.
Section to be changed
5.3.2.1 Documentation of diarrhoea
Description of change
“dehydration” 
Was changed to:
“hydration”
Rationale for change
Typo.
Section to be changed
Table 6.2.1:1, Table 6.2.2:1, Table 6.2.3:1, Table 
6.2.4:1
Description of change
Added: “and all SAEs”
Rationale for change
Clarification.
Section to be changed
9.1 Published references


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Description of change
Added: “P13-06250 Wu YL, Zhou C, Hu CP, 
Feng JF, Lu S, Huang Y, Li W, Hou M, Shi JH, 
Lee KY, Massey D, Shi Y, Chen J, Zazulina V, 
Geater SL.   LUX-Lung 6: a randomized, open-
label, phase III study of afatinib (A) vs 
emcitabine/cisplatin (GC) as first-line treatment 
for Asian patients (pts) with EGFR mutation-
positive (EGFR M+) advanced adenocarcinoma 
of the lung.   49th Ann Mtg of the American 
Society of Clinical Oncology (ASCO), Chicago, 
31 May - 4 Jun 2013 J Clin Oncol 31 (Suppl), 
(2013)”
Rationale for change
New reference.
Number of global amendment
2
Date of CTP revision
17 Jul 2017
EudraCT number
2009-017661-34
BI Trial number
1200.55
BI Investigational Product(s)
Afatinib (BIBW 2992)
Title of protocol
An open label trial of afatinib (Giotrif®) in 
treatment-naïve (1st line) or chemotherapy pre-
treated  patients with locally advanced or 
metastatic non-small cell lung cancer (NSCLC) 
harboring EGFR mutation(s)
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
X
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


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Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Number of entered patients changed from up to 
500 to 481
Rationale for change
To reflect the actual number
Section to be changed
Clinical Trial Protocol Synopsis – Duration of 
treatment and Section 3: Description of design 
and trial population
Description of change
The following sentence has been added: 
“…and/or have access to Afatinib via options 
included but not limited to an alternative clinical 
trial, marketed product, an expanded-access 
program, named patient use program, 
compassionate use protocol or other means based 
on local regulation,…”
Rationale for change
To ensure an on-going supply to patients who 
have not yet met the criteria for ceasing study 
treatment and to allow completion of the trial
Section to be changed
Section 3.3.4.1:
Description of change
The following statement has been added: 
Study treatment can be continued beyond 
radiological progression only (without 
symptomatic progression) until clinical 
progression if it is deemed in the patient’s benefit 
following a careful risk benefit assessment and 
confirmation of clinical benefit by the 
investigator. Each case must be discussed in 
details and agreed between the investigator and 
the Sponsor, and only after sponsor approval, the 
trial treatment can continue.
Rationale for change
Clarification 
Section to be changed
Section 3.3.4.1 Removal of individual patients
Description of change
The sponsor may remove patients from the study 
if the patient has access to afatinib via options 
included but not limited to an alternative clinical 
trial, marketed product, an expanded-access 
program, named patient use program, 
compassionate use protocol or other means based 
on local regulation. This may mean a change in 
packaging and labelling. The cost of any ongoing 
supply of study medication will be incurred by the 
sponsor until progression occurs. If a patient is 


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removed from the study treatment, an end of 
treatment 0-14 days later and a follow up visit 28 
days later will be performed to ensure all adverse 
events are followed up and then the patient will 
be considered to have completed the trial.
Rationale for change
To ensure an on-going supply to patients who 
have not yet met the criteria for ceasing study 
treatment and to allow completion of the trial
Section to be changed
Section 3.3.4.2: Discontinuation of the trial by the 
Sponsor
Description of change
The following point has been added: 
4.At the discretion of the sponsor. Drug supply 
will be arranged for ongoing patients if Sponsor 
decides to terminate the trial. 
Rationale for change
To ensure an on-going supply to patients who 
have not yet met the criteria for ceasing study 
treatment and to allow completion of the trial
Section to be changed
Section 7.3.4: Interim analyses 
Description of change
The following sentence has been added: “This is a 
single-arm open label study. The interim analysis 
may be done after recruitment has been 
completed. The analyses will include the 
assessment of safety and efficacy if conducted. 
The result from the interim analysis may be 
presented at professional conferences and 
published in articles after stop of recruitment.”
Rationale for change
Include interim analysis in protocol.
Number of global amendment
3
Date of CTP revision
08 Feb 2020
EudraCT number
2009-017661-34
BI Trial number
1200.55
BI Investigational Product(s)
Afatinib (BIBW 2992)
Title of protocol
An open label trial of afatinib (Giotrif®) in 
treatment-naïve (1st line) or chemotherapy pre-
treated  patients with locally advanced or 
metastatic non-small cell lung cancer (NSCLC) 
harboring EGFR mutation(s)
To be implemented only after 
approval of the 
X


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Number of global amendment
3
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
Flow chart
Description of change
The following footnotes have been added:
8  In the event of force majeure or other 
disrupting circumstances (e.g. pandemic, war), 
shipment of trial medication to patient’s home 
may be arranged or dispensation of two kits may 
be done.
*** In the event of force majeure or other 
disrupting circumstances (e.g. pandemic, war), 
patient visits may be performed remotely.
Rationale for change
Experiences from the COVID-19 first wave
situation; to allow flexibility in visit conduct in 
case required due to pandemic or other 
exceptional situations to ensure patients safety by 
ensuring continuous treatment.
Section to be changed
Cover page; Abbreviations;
Section 3.1.1 Administrative structure of the trial
Section 8.1 Study approval, Patient Information, 
and Informed Consent
Description of change
The following wording:
TCM Trial Clinical Monitor
CML Local Clinical Manager


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Number of global amendment
3
was changed to:
CTL Clinical Trial Leader
CTM Clinical Trial Manager
Rationale for change
Administrative change
Section to be changed
2.3 Benefit – risk assessment
Description of change
The following wording has been added:
Gastrointestinal perforation, including fatalities, 
has been reported during treatment with afatinib 
in 0.2% of patients across all randomized 
controlled clinical trials. In the majority of cases, 
gastrointestinal perforation was associated with 
other known risk factors, including concomitant 
medications such as corticosteroids, NSAIDs, or 
anti-angiogenic agents, an underlying history of 
gastrointestinal ulceration, underlying diverticular 
disease, age, or bowel metastases at sites of 
perforation. In patients who develop 
gastrointestinal perforation while taking afatinib, 
treatment should be permanently discontinued.
Rationale for change
Update based on the current IB
Section to be changed
Section 2.4 Benefit – risk assessment in context 
of COVID-19 infection.
Description of change
The section has been added.
Rationale for change
New information on benefit/risk due to COVID-
19 pandemic situation.
Section to be changed
3.3.4.1 Removal of individual patients
Table 4.1.4.1: 1 Dose reduction scheme
Description of change
If gastrointestinal perforations is diagnosed, 
afatinib (Giotrif®) must be discontinued and 
patient must complete trial participation.
Rationale for change
According to current IB
Section to be changed
Section 4.1.4 Drug assignment and administration 
of doses for each patient
Description of change
The following statement has been added: 


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Number of global amendment
3
In the event of force majeure or other disrupting 
circumstances (e.g. pandemic, war), physical 
patient visits to the sites may not be feasible or 
may need to be restricted to ensure patient safety. 
Based on a thorough assessment of the benefits 
and risks, the investigator may still decide to 
continue trial treatment. Where permitted by local 
law and regulations, trial medication may be 
shipped directly to the patients’ home or two 
bottles of trial medication may be dispensed at the 
beginning of a treatment cycle, so that the next 
visit can be performed remotely.
Rationale for change
Experiences from the COVID-19 first wave 
situation; to allow flexibility in visit conduct in 
case required due to pandemic or other 
exceptional situations to ensure patients safety by 
ensuring continuous treatment.
Section to be changed
Section 6.1.2: Treatment and safety evaluation 
visits;
Section 6.1.3: End of Treatment (EOT) visit
Description of change
The following statement has been added:
In the event of force majeure or other disrupting 
circumstances (e.g. pandemic, war,) patients visit
may be performed remotely to collect/report study 
data such as adverse events, concomitant 
therapies, clinical evaluation of tumour by 
symptoms and study medication compliance 
check. Where permitted by local law and 
regulations, trial medication may be shipped 
directly to the patients’ home or two bottles of 
trial medication may be dispensed at the 
beginning of a treatment cycle, so that the next 
visit can be performed remotely.
Rationale for change
Experiences from the COVID-19 first wave
situation; to allow flexibility in visit conduct in 
case required due to pandemic or other 
exceptional situations to ensure patients safety by 
ensuring continuous treatment.
Section to be changed
9 References
Description of change
Updates of references


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Number of global amendment
3
Rationale for change
Updates of references


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02215411
17.0
1200-0055--protocol-revision-03
An open label trial of afatinib (Giotrif) in treatment-naive (1st line) or chemotherapy
pre-treated  patients with locally advanced or metastatic non-small cell lung cancer
(NSCLC) harboring EGFR mutation(s)
Approval-Clinical Trial Leader
08 Feb 2021 15:06 CET
Approval-Therapeutic Area
08 Feb 2021 15:13 CET
Approval-Team Member Medicine
10 Feb 2021 09:17 CET
Approval-Team Member Medicine
10 Feb 2021 09:20 CET
Approval-Clinical Trial Leader
10 Feb 2021 09:35 CET
Approval-Therapeutic Area
10 Feb 2021 15:38 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02215411
17.0



SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c01527097-02
BI Trial No.:
1200.55
Title:
An open label trial of afatinib (Giotrif®) in treatment-naïve (1st 
line) or chemotherapy pre-treated patients with locally advanced or 
metastatic non-small cell lung cancer (NSCLC) harboring EGFR 
mutation(s).
Investigational
Product(s):
Afatinib (Giotrif®) (BIBW 2992)
Responsible trial 
statistician(s):
Phone:
Fax: 
Phone: 
Fax: 
Date of statistical 
analysis plan:
12 Jun 2017 Signed
Version:
Final
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1.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1.
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................3
2.
LIST OF ABBREVIATIONS ...............................................................4
3.
INTRODUCTION..................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......7
5.
ENDPOINTS ..........................................................................................8
5.1
PRIMARY ENDPOINT ......................................................................................8
5.2
SECONDARY ENDPOINTS..............................................................................8
5.2.1
Key secondary endpoints................................................................................8
5.2.2
Secondary endpoints .......................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS...........................................10
6.1
TREATMENT....................................................................................................10
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................10
6.3
PATIENT SETS ANALYSED..........................................................................13
6.5
POOLING OF CENTRES ................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................15
7.
PLANNED ANALYSIS.......................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........16
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................17
7.3
TREATMENT COMPLIANCE .......................................................................17
7.4
PRIMARY ENDPOINT ....................................................................................17
7.5
SECONDARY ENDPOINTS............................................................................17
7.5.1
Key secondary endpoints..............................................................................17
7.5.2
Secondary endpoints .....................................................................................17
7.7
EXTENT OF EXPOSURE................................................................................21
7.8
SAFETY ANALYSIS.........................................................................................22
7.8.1
Adverse events ...............................................................................................22
7.8.2
Laboratory data.............................................................................................24
7.8.3
Vital signs and physical examination ..........................................................24
7.8.4
ECG ................................................................................................................24
7.8.5
Others .............................................................................................................24
8.
REFERENCES.....................................................................................25
10.
HISTORY TABLE...............................................................................27


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LIST OF TABLES
Table 6.2: 1
Important protocol violations..........................................................................11
Table 10: 1
History table ....................................................................................................27


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2.
LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the TSAP
Term
Definition / description
AE
BAS
Adverse event
Biomarker analysis set  
BRPM
Blinded report planning meeting
CR
Complete response
CTCAE
Common Terminology Criteria for Adverse Events  
CTP
Clinical Trial Protocol
eCRF
Electronic case report form
ECG
Electrocardiography
ECOG
Eastern Cooperative Oncology Group
EGFR
Epidermal growth factor receptor
EMA
European Medicines Agency
EoT
End of treatment
HEP C
Hepatitis C
HIV
Human Immunodeficiency Virus
ICH
IPV
International Conference on Harmonisation
Important protocol violation
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MI
Myocardial infarction
Min
mRNA
Minimum
Messenger Ribonucleic Acid
N
Denotes number of patients
NSCLC
Non-small cell lung cancer
IPV
Important protocol violation
OR
Objective response
OS
Overall survival
PD
Progressive disease


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Term
Definition / description
PFS
Progression-free survival
PR
Partial response
PP
Per-protocol 
PT
Preferred term
SAE
Serious adverse event
SD
Standard deviation
SD
Stable disease
SOC
System organ class
TKI
Tyrosine kinase inhibitor
TS
Treated set
TSAP
TTSP
Trial statistical analysis plan
Time to symptomatic progression


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3.
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial 
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP Section 7 “Statistical Methods and 
Determination of Sample Size”. Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, 
randomization.
SAS® Version 9.2 or higher will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Section 7.3.2 of the CTP describes the “Secondary Analysis” of the efficacy endpoints.  It 
was decided to consider the efficacy endpoints as further endpoints rather than secondary 
endpoints due to disclosure requirements. Hence this TSAP describes these efficacy 
endpoints as further endpoints in Section 5.3 (Further Endpoints).


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5.
ENDPOINTS
This is an open-label, multi-centre, non-randomised, uncontrolled, single arm trial designed 
to evaluate the safety, tolerability and anti-tumour activity of afatinib (Giotrif®) in patients 
with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR 
mutation(s) and have never been treated with an EGFR-TKI. After the initial screening visit, 
patients will enter the open-label treatment period with safety visits at approximately every 
28 days until the end of the trial. The trial objective is to evaluate the safety tolerability and 
anti-tumour activity of afatinib (Giotrif®) in this cohort of patients. Of main interest are AEs, 
collected throughout the study.
No specific tumour measurements are required in this program.  Disease assessment will be 
based on the assessment of cancer related symptoms, tumour assessment (clinical, 
radiological or other), overall clinical benefit and, if available, radiologic assessments as per 
standard of care at the site.  Data on tumour response, progression-free survival (PFS) and
overall survival (OS) will be collected where possible. 
5.1
PRIMARY ENDPOINT
The number of patients with adverse events according to CTCAE V 3.0.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints 
There are no key secondary endpoints.
5.2.2
Secondary endpoints
There are no secondary endpoints.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT
There is only one treatment in this study, which is afatinib.  The starting dose for all patients 
is 40 mg with an option to reduce the dose to 30 mg or reduce further to 20 mg from 30 mg
based on individual tolerability.  Unless otherwise stated, for all analyses, treated patients will 
be presented under the starting dose.
The following study periods based on key visit dates and actual start and stop dates of study 
treatment administration are defined:

Screening: From day of informed consent to day prior to starting study treatment.
Special handling rule: 
If informed consent date = date of first administration of study treatment, derive start 
of screening phase on the day of informed consent – 1 day.

On-treatment: From day of first administration of study treatment to the day of last 
administration of study treatment.

Residual effect period: From day after last administration of study treatment to the 
28th day after last administration of study treatment

Follow-up: After the residual effect period and up to the last per protocol contact if 
last per protocol contact is after residual effect period.

Post-study: After the last per protocol contact or residual effect period (if last per 
protocol contact is same as 28th day after last administration of study treatment) but 
entered in the database before database lock.
For safety summaries, data recorded up to 28 days after last administration of study treatment 
will be considered as on-treatment (i.e. the actual on-treatment and residual effect periods 
defined above will be combined into one ‘on-treatment’ analysis period).
Safety data recorded after the residual effect period and up to the last per protocol contact 
will be listed as follow-up events. Those recorded after the last per protocol contact but 
entered in the database before lock will be listed as post-study events but not tabulated.
6.2
IMPORTANT PROTOCOL VIOLATIONS
No per protocol (PP) analysis will be performed for this study; however patients with 
potentially important protocol violations (IPVs) will be documented.  The following list of 
potentially IPVs will be used; note that this is a working list and may not be finalised until the 
final Blinded Report Planning Meeting (BRPM) prior to database lock.


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Table 6.2: 1
Important protocol violations
Category / 
Code
Description
Comment/Example
Efficacy/ 
Safety
A
Entrance Criteria Not Met
A1
Inclusion Criteria Not Met
A1.1
Locally advanced or metastatic Non-Small 
Cell Lung Cancer (NSCLC)
Inclusion criterion IN1 not 
met
E
A1.2
Epidermal Growth Factor Receptor (EGFR) 
mutation-positive result per the
institution’s testing methodology.
Inclusion criterion IN2 not 
met
or
EGFR mutation positive 
result is marked as No
E
A1.3
Male or female patients age ≥18 years
Inclusion criterion IN3 not 
met
or
patient’s age <18 years
E/S
A1.4.1
Adequate organ function as defined in 
protocol version 1
Inclusion criterion IN4 not 
met
E/S
A1.4.2
Adequate organ function as defined in 
protocol version 2
Inclusion criterion IN4 not 
met
E/S
A1.5
ECOG score between 0 – 2
Inclusion criterion IN5 not 
met
or
Baseline ECOG score not 
between 0-2
E
A2
Exclusion Criteria Met
A2.1
prior treatment with an EGFR tyrosine kinase 
inhibitor (TKI) 
Exclusion criterion EX1 
met
E
A2.2
Anti-cancer treatment within 2 weeks prior to 
start of trial treatment
Exclusion criterion EX2 
met
E
A2.3
Radiotherapy within 14 days prior to drug 
administration
Exclusion criterion EX3 
met
E
A2.4
Major surgery within 4 weeks before starting 
trial treatment or scheduled for surgery during 
the projected course of the trial
Exclusion criterion EX4 
met
E/S
A2.5
Known hypersensitivity to afatinib or any of 
its excipients
Exclusion criterion EX5 
met
S
A2.6
History or presence of clinically relevant 
cardiovascular abnormalities or MI within 6 
months prior to starting trial treatment
Exclusion criterion EX6 
met
S
A2.7.1
Women of child-bearing potential and men 
who are able to father a child, unwilling to  
use adequate contraception prior to trial entry, 
for the duration of trial participation and for at 
least 2 weeks after treatment has ended
(protocol version 1).  
Exclusion criterion EX7 
met
S
A2.7.2
Women of child-bearing potential and men 
who are able to father a child, unwilling to  
use adequate contraception prior to trial entry, 
for the duration of trial participation and for at 
least 28 days after treatment has ended
(protocol version 2).  
Exclusion criterion EX7 
met
S


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Table 6.2: 1
Important protocol violations (cont.)
Category / 
Code
Description
Comment/Example
Efficacy/ 
Safety
A2.8
Women of child-bearing potential who are 
nursing or pregnant or do not agree to submit 
to pregnancy testing as required by this 
protocol
Exclusion criterion EX8 
met
S
A2.9
Any history of or concomitant condition that, 
in the opinion of the investigator, would 
compromise the patient’s ability to comply 
with the trial or interfere with the evaluation 
of safety for the trial drug
Exclusion criterion EX9 
met
E/S
A2.10
Previous or concomitant malignancies at other 
sites, except effectively treated non melanoma 
skin cancers, carcinoma in situ of the cervix, 
ductal carcinoma in situ or effectively treated 
malignancy that has been in remission for 
more than 3 years and is considered to be 
cured.
Exclusion criterion EX10 
met
E/S
A2.11
Requiring treatment with any of the prohibited 
concomitant medications that cannot be 
stopped for the duration of trial participation
Exclusion criterion EX11 
met
E
A2.12
Known pre-existing interstitial lung disease 
Exclusion criterion EX12 
met
S
A2.13
Presence of poorly controlled gastrointestinal 
disorders that could affect the absorption of 
the trial drug
Exclusion criterion EX13 
met
E
A2.14
Active hepatitis B infection, active Hepatitis C 
(HEP C) and/or known Human 
Immunodeficiency Virus (HIV) carrier.
Exclusion criterion EX14 
met
S
A2.15
Meningeal carcinomatosis
Exclusion criterion EX15 
met
E/S
A2.16
Symptomatic brain metastases
Exclusion criterion EX16 
met
E/S
B
Informed Consent
B1
Informed consent not given
Inclusion criterion IN6 not 
met
or
Written informed consent 
by patient or guardian prior 
to admission into the trial is 
not given.
S
B2
Informed consent given too late
Inclusion criterion IN6 not 
met
S
B3
Incorrect or not updated Informed 
consent given
S
B4
Informed consent conducted by staff 
not on trial staff list 
S
B5
Incomplete informed consent
S
B6
Informed consent not completed by 
patient
S


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Table 6.2: 1
Important protocol violations (cont.)
Category / 
Code
Description
Comment/Example
Efficacy/ 
Safety
C
On Study
C1
Serious GCP non-compliance [e.g.
delayed SAE reporting, expired drugs, 
incorrect trial medication dose, source 
data not available]
S
C2
Incorrect timing of measurements at 
visit days
S
C3
Other PV affecting efficacy and 
possibly safety
E/S
C4
Other PV affecting safety only
S
Note: Missing visits, evaluations, and tests will be considered missing data, not protocol violations. All the potential 
IPVs listed in the table will be identified programmatically.
6.3
PATIENT SETS ANALYSED
Enrolled set (ES)
The enrolled set consists of all patients who signed informed consent.
Treated set (TS)
All planned analyses will be based on the Treated Set (TS) which includes all patients who 
were dispensed study treatment (afatinib) and are documented to have taken at least one dose
of study treatment (afatinib).


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6.5
POOLING OF CENTRES
This section is not applicable because there will be no pooling of centres or countries and no 
modelling thereof.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”).(1)
For efficacy data, the following rules will apply:

For PFS, duration of objective response and duration of disease control, if a patient is 
known to have progressed during the treatment period, but the date of progression is 
not attainable, the following sequence for imputation of progression date will be 
followed:
o
Use the date of cancer-related symptoms assessment or visit date in which the 
progression was recorded (whichever is earliest).
o
If this is missing, the last known visit date or cancer related symptoms
assessment date prior to the recorded progression (regardless of the disease 
assessment result at that visit) will be used.
o
If any such patient has no visit date or cancer related symptoms assessment 
date recorded at all, the date of first administration of study medication will be 
used as the date of disease progression.

For overall survival, if a patient is known to have died (due to any cause), but date of 
death is not attainable, the last date when the patient is known to be alive will be used 
as date of death.
For partial treatment discontinuation date, the following logic is applied:
If month and year are known but day is missing, then use date of death if within the same 
month for a patient who died. Otherwise use last day of the month. 
Missing biomarker values will not be imputed.


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baseline is defined as the last non-missing value prior to first administration of afatinib.  
The time windows for subsequent clinic visits is 28 -7/+2 days.  The end of treatment (EoT) 
visit can be anything up to a maximum of 14 days after the last intake of afatinib and the 
follow-up visit should be between 21 and 28 days after the EoT visit.
Nominal visit numbers as recorded in the eCRF will be used where required and there will be 
no windowing.  
Study day will be calculated relative to the date of the first administration of afatinib.  The 
day prior to first administration of afatinib will be ‘Day -1’ and the day of first administration 
of afatinib will be ‘Day 1’; therefore ‘Day 0’ will not exist.


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7.
PLANNED ANALYSIS
Unless otherwise stated, for end of text tables, the set of summary statistics is: N / Mean / SD 
/ Min / Median / Max.
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group, unless otherwise stated. Percentages will be rounded to one 
decimal place. The category missing will be displayed only if there are actually missing 
values. 
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. Demographic and 
baseline characteristic parameters collected and to be presented include:

Age [years]

Age class  (<65, ≥65 years and <75,≥75 years)

Gender  (Male, Female)

Race (as defined in the eCRF)

Country

Height [cm]

Weight [kg]

Body mass index [kg/m2] (defined as weight [kg]/(height [cm]/100)2)

Body surface area [m2] (defined as: 0.007184*(height0.725)*(weight0.425))

Smoking status  (Never-smoked, Ex-smoker, Current smoker)

Smoking history [pack-years]

Baseline ECOG score

EGFR mutation type: common, uncommon only

Oncology history details
o
Previous therapies:

Systemic chemotherapies

Other anti-cancer therapies

Radiotherapies (listed only)
o
Previous surgeries for trial disease


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This section will include a summary of all the subgroup variables detailed in Section 
6.4(Subgroups). This is presented based on treated set.
It is expected that biomarker values will only be available for a subset of the study 
population. Therefore, demographics and baseline characteristics will be provided for the 
BAS as well and compared with the study population.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. Only concomitant 
therapies for rash and diarrhoea were collected on the eCRF and will be summarised.
For baseline conditions and signs and symptoms of the trial disease also only descriptive 
statistics will be presented.
7.3
TREATMENT COMPLIANCE
There is no analysis planned for treatment compliance as no data on compliance is collected.
7.4
PRIMARY ENDPOINT
Refer to Section 7.8 (Safety Analysis).
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been specified in the 
protocol.
7.5.2
Secondary endpoints
This section is not applicable as no secondary endpoints have been specified in the protocol.


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7.7
EXTENT OF EXPOSURE
Total treatment time (days) will be calculated for each patient; total treatment time will 
include any dose interruptions or off-drug periods. 
The definition of exposure is:


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Treatment stop date – treatment start date + 1
In case of death (due to any cause), the treatment stop date will be imputed as the earlier of 
(date of last administration of afatinib, date of death) + 1 day.
Standard descriptive summaries of these data will be provided for the treated set of patients.
Total treatment time (days) will be summarized by afatinib dose level (40 mg, 30 mg, 20 mg 
and total), and by number of therapy lines at the 40 mg dose. The number of therapy lines for 
afatinib will be derived as: the number of all previous therapy lines + 1. The number of all 
previous therapy lines that the patient received prior to the start of treatment includes number 
of lines of all of the following:

Systemic chemotherapies: count the number of previous chemotherapies with 
“therapy mode” as “advanced/palliative” on the previous chemotherapies eCRF page.  
If “therapy mode” is “neo-adjuvant” or “adjuvant” and taken within 1 year prior to 
study enrolment, then count them as a separate “line of therapy”. 

Other anti-cancer therapies: count the number of anti-cancer therapies with “therapy 
mode” as “advanced/palliative” on the other anti-cancer therapies eCRF page.  If 
“therapy mode” is “neo-adjuvant” or “adjuvant” and taken within 1 year prior to study 
enrolment, then count them as a separate “line of therapy”. If there is a therapy with 
the same name and same start and end dates as a therapy present in previous systemic 
chemotherapies eCRF page, then ignore this as it has already been counted earlier.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. 
7.8.1
Adverse events
The intensity of AEs were classified and recorded according to the Common Terminology 
Criteria for Adverse Events (CTCAE) version 3.0 in the eCRF.
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of patients with AEs and NOT on the number of AEs.
Furthermore, for analysis of AE attributes such as duration, severity, etc. multiple AE 
occurrence data on the CRF, will be collapsed into AE episodes provided that all of the 
following apply:

The same MedDRA lowest level term was reported for the occurrences

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence)

Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence


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For further details on summarization of AE data, please refer to the guideline ‘Handling and 
summarization of AE data for clinical trial reports and integrated summaries’ (2) [001-MCG-
156]
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs occurring between first study treatment intake until 28 days after last study 
treatment intake will be assigned to be treatment-emergent. All AEs occurring outside of this 
period will be handled according to the treatment definition period definitions detailed in 
section 6.1(Treatment) and will only be listed unless stated otherwise.
An overall summary of AEs will be presented.  This summary will exclude the rows ‘Severe 
AEs’, ‘Significant AEs’ and ‘Other significant AEs’ but will include additional rows for ‘AEs 
leading to dose reduction’ and ‘AEs by highest Common Terminology Criteria for Adverse 
Events (CTCAE)’ grade.  
The frequency of patients with AEs will be summarised by highest CTCAE grade (grades 3, 
4, 5 and all grades including grade 1 and 2), treatment, primary system organ class (SOC) and 
preferred term (PT) for each of the following AE tables:

All AEs collected

Drug related AEs

AEs leading to dose reduction

AEs leading to treatment discontinuation

Drug related AEs leading to treatment discontinuation

Serious AEs

Drug related serious AEs

AEs leading to death       
All tables will be sorted by SOC according to the standard sort order specified by the 
European Medicines Agency (EMA); PTs will be sorted by frequency (within SOC).
The above tables except for AEs leading to death will be repeated for the project-defined 
grouping of AE terms (rash, stomatitis, ocular effects, lip effects, nail effects and fatigue).  
Details of the project-defined groupings are defined in the technical TSAP.  In these tables 
the grouped AEs will replace the original PTs for all AEs that are included within the 
grouped term.  The grouped AE categories will then be tabulated along with all remaining 
MedDRA PTs, sorted by descending frequency.  A reference table presenting all of the 
project defined groupings and MedDRA PTs within each grouping will also be produced.
Additional AE tables will be produced for AEs of special interest (diarrhoea, and the project 
defined groupings of rash and renal insufficiency), providing further details on highest
CTCAE grade, action taken with study drug and time to first onset of AE.
Number of patients with AEs with an incidence greater than 5% will be summarised by 
treatment, primary SOC and PT.


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7.8.2
Laboratory data
Only the date of samples is collected; laboratory data are not collected. Laboratory values 
that are considered clinically relevant will be recorded as baseline conditions or AEs as 
appropriate.
7.8.3
Vital signs and physical examination
Only descriptive statistics are planned for this section of the report. A summary of the 
absolute values and the changes from baseline will be presented in 4-week periods and at the 
EoT visit for the following parameters: systolic blood pressure, diastolic blood pressure, 
pulse rate, temperature, and body weight. 
Other than at baseline, repeat, adhoc or unscheduled data will not be included in the summary 
tables.
A listing for pregnancy test results of patients with child bearing potential will be provided.
A listing for LVEF results of patients will also be provided. Patients with a significant LVEF 
event will be flagged in the listing; a significant event is defined as a decrease of ≥20% from 
baseline that is also below the lower limit of normal for the particular site (50% will be used 
if the lower limit of normal is missing).
7.8.4
ECG
Only the date of the tracing is collected. Abnormalities will be recorded as baseline 
conditions or AEs as appropriate.
7.8.5
Others
Not applicable.


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8.
REFERENCES
1
001-MCG-156_RD-01: “Handling of missing and incomplete AE dates”, current 
version; IDEA for CON.
2
001-MCG-156: “Handling and summarisation of adverse event data for clinical 
trial reports and integrated summaries”, current version; IDEA for CON.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Final
24-Apr-2017
None
This is the final TSAP without any 
modification