Conditions: Carcinoma, Non-Small-Cell Lung
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 795
Healthy volunteers: no

Brief summary:
This randomised, open-label phase III trial will be performed in patients with advanced squamous cell carcinoma of the lung requiring second-line treatment after receiving first-line platinum-based chemotherapy. The primary objective of this trial is to compare the efficacy of BIBW 2992 to erlotinib as second-line treatment in this group of patients.

Detailed description:

Arms:
arm 1: Patients receive afatinib tablets once daily arm 2: Patients receive erlotinib tablets once daily

Interventions: intervention 1: afatinib intervention 2: erlotinib
Intervention descriptions: intervention 1: Afatinib taken once daily, continuously until disease progression or unacceptable toxicity. intervention 2: erlotinib taken once daily

Protocol document:
Prot_000.pdf: 
Clinical Trial Protocol
Doc. No.: U11-3487-03
EudraCT No.:
BI Trial No.:
2011-002380-24
1200.125
BI Investigational
Product:
Giotrif® / Gilotrif®, afatinib
Title:
LUX-Lung 8:  A randomized, open-label Phase III trial of afatinib versus 
erlotinib in patients with advanced squamous cell carcinoma of the lung as 
second-line therapy following first-line platinum-based chemotherapy 
Clinical Phase:
III
Sponsor 
Contacts:
Trial Clinical Monitor:
Phone:
Fax :
Email:
Team Member Medicine:
Phone:
Fax : 
Email:
Co-ordinating 
Investigators:
Phone:
Phone:
Status:
Revised Protocol based on Global Amendment 2
Version and Date:
Version: 3 Date: 24 June 2016  
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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:
Giotrif® / Gilotrif®, Afatinib
Name of active ingredient:
BIBW 2992
Protocol date:
Trial number:
Revision date:
24 June 2016
15 Nov 2011
1200.125
Title of trial:
LUX-Lung 8:  A randomized, open-label Phase III trial of afatinib versus erlotinib in 
patients with advanced squamous cell carcinoma of the lung as second-line therapy 
following first-line platinum-based chemotherapy
Co-ordinating 
Investigators:
Trial sites:
Multi-center trial
Clinical phase:
III
Objectives:
Primary:  Compare efficacy of afatinib with erlotinib as second-line treatment for 
patients with squamous cell carcinoma of the lung, as measured by progression-free 
survival (PFS).  
Key secondary: Compare overall survival (OS) in both treatment groups
Secondary: Objective response rate (ORR), disease control rate (DCR), tumour
shrinkage and the assessment of Health-related Quality of Life (HRQoL) and safety in 
both treatment groups
Methodology:
Randomised, open-label, active control study comparing afatinib vs. erlotinib.  
Eligible patients will be randomized to receive either afatinib or erlotinib in a 1:1 
ratio.  Independent assessment of the primary endpoint will be completed in a 
treatment-blinded manner.  Randomization will be stratified based on race (Eastern 
Asian vs. non-Eastern Asian).
No. of patients: 
total entered:
795
each treatment:
Afatinib: 398
Erlotinib: 397
Diagnosis :
Patients with diagnosis of advanced NSCLC squamous or mixed histology, who have 
completed at least 4 cycles of platinum-based doublet chemotherapy and who are 
eligible to receive 2nd line therapy.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Giotrif® / Gilotrif®, Afatinib
Name of active ingredient:
BIBW 2992
Protocol date:
Trial number:
Revision date:
24 June 2016
15 Nov 2011
1200.125
Main criteria
for inclusion:

Diagnosis of advanced stage NSCLC considered to be squamous histology, 
including mixed histology, in the opinion of the investigator.

Eligible for EGFR-directed therapy in 2nd line setting.

Measurable disease according to RECIST 1.1.

Eastern Cooperative Oncology Group (ECOG) score: 0 or 1.

Availability of tumour tissue material for correlative studies.  Archived tumour
tissue is acceptable.

Adequate organ function.

No prior treatment with EGFR directed small molecules or antibodies.
Test products:
Afatinib (BIBW 2992)
dose:
Starting dose 40 mg once daily.  Escalation to 50 mg/day at beginning of Course 2 in 
patients meeting specified safety and compliance criteria. Dose reduction to 40 (if 
applicable), 30, and 20 mg/day in the presence of drug-related adverse events.
mode of admin.:
Oral
Comparator products:
Erlotinib 
dose:
Starting dose of 150 mg once daily.  Dose reduction to 100 and 50 mg/day in the 
presence of known drug-related adverse events.
mode of admin.:
Oral
Duration of treatment: Until patient experiences disease progression, according to RECIST 1.1.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Giotrif® / Gilotrif®, Afatinib
Name of active ingredient:
BIBW 2992
Protocol date:
Trial number:
Revision date:
24 June 2016
15 Nov 2011
1200.125
Criteria for efficacy:
The primary endpoint of this study is progression-free survival, as determined by 
RECIST 1.1.
Key Secondary endpoint:
Overall survival
Secondary endpoints of this trial are:

Objective response (CR, PR) according to RECIST 1.1

Disease control (CR, PR, SD) according to RECIST 1.1 

Tumour shrinkage

Health-related Quality of Life (HRQoL)
Criteria for safety:
Safety of afatinib and erlotinib will be evaluated by intensity and incidence of adverse 
events, graded according to NCI CTCAE version 3.0, including:
The overall incidence and intensity of adverse events
Gastrointestinal events (vomiting, nausea, diarrhoea)
Skin reactions (rash, acne)
Tolerability of afatinib and erlotinib will be assessed based on dosage reductions and 
discontinuation due to adverse events.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Giotrif® / Gilotrif®, Afatinib
Name of active ingredient:
BIBW 2992
Protocol date:
Trial number:
Revision date:
24 June 2016
15 Nov 2011
1200.125
Statistical methods:
The primary analysis will compare afatinib vs erlotinib in terms of progression-free 
survival (PFS).  The randomised treatment regimens will be compared using a log-
rank test stratified by race (Eastern Asian vs non-Eastern Asian).  A stratified Cox 
proportional-hazards model will be used to derive the hazard ratio and 95% 
confidence interval (CI) between the two regimens. Kaplan-Meier estimates and 95% 
CI will be calculated at landmark time points. Three hundred seventy-two PFS events 
would be expected to provide 90% power for the log-rank test, assuming a hazard 
ratio of 0.714 for afatinib relative to erlotinib (corresponding to median times of 14 vs 
10 weeks, respectively) with two-sided α = 0.05. 
An interim analysis will be performed after at least 300 patients have been 
randomized and when 130 patients have experienced PD, as determined by 
assessment at the study sites, among the first 176 patients randomized into the trial.  
The analysis will be reviewed by the DMC and will result in one of the following 
decisions:  1.) No change in planned accrual, 2.) partial curtailment of accrual, or 3.) 
stop of accrual.
Overall survival (OS) is a key secondary endpoint.  The analysis of OS will estimate 
the hazard ratio and the corresponding 95% confidence interval based on a Cox-PH 
model. Additionally, a stratified log-rank test will be performed.  Kaplan-Meier 
estimates of OS will be tabulated.  632 deaths would be expected to provide 80% 
power for log-rank test, presuming a hazard ratio of 0.800 for afatinib relative to 
erlotinib (corresponding to median survival times of 8.75 vs. 7.00 months, 
respectively) with two-sided α = 0.05.
OS will be analysed twice. The first analysis will be performed at the time of the 
primary PFS analysis using a Haybittle-Peto stopping boundary for efficacy (p-value 
<0.0001). The primary analysis of survival is planned at 632 deaths.  However, if the 
futility analysis curtails accrual at 500 patients, the primary analysis of OS will be 
performed after 80% of the randomized patients have died.


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FLOW CHART
Visit
Screening 
Course 1
Course 2 
and 
subsequent 
courses*
End of 
treatment **
Follow-up 
Observation 
Period
Visit Abbreviation
SCR
C1V1 
C1V2 
CxV1a
EOT
FUP
OPyb
Day 
Up to 28 
days 
before 
treatment
Day 
1***
Day 8
(± 2 
days)
Day 1 of 
each 
course
(- 3 to +2
days)****
0-7 days after 
permanent 
discontinuation 
of study drug
28 Days after 
discontinuation 
of study drug
(+ 7 days)
Every 28 
Days 
(± 7 days) 
after FUP
Informed consent
X
Tumour sample 
shipment 1
X
Demographics 
X
Medical history 
X
Complete Physical 
exam 2
X
X
Clinical Assessment 3
X
X
X
X
Vital signs 
X
X
X
X
X
X
Performance status 
X
X
X
X
X
ECG (as indicated)4
X 
X
X4
X
Safety laboratory tests 5
X
X
X
X
X
Pregnancy Test
X
X
X
ECHO or MUGA6
X
X6
X6
Review of in-
/exclusion criteria 
X
X
Randomization
X
 
Collection of blood for 
Biomarker analysis8
X
X
X
Patient-reported 
outcomes9
X
X9
X
X
Adverse event 
evaluation10
X----------------------------------------------------------------------X
 
Concomitant therapy 
X
X----------------------------------------------------------------------X
Tumour assessments12
X
Tumour assessments are completed at weeks 8, 12, 16, and every 8 
weeks thereafter. After approval of protocol version 3, assessments to 
be performed every 18 weeks unless clinically indicated.
Treatment Adherence 
Check13
X
X
X
Dispense Trial Drug
X
X
Termination of trial 
medication
X
IXRS
X
X
X
X
Collection of Vital 
Status14
X


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* All courses are 4 weeks in duration (28 days). Patients may continue on treatment for unlimited courses, until the criteria 
for stopping medication are met (see Section 3.3.4.1).
** If the decision to permanently discontinue study drug is taken during a scheduled visit, the EOT visit should be performed 
instead of the scheduled visit.
*** Randomization into the study via the IXRS is permitted up to 2 days prior to the C1V1 if site procedures require 
advance randomization to accommodate the logistics of dispensing study medication to patients.  Sites that use this option 
must include a copy of this policy in the ISF and submit a copy to the sponsor.
**** Except as noted for ECHO or MUGA and tumour assessments
a x is the course number in CxV1      
b y is the visit number  in Opy
1.
Randomization into study does not need to be delayed for shipment of tumour sample; however, 
availability of tumour sample for shipment to central laboratory must be confirmed prior to randomization
and shipped within 28 days of randomization.
2.
Includes height (at screening only) and weight.
3.
Limited physical examination to capture clinical assessment of ongoing or new adverse events and monitor 
for signs and symptoms of clinical response.
4.
A 12-lead resting digital electrocardiogram (ECG) will be performed at Screening to establish a baseline 
assessment, at C1V2 (Day 8 of treatment), at the start of every third course thereafter (C4, C7, etc.) and 
EOT. After approval of Protocol Version 3.0, ECG will only be performed if clinically indicated. 
5.
Includes hematology, serum biochemistry, and urinalysis. Refer to the Investigator Site File (ISF).
6.
ECHO or MUGA (At German sites, only ECHO is allowed) will be performed during screening, at Course 
4 and then at every third course (Course 7, 10, 13 etc.), and at EOT (if not performed in the previous 8 
weeks).  Requirement for EOT ECHO or MUGA may be waived for patients meeting all of the following 
criteria:  1) too sick from their disease or disease related symptoms to travel in the opinion of the 
investigator, 2) have had evidence of stable LVEF on the previous scheduled post treatment assessment
and 3) have no evidence of cardiovascular disease.   For LVEF evaluations, the assessment can occur 
+7days of the scheduled Day 1 of the corresponding course.
After approval of Protocol Version 3.0, ECHO or MUGA will only be performed if clinically indicated.   
 
8.
Blood sample will be collected and plasma will be sent to logistics laboratory at baseline (C1V1), C2, and 
at EOT or determination of disease progression. After approval of Protocol Version 3.0, the collection of 
blood sample at EOT will no longer be required.
9.
EQ-5D, EORTC QLQ-C30 and EORTC QLQ LC-13 questionnaires will be completed at baseline and 
then (before seen by the investigator) at the start of course 2, 3, 4, and every 2nd course thereafter, EOT 
and FUP. After approval of Protocol Version 3.0, the collection of EQ-5D, EORTC QLQ-C30 and 
EORTC QLQ LC-13 questionnaires will no longer be required.
10.
See Appendix 10.7:  Adverse Event Reporting Process 
 
12.
Tumour assessments should include CT scans of the chest and abdomen and, if clinically indicated, 
imaging of any other known or suspected sites of disease (e.g. pelvis, brain) using an appropriate method 
(CT scan or MRI).  See Appendix 10.1 for lesion measurement specifications.  Assessment will be 
performed at the following timepoints until progression or start of further treatment for disease.  In the 
event of early discontinuation due to Adverse Events or an interruption/delay to treatment the tumour 
assessment schedule will not be changed.
Screening Period (up to 21 days before randomization)
During week 8 (56-64 days after randomization)


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During week 12 (84-91 days after randomization).  German sites only will have an X-ray 
completed instead of a CT or MRI for the week 12 assessment.  If disease progression is 
suspected, a follow-up CT or MRI will then be completed
During week 16 (112-119 days after randomization)
Every 8 weeks thereafter until progression/ start of further treatment.
After approval of protocol version 3, tumour assessments to be performed every 18 weeks unless 
clinically indicated until progression or start of further treatment.
13.
Confirm adherence to study medication and supportive care for adverse events noted in Section 4.1.4
14.
Collection of information on progression, further anti-cancer treatment and death. Information should be 
collected from the patient notes or by telephone contact with the patient. In countries where regulations 
allow, public records may be utilized to assess the mortality status for patients lost to follow up or where 
mortality information is not readily available through 3 attempted contacts.  A formal study visit is not 
required. Once Protocol Version 3.0 is final (and where required locally, approvals are obtained by the site 
as per Section 8.1), the collection of Observation Period data will no longer be required.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................6
TABLE OF CONTENTS ...................................................................................9
ABBREVIATIONS.......................................................................................... 13
1.
INTRODUCTION.................................................................................... 16
1.1
MEDICAL BACKGROUND............................................................................16
1.2
DRUG PROFILE...............................................................................................19
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 21
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................21
2.2
TRIAL OBJECTIVES.......................................................................................21
2.2.1
Primary Objective.................................................................................21
2.2.2
Secondary Objectives............................................................................21
2.3
BENEFIT - RISK ASSESSMENT ...................................................................22
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 23
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................23
3.1.1
Administrative structure of the trial...................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................25
3.3
SELECTION OF TRIAL POPULATION ......................................................26
3.3.1
Main diagnosis for study entry............................................................26
3.3.2
Inclusion criteria...................................................................................27
3.3.3
Exclusion criteria ..................................................................................28
3.3.4
Removal of patients from therapy or assessments.............................30
3.3.4.1
Removal of individual patients................................................30
3.3.4.1.1Patient discontinuation of study participation..........................30
3.3.4.2
Discontinuation of the trial by the sponsor..............................31
4.
TREATMENTS........................................................................................ 32
4.1
TREATMENTS TO BE ADMINISTERED....................................................32
4.1.1
Identity of BI investigational product and comparator 
products .................................................................................................32
4.1.2
Method of assigning patients to treatment groups ............................32
4.1.3
Selection of doses in the trial................................................................33
4.1.4
Drug assignment and administration of doses for each patient .......33
4.1.4.1
Afatinib assignment and administration ..................................33
4.1.4.1.1Dose escalation for afatinib .....................................................34


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4.1.4.1.2Dose reduction for afatinib ......................................................34
4.1.4.2
Erlotinib ...................................................................................36
4.1.4.2.1Dose reduction and discontinuation of erlotinib......................36
4.1.5
Blinding and procedures for unblinding ............................................38
4.1.5.1
Blinding....................................................................................38
4.1.5.2
Procedures for emergency unblinding .....................................38
4.1.6
Packaging, labelling, and re-supply ....................................................39
4.1.7
Storage conditions.................................................................................39
4.1.7.1
Storage conditions for afatinib.................................................39
4.1.7.2
Storage conditions for erlotinib ...............................................39
4.1.8
Drug accountability ..............................................................................39
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................40
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................40
4.2.2
Restrictions............................................................................................41
4.2.2.1
Restrictions regarding concomitant treatment .........................41
4.2.2.2
Restrictions on diet and life style.............................................43
4.2.2.3
Women of child-bearing potential and pregnancy prevention.43
4.2.3
Management of expected adverse events............................................43
4.2.3.1
Management of diarrhoea and hydration status.......................44
4.2.3.2
Management of dermatological AEs .......................................45
4.2.3.3
Management of mucositis/stomatitis .......................................48
4.3
TREATMENT COMPLIANCE.......................................................................49
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 51
5.1
EFFICACY.........................................................................................................51
5.1.1
Endpoints of efficacy.............................................................................51
5.1.2
Assessment of efficacy...........................................................................51
5.1.2.1
Tumour Assessment.................................................................51
5.1.2.1.1Central imaging........................................................................51
5.2
SAFETY..............................................................................................................52
5.2.1
Endpoints of safety................................................................................52
5.2.2
Assessment of adverse events...............................................................52
5.2.2.1
Definitions of adverse events...................................................52
5.2.2.2
Adverse event and serious adverse event reporting.................54
5.2.3
Assessment of safety laboratory parameters......................................56
5.2.4
Electrocardiogram................................................................................57
5.2.5
Assessment of other safety parameters...............................................57
5.2.5.1
Physical Examination, Performance Status .............................57
5.2.5.2
Vital Signs................................................................................58
5.2.5.3
Left ventricular function ..........................................................58
5.3
OTHER...............................................................................................................58


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5.3.1
Other endpoints.....................................................................................58
 
5.3.2
Other assessments .................................................................................60
5.3.2.1
Demographics and history .......................................................60
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................61
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................61
5.6
BIOMARKERS..................................................................................................61
5.6.1
Endpoints based on biomarkers ..........................................................62
5.6.2
Methods of sample collection...............................................................62
5.6.3
Analytical determinations ....................................................................62
6.
INVESTIGATIONAL PLAN.................................................................. 63
6.1
VISIT SCHEDULE............................................................................................63
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................63
6.2.1
Screening................................................................................................63
6.2.2
Treatment period ..................................................................................63
6.2.3
End of trial and follow-up period........................................................64
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 65
7.1
STATISTICAL DESIGN - MODEL................................................................65
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................65
7.3
PLANNED ANALYSES....................................................................................65
7.3.1
Primary analyses...................................................................................65
7.3.1.1
Primary endpoint PFS..............................................................66
7.3.2
Secondary analyses ...............................................................................66
7.3.2.1
Other secondary analyses.........................................................67
7.3.2.1.1Other analyses for PFS.............................................................67
7.3.2.1.2Best RECIST assessment.........................................................67
7.3.2.1.3Tumour shrinkage....................................................................68
7.3.2.1.4Patient-reported Outcomes.......................................................68
 
7.3.3
Safety analyses.......................................................................................69
7.3.4
Interim analyses ....................................................................................71
7.4
HANDLING OF MISSING DATA ..................................................................71
7.5
RANDOMISATION ..........................................................................................72
7.6
DETERMINATION OF SAMPLE SIZE ........................................................72
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 74


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8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................74
8.2
DATA QUALITY ASSURANCE .....................................................................75
8.3
RECORDS..........................................................................................................75
8.3.1
Source documents .................................................................................75
8.3.2
Direct access to source data and documents.......................................75
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................75
8.4.1
Listedness...............................................................................................75
8.4.2
Expedited reporting to health authorities and IECs/IRBs................76
8.5
STATEMENT OF CONFIDENTIALITY.......................................................76
8.6
COMPLETION OF TRIAL..............................................................................76
9.
REFERENCES......................................................................................... 77
9.1
PUBLISHED REFERENCES...........................................................................77
10. APPENDICES .......................................................................................... 83
10.1
RECIST 1.1 CRITERIA...................................................................................83
10.2
ECOG PERFORMANCE STATUS.................................................................88
10.3
FORMULA FOR ESTIMATED CREATININE CLEARANCE RATE .....89
10.4
NYHA CLASSIFICATION OF HEART FAILURE......................................90
10.5
LIST OF POTENT INHIBITORS AND INDUCERS OF P-
GLYCOPROTEIN (MDR1) .............................................................................91
10.6
LIST OF STRONG CYP3A4 INHIBITORS INDUCERS.............................92
10.7
ADVERSE EVENT/SERIOUS ADVERSE EVENT REPORTING.............93
10.8
QOL QUESTIONNAIRES ...............................................................................94
10.9
CLINICAL EVALUATION OF LIVER INJURY .......................................100
10.9.1 Introduction.........................................................................................100
10.9.2 Procedures ...........................................................................................100
11. DESCRIPTION OF GLOBAL AMENDMENTS............................... 102


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ABBREVIATIONS
AE
Adverse Event
ADL
Activities of Daily Living
AJCC
American Joint Committee on Cancer
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
ANCOVA
Analysis of Covariance
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
ATP
Adenosine Triphosphate
AUC
Area Under the Concentration-time curve
Β-HCG
Beta-Human Chorionic Gonadotrophin
BI
Boehringer Ingelheim
BSA
Body Surface Area
BUN
Blood Urea/ Blood Urea Nitrogen
CA
Competent Authority
CI
Confidence Interval
CK
Creatinine Kinase 
CML
Clinical Monitor Local
CR
Complete Response
CRA
Clinical Research Assistant/Associate
CRF/eCRF
Case Report Form / electronic Case Report Form
CRO
Contract Research Organisation
CT
Computed Tomography
CTC
Common Terminology Criteria
CTC AE
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
DCR
Disease Control Rate
DILI
Drug-Induced Liver Injury
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
EC/IEC
(Independent) Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EGFR
Epidermal Growth Factor Receptor
erbB
Epidermal Growth Factor family of receptors
EudraCT
European Clinical Trials Database
EORTC
European Organisation for Research and Treatment of Cancer
EOT
End of Treatment
FDA
Food and Drug Administration
FISH
Fluorescence In Situ Hybridisation
FU/FUP
Follow Up
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate


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GGT
Gamma-glutamyltansferase
HER2
Human Epidermal Growth Factor Receptor 2
HIV
Human Immunodeficiency Virus
HR
Hazard Ratio
HRQoL
Health-Related Quality of Life
IB
Investigator Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
ILD
Interstitial Lung Disease
INN
International Nonproprietary Name
INR
International Normalized Ratio
IRB
Institutional Review Board
ISF
Investigator Site File
Iv
Intravenous
IUD
Intrauterine Device
IXRS
Combined Interactive Voice Response System and 
Interactive Web-based Response System
LD
Longest Diameter
LDH
Lactate dehydrogenase 
LVEF
Left Ventricular Ejection Fraction
MedDRA
Medical Dictionary for Drug Regulatory Activities
Mg
Milligram
MOS
Median Overall Survival
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
MUGA
Multi Gated Acquisition Scan
NCI
National Cancer Institute
NE
Not Evaluated
NSCLC
NYHA
Non Small Cell Lung Cancer
New York Heart Association
OP
Observation Period
OPU
Operative Unit (of BI)
ORR
Objective Response Rate
OS
Overall Survival
PABA
Para-Aminobenzoic Acid
PD
Progressive Disease
PFS
Progression Free Survival
PI
Package Insert
PK
Pharmacokinetic
PR
Partial Response
PS
Performance status
PT
Prothrombin Time/ Preferred Term
PVC
Polyvinyl Chloride


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RECIST
Response Evaluation Criteria in Solid Tumours
SAE
Serious Adverse Event
SCCHN
Squamous Cell Cancer of Head and Neck
SD
Stable Disease
SMQ
Standard MedDRA Query
SOC
System Organ Class
SOP
Standard Operating Procedure
SPC
Summary of Product Characteristics
SPF
Sun Protection Factor
SUSAR
Suspected Unexpected Serious Adverse Reaction
tmax
Time to maximum plasma concentration
TK
Tyrosine Kinase
TKI
Tyrosine Kinase Inhibitor
TSAP
Trial Statistical Analysis Plan
TSH
Thyroid-Stimulating Hormone
ULN
Upper Limit of Normal
UV
Ultraviolet
WBC
White Blood Cell
WOCBP
Women of Child Bearing Potential
Wt
Wild-type


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Non-small cell lung cancer (NSCLC) is a leading cause of cancer death globally.  It has been 
the most commonly diagnosed cancer each year since 1985 with an estimated 1.35 million 
new cases diagnosed and approximately 1.2 million deaths each year worldwide (R05-0876, 
R06-0221). The disease is associated with high mortality and morbidity with 5-year-survival 
rates estimated in the United States at 16% for patients with metastatic disease (R11-0764). 
Surgical resection is reserved as initial treatment option for eligible patients with early stage 
disease while systemic therapy is the mainstay for those with advanced stage or metastatic 
disease. Many patients carry comorbidities from smoking history and advanced age such as 
limited cardio-pulmonary reserve that restricts treatment options. 
Patients with locally advanced and/or metastatic NSCLC in good performance status and 
those able to tolerate are generally treated with platinum based combination chemotherapy as 
a first-line treatment. The goal is prolongation of survival and palliation of symptoms but
cure is rarely seen. Despite responses and transient regressions, most patients eventually 
relapse and succumb to their illness. Many patients such as elderly and those with poor 
performance status or significant co-morbidity may also not be able to tolerate the side effects 
associated with chemotherapy and thus choices may be limited further for these patients.  
Novel therapies that improve survival with a better tolerability profile are thus needed.
Patients relapsing after first-line chemotherapy may be eligible for additional chemotherapy 
with alternate single agents such as docetaxel and pemetrexed. While systemic chemotherapy 
has been the mainstay of treatment options in advanced NSCLC, its activity is at best modest 
with significant morbidity.  Several agents have shown activity in this setting however only a 
few have been approved. In most instances, it has been difficult to identify and select 
populations where individual chemotherapeutic agents have a higher likelihood of benefit. 
While docetaxel has been studied and approved as second-line therapy across NSCLC 
histology, benefit from pemetrexed is limited only to patients with adenocarcinoma histology. 
However, in the recent years novel targeted therapies based on specific molecular and 
biological characteristics have emerged as a new treatment paradigm in select populations,
offering an alternative to chemotherapy with an improved safety and efficacy profile. The 
targets most extensively studied include the epidermal growth factor receptor (EGFR) or the 
Subclass I of the superfamily of transmembrane kinase inhibitors (R06-1302, R07-1049, 
R07-1135). 
Aberrant activation of EGFR is frequently observed in a variety of malignant tumours and 
may be caused by a variety of molecular processes including mutations, receptor 
overexpression, ligand-dependent receptor dimerization, and ligand-independent activation.  
Overexpression of EGFR has been detected in 40-80% of NSCLC, validated as a therapeutic 
target and has led to the development of specific small molecule EGFR antagonists to treat 
this disease (R06-1301, R06-1393, R06-1394).  First-generation EGFR small molecule 
tyrosine-kinase inhibitors (TKI) act as ATP analogues, compete reversibly for the tyrosine 
kinase (TK) catalytic site, and include gefitinib (Iressa®) and erlotinib (Tarceva®).  Recent 


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clinical experience with these agents has demonstrated tumour regression in about 10-15% of 
unselected NSCLC patients (R05-0867, R06-1301, and R06-1306). This benefit has been 
demonstrated across NSCLC histology in patients progressing after initial chemotherapy as 
well as in a maintenance setting following initial platinum based chemotherapy. While the 
most impressive responses are noted in the molecularly defined select population of 
adenocarcinoma with activation mutations of EGFR (R08-5155, R09-4437, R11-1274), 
patients with wild type (wt) EGFR including those with squamous histology seem to benefit 
as well.  
Erlotinib, a first-generation EGFR TKI, is approved as monotherapy in second- and third-line 
setting in patients with locally advanced and/or metastatic NSCLC. Its approval was based on 
the BR21 trial conducted in patients with Stage IIIB/IV NSCLC that had failed one or two 
prior chemotherapy regimens. Patients randomized to erlotinib achieved improved response 
rates (8.9% vs. 0.9%) and prolongation of median overall survival (MOS) (6.7 vs. 
4.7 months) and progression free survival (PFS) (9.9 vs. 7.9 weeks) versus placebo
(R05-0867). Of the 488 patients randomized in a 2:1 fashion to erlotinib vs. 243 to placebo, 
29.5% had squamous histology in the erlotinib arm vs. 32.1% in placebo arm. In addition 
erlotinib has demonstrated activity as a single agent in the maintenance setting in 
non-progressive patients following first-line chemotherapy with a platinum doublet 
combination. In the Sequential Tarceva® (erlotinib) in Unresectable NSCLC (SATURN) 
study 889 patients who did not have progressive disease following four cycles of platinum 
based chemotherapy were randomized into the maintenance part of the study to receive either 
erlotinib (437 patients eligible for PFS analysis) or placebo (447 patients eligible for PFS 
analysis). Of these, 166 patients receiving erlotinib had squamous cell carcinoma compared 
to 194 receiving placebo. PFS was reported to be prolonged in patients independent of all 
histology and irrespective of EGFR status: 12.3 weeks for patients in the erlotinib group vs. 
11.1 weeks for those in the placebo group (HR 0.71, 95%CI= 0.62-0.82; p<0.0001). The 
objective response rate was 11.9% (52 patients) with erlotinib vs 5.4% (24 patients) with 
placebo (P=0.0006) (R11-1185).
In contrast docetaxel and pemetrexed, two of the most commonly used agents in the 
second-line treatment of advanced NSCLC (R05-1054) have shown response rates of 8.8% 
and 9.1% respectively with median PFS and OS in similar ranges to erlotinib (median PFS of 
2.9 months in each arm, and median survival time of 8.3 months for pemetrexed versus 
7.9 months for docetaxel, p=not significant). Docetaxel is associated with significant risk of 
febrile neutropenia and the benefit of pemetrexed is restricted to non-squamous histology
(R04-2230).
Thus, despite the availability of these options to treat locally advanced and/or metastatic 
NSCLC, further alternatives are needed. Even patients eligible for these second-line therapies 
may have limited tolerability to these agents.  Similarly, given the selective efficacy of 
pemetrexed in patients with adenocarcinoma and improved efficacy of EGFR TKIs in 
patients with EGFR mutations (most frequently seen in patients with adenocarcinoma, 
non-smokers) these patients may also have a wider selection of treatment options as 
compared to those with squamous histology and prior smoking history highlighting a high 
unmet medical need.


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Afatinib is a member of the second generation TKIs which binds irreversibly to the erbB 
family of receptors.  It is hypothesised that the prolonged and irreversible inhibition of the 
receptor has the potential for further improvement in response to treatment over the first 
generation TKIs such as erlotinib and gefitinib (U03-3218).
Afatinib has demonstrated activity in the treatment of NSCLC in several clinical studies.  The 
results from LUX-Lung 1, a placebo-controlled, Phase III trial in patients who progressed 
after receiving chemotherapy and a first-line-EGFR TKI demonstrated clinical activity of 
afatinib in this NSCLC population with adenocarcinoma histology.  A tripling in the median 
PFS of afatinib compared to placebo (3.3 months vs. 1.1 month) was observed (P10-12529). 
Similarly significant responses have been noted in patients with mutated EGFR in the 
LUX-Lung 2 trial, reporting a confirmed ORR of 60% (78 of 129 patients), that support the 
hypothesis of improved efficacy with the irreversible inhibition of the target(P10-09976, 
P10-12524). At the time of publication for this protocol, two Phase III trials comparing 
afatinib to platinum based chemotherapy in patients harboring EGFR mutation as first-line
treatment are ongoing.
Albeit there is a preponderance of data of efficacy in adenocarcinoma histology of NSCLC, 
there is growing evidence that patients with squamous histology also derive benefit from 
EGFR TKIs. In addition to the data outlined above for erlotinib, additional proof of activity 
in this subset has been noted with another irreversible inhibitor of EGFR family of TKI –
PF299804.  In a randomized Phase II study PF299804, a second-generation TKI, was 
compared to erlotinib in patients with advanced NSCLC who had failed at least one line of 
chemotherapy.  Of the 188 patients enrolled in this 1:1 randomized study that included nearly 
a third of patients with non-adenocarcinoma histology and approximately 60% with wild type 
EGFR, PF299804 demonstrated a significant improvement in median PFS compared to 
erlotinib (12.4 weeks vs. 8.3 weeks) (R10-6208).  The potential activity of PF299804 in 
squamous histology was also reported in a Phase II study in recurrent and/or metastatic 
squamous cell carcinoma of the head and neck (SCCHN) where ORR of 10.5% was noted. A 
median PFS of 3.4 months was reported along with 63.2% of patients achieving SD as their 
best response (R11-1184).
In the current ongoing trials of afatinib additional proof of activity in cancers of squamous 
histology and beyond NSCLC with mutated EGFR has been observed. In a Phase II trial 
(1200.40) of EGFR FISH positive NSCLC patients, 12 of 59 (20%) evaluable patients on 
afatinib achieved an objective response with 8 confirmed responses (1 CR, 7 PR) so far and 
21 (36%) of all patients had disease control for at least 16 weeks. Of the 28 evaluable patients 
that tested negative for EGFR mutation so far the ORR was still 21% (6/28) and of the 
4 patients treated with afatinib with squamous histology 1 achieved PR and 2 SD as their best 
evaluable response. In addition, LUX-Lung 5 (1200.42) is a large ongoing randomized Phase
III trial of afatinib plus weekly paclitaxel versus investigator’s choice of chemotherapy 
following afatinib monotherapy in NSCLC patients failing previous erlotinib or gefitinib 
treatment. At the time of publication of this protocol, preliminary RECIST tumour 
assessment was available for 54 patients with squamous cell histology receiving the initial 
afatinib monotherapy.  Two patients (3.7%) and 35 (65%) patients achieved an overall best 
assessment of PR and SD respectively regardless of confirmation (Data on File).


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In LUX-Lung 1 (1200.23) a randomized Phase IIb/III trial comparing afatinib to placebo in a 
clinically enriched population for EGFR mutations and prior EGFR TKI therapy; 5 patients 
with squamous histology were treated on afatinib (protocol violations). Four of these had SD 
and 1 an unconfirmed PR (Data on File).
Additional proof of concept of afatinib in squamous histology is derived from trial 1200.28 in 
patients with recurrent/metastatic SCCHN who had failed prior platinum-containing 
chemotherapy. Sixty-one patients were randomized to receive afatinib vs. 60 to receive 
cetuximab (a monoclonal antibody against the EGFR) and upon progression cross over were 
allowed. In a preliminary analysis reported in 2010, of the 34/74 patients randomized to 
afatinib in Stage 1 of the trial 6/34 patients achieved PR and 18/34 had SD (P10-12525, 
P10-12526). An expansion into two Phase III trials was in preparation at the time of initial 
publication of this protocol.
The 1200.125 trial (LUX-Lung 8) will build on the positive data to date observed with 
second-generation TKIs in squamous histology cancers by further evaluating afatinib’s 
activity in this NSCLC population. The patients with squamous histology represent a 
significant population of patients with advanced NSCLC who have a large unmet medical 
need. With the inbuilt futility analysis into this trial and the large unmet medical need in this 
population, it is conceived that the current design is a valid approach to test the hypothesis in 
a reasonable time frame. 
1.2
DRUG PROFILE
For the latest information on the drug profile of afatinib, please refer to the current 
Investigator’s Brochure (IB) (U03-3218).  All references in this protocol concerning afatinib 
(BIBW 2992) refer to the free base compound which is used as the oral formulation.
Afatinib is a small molecule, selective and irreversible erbB family blocker. In preclinical 
models it effectively inhibits phosphorylation of erbB receptors resulting in tumour growth 
inhibition and regression of established subcutaneous tumours derived from four human 
cell-lines known to co-express erbB receptors. 
Afatinib is moderately fast absorbed after oral administration, with median 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 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. The 
major route of elimination of afatinib was via faeces. After food intake, a decreased systemic 
exposure was observed compared to administration under fasted conditions. The PK 
characteristics in Caucasian cancer patients were comparable to those observed in Japanese 
cancer patients. 
Afatinib is bound covalently to proteins to a variable extent and covalent protein adducts 
were the major circulating metabolites in the plasma. Afatinib did not show relevant 


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inhibition or induction of cytochrome P450 isoenzymes, and it appears unlikely that drug-
drug interactions based on this mechanism will occur. 
 
 
 
 
 
 
In pre-clinical studies afatinib is not an irritant to intact skin but an ocular irritant. Afatinib 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 studies determined the MTD with continuous dosing 
of afatinib in patients with advanced solid tumours at 40mg and 50mg daily (U07-3128, 
U08-1023). Adverse events (AEs) observed with afatinib are consistent with those reported 
for other EGFR and dual EGFR/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), 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.  
Giotrif® (Afatinib) has been approved in EU to treat patients with locally advanced or 
metastatic NSCLC of squamous histology progressing on or after platinum-based 
chemotherapy. In the US, Gilotrif® (Afatinib) has also been approved to treat patients with 
metastatic squamous NSCLC progressing after platinum-based chemotherapy.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Patients with NSCLC squamous cell histology represent a population with a large unmet 
medical need. Chemotherapy choices for these patients is not only restricted from an efficacy 
standpoint but also limited by the ability of these patients to tolerate these agents. These 
patients tend to be older, have prevalent smoking history and are associated with higher 
comorbidities. In the second-line setting their choices are mostly restricted to single agents. 
Although several treatments may have shown limited activity, only docetaxel and erlotinib
are approved.  Afatinib is an ideal candidate that needs further evaluation in this setting. 
From a mechanistic standpoint it offers the chance to irreversibly inhibit the erbB family of 
receptors compared to the first generation EGFR TKI erlotinib and its adverse event profile 
appears comparable to erlotinib as well. Afatinib has established proof of concept in SCCHN
and has shown evidence of activity in NSCLC squamous-cell histology. Similar agents have 
already established randomized Phase II data in NSCLC that supports further exploration of 
this concept in a direct comparison to erlotinib.
Given the large unmet medical need and a desire to provide patients with treatment 
alternatives that are time and cost efficient the current trial is proposed. The trial is designed 
with an inbuilt futility analysis to be completed in the first 176 patients enrolled to provide 
adequate confidence of futility of this direct comparison with erlotinib.  Details of the 
analysis are further provided in Section 7.3.4.
2.2
TRIAL OBJECTIVES
This randomized, open label Phase III trial will be performed in patients with squamous cell 
carcinoma of the lung.
2.2.1
Primary Objective
The primary objective of the trial is to compare the efficacy of afatinib with erlotinib as 
second-line treatment for this group of patients, as measured by PFS.  
2.2.2
Secondary Objectives
The key secondary trial objective is to compare the OS in both treatment groups.  
Other secondary objectives are to compare the ORR, DCR and tumour shrinkage of afatinib 
with erlotinib, and the assessment of HRQoL and safety in both treatment groups.
Study endpoints are provided in Sections 5.1, 5.2, and 5.3.


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2.3
BENEFIT - RISK ASSESSMENT
Treatment options for patients with advanced squamous cell carcinoma of the lung are 
limited following first-line chemotherapy, with most patients recurring and eventually 
succumbing to their disease. For patients eligible to tolerate, chemotherapy has been an 
option and docetaxel is indicated in the second-line setting for patients with advanced 
NSCLC with associated chemotherapy related morbidity. Afatinib is an irreversible EGFR 
inhibitor with a favourable risk benefit ratio that is currently in Phase III clinical trials in lung 
cancer, breast cancer and squamous cancer of head and neck (SCCHN). The clinical 
experience of afatinib includes over 2000 patients. Afatinib is relatively well tolerated, with 
most common adverse events being diarrhoea, rash and stomatitis as expected for this class of 
agents.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this study requires timely detection, evaluation, and 
follow-up of laboratory alterations of selected liver laboratory parameters to ensure patients´ 
safety.
Afatinib has shown evidence of clinical activity in patients with squamous cancer of the head 
and neck in a randomized clinical Phase II trial and early evidence of clinical activity in 
patients with squamous carcinoma of the lung in ongoing clinical trials (P10-12525, 
P10-12526). This study will have an interim futility analysis planned for the first 176 patients 
and is outlined in Section 7.3.4.  In addition a Steering Committee providing study oversight 
and a Data Monitoring Committee (DMC) is planned.  See Section 3.1.1 for a detailed 
description of the procedures of these committees.  
The large unmet medical need of this patient population combined with the above and the 
planned interim futility analysis supports the validity of this study.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This randomized, open-label Phase III trial is designed to compare the efficacy of afatinib 
with erlotinib for the second-line treatment of patients with advanced NSCLC of squamous or
predominantly squamous histology.  The primary endpoint of the trial will be progression-
free survival.  
Eligible patients will be randomized in a 1:1 fashion to receive either afatinib or erlotinib.  
Patients will receive continuous daily dosing of study drug assigned until disease progression, 
unacceptable adverse events or other reason necessitating withdrawal (see Appendix 10.1 and 
Sections 4.1.4 and 3.3.4).  Study drug dose will be modified as in Section 4.1.4 for the 
management of adverse treatment effects.  The starting dose of afatinib will be 40 mg daily 
oral and erlotinib will be 150 mg daily oral. For patients adequately tolerating therapy the 
dose of afatinib will be further titrated to 50 mg daily oral at the end of 4 weeks.
Patients will have tumour assessments at the intervals specified in the flow chart for 
assessment of response.  Tumour assessment must continue for patients who discontinue 
study drug due adverse events until the patient experiences disease progression or starts other 
anti-cancer treatment.  Tumour response and progression will be assessed according to 
RECIST 1.1 (R09-0262) and assessment at the investigator site will be sufficient for 
decisions on continuation of treatment (Appendix 10.1).  An independent analysis of response 
will also be performed by a Central Imaging Unit (see Section 5.1.2.1.1); however this will 
not be used to make treatment decisions. After approval of Protocol Version 3.0, the central 
imaging review of tumour response will be discontinued.
All patients will also have regular evaluations for assessment of safety parameters as detailed 
in the flow chart.
An End of Treatment (EOT) evaluation is to be completed when a patient permanently 
discontinues study drug, either for disease progression or any reason listed in Section 3.3.4.  
The assessments required are listed in the flow chart.  Patients who discontinue study drug 
due to toxicity will continue to have tumour assessments according to the Flow Chart until 
disease progression.
A Follow-up evaluation will be completed 28 (+7) days after permanent discontinuation of 
study drug.  Refer to the flow chart and diagram below for details.  This visit will be defined 
as the last visit for this trial.
Patients will subsequently be monitored for vital status in the Observation Period of this 
protocol. Once Protocol Version 3.0 is final (and where required locally, approvals are 
obtained by the site as per Section 8.1), the collection of vital status data will no longer be 
required.
The trial is considered completed when:


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1.) The PFS and OS events required for analysis in Section 7.3 have occurred.
AND
2.) All patients have discontinued trial medication, as explained in Section 3.3.4.
The diagram below depicts the stages of a patient’s participation in this protocol.
*For patients who discontinue study drug due to Adverse Event
3.1.1
Administrative structure of the trial
The coordinating investigators are oncologists with experience with this type of trial and 
investigations. The coordinating investigators have been designated by BI and will sign the 
clinical trial report.
The trial will be performed by investigators specialised in oncology.
Ongoing Tumour Assessments until PD or anti-
cancer treatment*  
RANDOMIZATION
afatinib: 
erlotinib (1:1)
Stratified by:  
Race (Eastern 
Asians vs. 
non-Eastern 
Asians)
TREATMENT 
PERIOD
28 Day 
courses
Continuous 
treatment 
with afatinib 
or erlotinib
END OF 
TREATMENT
0-7 Days 
after 
permanent 
discontinua
tion of 
study drug
for any
reason
OBSERVATION 
PERIOD
Vital status 
assessment 
FOLLOW-
UP
28 Days 
(+7) after 
discontinu
ation of 
study drug
SCREENING
Up to 28 days 
before 
randomization 
for all 
processes 
EXCEPT 
tumour 
assessments.  
Tumour 
assessment 
required within 
21 days of 
randomization
Tumour Assessments
At times specified in Flow Chart until Progressive Disease
On-Study Period
For collection of Adverse Events and Serious Adverse Events 


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A steering committee including the coordinating investigators, experienced investigators and 
BI representatives will monitor the trial on a regular basis (all operational aspects, 
recruitment issues, data quality, etc.). A steering committee charter will be prepared 
specifying the objectives of the committee.
A data monitoring committee (DMC) will be formed consisting of three experienced and 
independent members, including two clinicians and one biostatistician who, collectively, 
have expertise in the management of patients with lung cancer and in the conduct and 
monitoring of randomised clinical trials.
The DMC will meet regularly and their responsibility is to continuously assess the trial data 
to ensure overall safety in the treated patients, monitor the quality and provide BI and the trial 
steering committee with advice about the conduct of the trial and the integrity of the data. 
The DMC will oversee the interim analysis planned in the study.  Details of the DMC 
responsibilities will be described in the DMC charter. 
Inclusion of patients in the trial will continue during the scheduled meetings of the DMC. 
Decisions on trial termination, amendment or cessation of patient recruitment, based on 
safety or outcome findings will be made after recommendations from the DMC have been 
assessed by the sponsor.
, a Contract Research Organization (CRO), will be responsible for DMC management 
and oversight.  
 will also coordinate and provide medical writing support for the DMC 
charter.  Clinical Trial Master File (CTMF) contents relating to DMC conduct will be 
maintained at 
 through the course of the study, and will be transferred to the BI CTMF at 
the end of the trial.
On-site monitoring will be performed by BI or a CRO appointed by BI.
BI will appoint CROs and independent service providers for special services such as central 
independent review of CT scans and MR images, central laboratory services, electronic 
collection of QoL questionnaires, and Interactive Voice/Web Response System (IXRS) for 
randomisation and trial medication logistics.
All trial relevant documentation will be stored in the clinical trial master file (CTMF) at BI, 
with the exception of DMC correspondence as explained above. In addition each site will 
have an Investigator Site File (ISF) containing all trial documents relevant for the site.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
This study will be a head-to-head comparison of a reversible first-generation TKI (erlotinib) 
to an irreversible second-generation TKI (afatinib) as second-line treatment in patients with 
advanced squamous NSCLC.  These patients have a limited life expectancy after disease 
progression following first-line therapy. This study will evaluate PFS as a primary endpoint; 
however, the study has adequate statistical power to meet the key secondary endpoint of 
increased OS in the patients receiving afatinib.


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The unique management of adverse events for afatinib and the comparator, which includes 
temporary and permanent discontinuation of study drug, presents significant challenges to 
effectively managing this trial while monitoring patient safety if the patient treatment 
assignment were blinded to the trial team.  Additionally, a double-blinded trial would require 
either over-encapsulation and subsequent equivalency testing be completed for two distinct
packaging schema of the comparator (i.e. bottles in the US and PVC blister-packaging in the 
rest of world).  Therefore, this study will be conducted in an open-label fashion with ICH E9 
recommendations to minimize potential bias incorporated (R08-2251).
Steps to minimize potential bias, especially in the assessment of the primary objective, are in 
place for this study.  These include the use of a central randomization method, to eliminate 
the potential that an investigator’s decision to enroll the next study patient be influenced by 
knowing the next treatment assignment.  The PFS primary endpoint will have an independent 
radiology review in which the assessors will be blinded.  Potential bias of the sponsor 
management of the trial will be minimized by not allowing the trial team access to aggregate 
data analysis by assigned treatment groups during the conduct of the study up to formal 
disclosure of PFS and/or OS results to the trial team (see Section 4.1.5.1). Any data reviews 
will present patients in Dummy treatment groups, and all options to complete reviews by 
aggregate treatment group (i.e. by use of JReview data review tool) will be disabled to all 
trial team members. The treatment group assignment will be known on a per-patient basis in 
the eCRF.
Several studies enrolling all NSCLC histologies have been completed with first-generation 
TKIs.  Details of these have been discussed in Sections 1 and 2.
Initial activity of afatinib in squamous cell carcinoma including NSCLC has been assessed in
several trials as described in Sections 1 & 2. 
It is considered that a difference of four weeks improvement in PFS for afatinib compared to 
the approved treatment (erlotinib) is clinically meaningful in this tough to treat patient 
population that has limited alternatives for treatment.
3.3
SELECTION OF TRIAL POPULATION
Approximately 800 patients will be randomized at approximately 200 study sites globally.  
The study will be conducted in approximately 24 countries.  The rate of randomization will 
vary by study site, but is expected to be approximately 2-15 patients per site. 
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 
randomized into the trial or not.
3.3.1
Main diagnosis for study entry 
This study will enroll patients with a diagnosis of advanced NSCLC squamous cell histology;
who have disease progression after completion of at least 4 cycles of platinum-based doublet 


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chemotherapy treatment in the 1st line setting of advanced disease; and who are eligible to 
receive 2nd-line therapy.
NOTE:  All staging criteria listed below are based on AJCC Staging for NSCLC 7th Edition
(R11-1417).
3.3.2
Inclusion criteria
1.
Diagnosis of advanced stage NSCLC considered to be squamous histology, including 
mixed histology, in the opinion of the investigator.
2.
Completion of at least 4 cycles of platinum-based doublet chemotherapy, with or 
without additional [non-EGFR] targeted agents, as 1st line treatment of Stage IIIB/IV 
NSCLC.   Note the below scenarios are also considered to meet this requirement:
a.
Patients relapsing within 6 months of completing adjuvant/neo-
adjuvant/curative -intent chemotherapy/chemoradiotherapy (Note: these 
patients are still required to have had the equivalent of 4 cycles of platinum-
based doublet chemotherapy except in setting noted below).
OR
b. Patients intending to receive four cycles of platinum-based doublet 
chemotherapy but due to toxicity, and not PD, discontinue just the platinum 
agent after at least two cycles of platinum doublet had been administered.
3.
Eligible to receive 2nd line therapy in the opinion of the investigator.  Patients who 
received non-EGFR based therapy for maintenance are eligible.
4.
Measurable disease according to RECIST 1.1 (R09-0262). Refer to Appendix 10.1.
5.
Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 (R01-0787). Refer to 
Appendix 10.2.
6.
Availability of tumour tissue material for correlative studies (refer to Section 5.6).  
Archived tumour tissue is acceptable.
7.
Adequate organ function, defined as all of the following:
a.
LVEF >50% or within institution normal values.
b.
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).
c.
Platelet count >75,000 / mm3.
d.
Estimated creatinine clearance > 45ml / min.  Refer to Appendix 10.3.


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e.
Total bilirubin < 1.5 times institutional ULN (Patients with Gilbert’s 
Syndrome total bilirubin must be <4 times institutional ULN).
f.
Aspartate amino transferase (AST) or alanine amino transferase (ALT) 
< three times the institutional upper limit of normal (ULN) (if related to liver 
metastases < five times institutional ULN).
8.
Recovered from any previous therapy related toxicity to ≤CTCAE Grade 1 at study 
entry (except for stable sensory neuropathy ≤CTCAE Grade 2 and alopecia).
9.
Ability to take oral medication in the opinion of the investigator.
10. Age ≥ 18 years.
11.
Written informed consent that is consistent with ICH-GCP guidelines.
3.3.3 Exclusion criteria
1.
Prior treatment with EGFR directed small molecules or antibodies.
2.
Curative intent chemoradiotherapy as the only treatment for stage IIIB NSCLC unless 
relapse occurs within 6 months of completion of treatment, and in the opinion of the 
investigator the patient has received an equivalent of 4 cycles of platinum-based 
doublet therapy.
3. Radiotherapy within 4 weeks prior to randomization, except as follows:
a. Palliative radiation to target organs other than chest may be allowed up to 
2 weeks prior to randomization, and
b. Single dose palliative treatment for symptomatic metastasis outside above 
allowance to be discussed with sponsor prior to enrolling.
4.
Active brain metastases (stable for <4 weeks, symptomatic, or leptomeningeal 
disease).  Dexamethasone therapy will be allowed if administered as a stable dose for 
at least 4 weeks before randomization.
5.
Any other current malignancy or malignancy diagnosed within the past three (3) 
years (other than basal-cell carcinoma of the skin, in situ cervical cancer, in situ 
prostate cancer).
6.
Known pre-existing interstitial lung disease.
7.
Significant or recent acute gastrointestinal disorders with diarrhoea as a major 
symptom e.g. Crohn's disease, malabsorption or CTC grade ≥2 diarrhoea of any 
aetiology, based on investigator assessment.


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8.
History or presence of clinically relevant cardiovascular abnormalities such as 
uncontrolled hypertension, congestive heart failure NYHA classification of 3 (Refer 
to Appendix 10.4), unstable angina or poorly controlled arrhythmia as determined by 
the investigator. Myocardial infarction within 6 months prior to randomisation.
9.
Any other concomitant serious illness or organ system dysfunction which in the 
opinion of the investigator would either compromise patient safety or interfere with 
the evaluation of the safety of the test drug.
10.
Women of child-bearing potential and men who are able to father a child, unwilling 
to be abstinent or use adequate contraception prior to study entry, for the duration of 
study participation and for at least 2 months after treatment has ended. Adequate 
methods of contraception and Women of Child-Bearing Potential are discussed in 
Section 4.2.2.3.
11.
Female patients of childbearing potential (see Section 4.2.2.3) who are nursing or are 
pregnant.  
12.
Patients unable to comply with the protocol in the opinion of the investigator.
13.
Active hepatitis B infection (defined as presence of Hep B DNA), active hepatitis C
infection (defined as presence of Hep C RNA) and/or known HIV carrier.
14.
Known or suspected active drug or alcohol abuse in the opinion of the investigator.
15.
Requirement for treatment with any of the prohibited concomitant medications listed 
in Section 4.2.2.
16.
Any contraindications for therapy with afatinib or erlotinib.
17.
Known hypersensitivity to erlotinib, afatinib or the excipients of any of the trial 
drugs.
18.
Major surgery within 4 weeks of starting study treatment.
19.
Prior participation in an afatinib clinical study, even if not assigned to afatinib.
20.
Use of any investigational drug within 4 weeks of randomisation (unless a longer 
time period is required by local regulations or by the guidelines for the 
investigational product).
21.
Patients without Progressive disease.


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3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
The Investigator or subject themselves may stop study treatment at any time for safety or due 
to patient personal reasons.  
If a patient is entered in violation of inclusion/exclusion criteria, the sponsor will determine 
the medical risk/benefit on a case-by-case basis and can require such a patient be 
discontinued from the study treatment.
A patient is to discontinue study medication if the patient:
1. Withdraws consent to further study medication.
2. Has radiologically documented progressive disease (Section 5.1.2).
3. Becomes pregnant (Section 5.2.2.2).
4. Is diagnosed with ILD.
5. Has the need for study drug discontinuation due to AEs or for further dose reductions 
considered necessary but not allowed according to the protocol (Section 4.1.4).
The sponsor may remove patients from the study after completion of the primary efficacy 
analysis if the patient has access to study treatment 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 (afatinib or erlotinib) will be incurred by the sponsor until disease progression 
occurs. If a patient is removed from the study treatment, an end of treatment 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.
Patients who withdraw from the trial after randomisation will not be replaced.
3.3.4.1.1 Patient discontinuation of study participation
A patient who has discontinued study drug for any of the reasons listed above except reason 5 
(i.e. study drug toxicity), will complete a FUP visit and then continue in the Observation 
Period of the study for vital status and anti-cancer treatment monitoring.  Patients who 
discontinue study drug due to any reasons other than 2 or 3 above will continue to have 
tumour assessments until disease progression or start of new anti-cancer therapy, following 
the same schedule Observation Period assessments will be completed as indicated in the Flow 
Chart. Once Protocol Version 3.0 is final (and where required locally, approvals are obtained 
by the site as per Section 8.1), the collection of vital status data will be ceased.


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If a patient withdraws consent for any further trial procedures and follow-up activities, no 
additional study assessments will be completed.  This will be documented in the eCRF.  
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. Failure to meet expected enrollment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information that could significantly affect 
continuation of the trial.
3. Violation of GCP, the CTP, or the contract by a trial site or investigator, disturbing 
the appropriate conduct of the trial.
4. The recommendation of the DMC that would require discontinuation of the trial, or 
the planned futility analysis response is not met.
5. Discontinuation of the clinical development programme with afatinib due to emerging 
data on afatinib.
6. The primary analysis has been completed and all patients have either ended study 
treatment or are eligible to receive afatinib under the conditions indicated in 3.3.4.1.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
Patients will be randomized to receive either afatinib or erlotinib.
4.1.1
Identity of BI investigational product and comparator products
Substance (INN):
Afatinib
Pharmaceutical form:
Film-coated Tablet
Source: 
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
50 mg, 40mg, 30mg and 20mg film-coated Tablets (the dose of 
afatinib in the film-coated Tablets is related to the free base 
equivalent of afatinib)
Posology:
Once daily
Route of administration:
Oral (swallowed)
Substance (INN):
Erlotinib (Tarceva®)
Pharmaceutical formulation: Film-coated Tablets
Source:
OSI Pharmaceuticals Inc. and Roche Ltd.
Unit Strength:
150 mg, 100mg, 25mg film-coated Tablets (the dose of strength 
of erlotinib hydrochloride of 163.9 mg, 109.3 mg and 27.3 mg 
is equivalent to erlotinib strengths 150 mg, 100 mg, and 25 mg, 
respectively)
Posology:
Once daily
Route of administration:
Oral (swallowed)
4.1.2
Method of assigning patients to treatment groups
Patients will be randomised 1:1 to either afatinib or erlotinib. The randomisation will be 
stratified based on race (Eastern Asian vs. non-Eastern Asian), as specified in the flow chart.
Randomisation will be carried out centrally using an Interactive Voice/Web Response System 
(IXRS). The company that provides the IXRS system will receive the randomisation list from 
Boehringer Ingelheim Clinical Trial Support Group or a CRO appointed by the Sponsor. The 
BI standard validated random number generating system will be used to generate the 


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randomisation schedules which will be verified by an independent statistician who is not 
involved in the study. The access to the randomisation code will be supervised by Clinical 
Trial Support Group. Persons directly involved in the conduct and analysis of the trial have 
no access to the randomisation schedule prior to database lock. 
Investigators and site staff delegated IXRS responsibilities will receive unique user IDs and 
passwords; and a manual describing how to access and use the IXRS.
4.1.3
Selection of doses in the trial
Based on early phase clinical trials, a daily dose of 50 mg in the monotherapy setting was 
identified as the dose for further development. This was used initially in EGFR TKI 
refractory population and several other Phase II/III and proof of concept trials.  Given a 
higher propensity of grade 3/4 AEs (especially diarrhoea) and no loss of efficacy especially in 
the EGFR mutation positive population, the dose was reduced to 40 mg in the pivotal Phase 
III trials in EGFR mutated population (P10-12524, P10-12525, P10-12529).  The 1200.22 
(LUX-Lung 2) study enrolled 99 patients who started afatinib at 50mg, and 30 patients 
starting at 40mg.  While there was no substantial change in the occurrence of all AE grades 
for the two most frequent AEs, diarrhoea (96.7% in the 40 mg group compared to 93.9% in 
the 50 mg group) and rash/acne (90.0% in the 40 mg group compared to 92.9% in the 50 mg 
group); there was a substantial difference in the occurrence of grade 3 AEs for diarrhea (6.7% 
in the 40 mg group vs 24.2% in the 50mg group) and rash/acne (6.7% in the 40 mg group and 
25.3% in the 50 mg group).  Neither group had grade 4 or 5 AEs reported for these terms 
(P10-12524).  Refer to the current IB for additional details (U03-3218).  In NSCLC and other 
indications, durable responses (>20 months) have been observed with daily dosing of afatinib 
of 40 mg and less (P10-09678).  The dose selection for this trial follows the above principle
especially noting that the population in the trial will be naive to EGFR TKI, and with 
associated comorbidities from smoking history may be at risk for higher rate of 
discontinuation if a starting dose of 50 mg daily were chosen. Additionally, squamous cell 
NSCLC patients represent EGFR wt population that may benefit from intensifying maximal 
doses. Thus, in this trial development of afatinib will continue at a starting dose of 40 mg to 
optimize the tolerability and efficacy balance.  The daily dose will be modified following 
careful monitoring of patient’s drug-related adverse events and medication compliance; with 
option to dose-escalate to 50 mg for patients meeting the criteria specified in Section 4.1.4.1.
The starting dose for erlotinib is 150 mg daily continuously in accordance with the Tarceva® 
package insert.  In case of drug-related adverse events, the dose will be reduced to 100 mg 
and 50 mg daily, as described in Section 4.1.4.2.1.
4.1.4
Drug assignment and administration of doses for each patient
4.1.4.1
Afatinib assignment and administration
Patients randomised to the afatinib arm will take a single oral dose of afatinib each day 
starting at a dose of 40 mg, continuously, until the development of progressive disease or 


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unacceptable adverse events.  Dose escalation and reductions can occur.  See 
Sections 4.1.4.1.1 and 4.1.4.1.2.
The medication should be taken at the same time each day at least one hour before food 
intake and at least three hours after food intake.  The tablet should be swallowed with a glass 
of water (250 mL).
Missed doses of afatinib can be made up during the same day, following the administration 
guidelines in the above paragraph.  Otherwise, the dose must be skipped and patients should 
take the next scheduled dose at the usual time.  Patient with emesis must not take a 
replacement dose.
Medication will be dispensed in bottles containing 30 tablets at the beginning of each 
treatment course.  For administrative purposes, a treatment course is defined as 28 days. 
Treatment will start when the patient is randomized and stop when the patient is determined 
to have disease progression or for any reasons detailed in Section 3.3.4.1.  Study drug will be 
prescribed by the investigator and may be dispensed either by the investigator, site staff or 
affiliated pharmacy.
4.1.4.1.1 Dose escalation for afatinib
The dose of afatinib administered may be escalated to 50 mg at the start of Course 2 if all of 
the following criteria are met during Course 1:
Drug-related CTCAE grade <1 skin rash
Absence of diarrhoea, mucositis, and/or any drug-related event (any grade) other than 
skin rash CTCAE <1
Afatinib dose was not previously reduced due to any of the AEs depicted in the Dose 
reduction scheme Table 4.1.4.1.2: 1
Compliant dosing of afatinib, as described in Section 4.3
Dose escalation is prohibited in any situation other than that prescribed above.  The patient 
should remain on 50 mg unless dose reduction becomes necessary (see Table 4.1.4.1.2: 1).
4.1.4.1.2 Dose reduction for afatinib
In the event of treatment-related toxicities, the treatment with afatinib should be handled 
according to the schedule in Table 4.1.4.1.2: 1.


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Table 4.1.4.1.2: 1
Dose reduction scheme for afatinib
AE type and CTCAE Grade
Action
Dose reduction scheme
Events related to study drug:
Diarrhoea 
Grade 2 persisting for 2 or more 
consecutive days (48 hours) 
despite adequate anti-diarrhoeal 
medication/hydration               
Nausea and/or Vomiting    
Grade 2 persisting for 7 or more 
consecutive days despite anti-
emetic treatment/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 
reduced dose according 
to schedule opposite.
If 
patient 
has 
not 
recovered to Grade ≤1 or 
baseline1 within 14 days 
study treatment must be 
permanently 
discontinued2.
If patient was receiving      
50 mg, resume treatment 
at a dose of 40 mg.
If patient was receiving      
40 mg, resume treatment 
at a dose of 30 mg.
If patient was receiving      
30 mg, resume treatment 
at a dose of 20 mg.
If patient was receiving 20 
mg, discontinue afatinib.
Acute onset and/or unexplained 
worsening of pulmonary systems 
(dyspnea, 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 at current 
dose.  If AEs are drug 
related, follow directions 
in row above.
If ILD is confirmed, 
discontinue afatinib
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 
judgement, further treatment with afatinib will be decided in agreement between the sponsor and the 
investigator.
In the event of any unrelated adverse events, the investigator may choose to interrupt the 
medication for up to 14 days, but no dose reduction should occur.  If the medication is 
interrupted for more than 14 days, the decision to continue with afatinib will be made by the 


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investigator in agreement with the BI Clinical Monitor. Continuous dose interruption of 
>28 days is not allowed.
4.1.4.2
Erlotinib
Patients randomised to the erlotinib arm will take a single oral dose of erlotinib each day 
starting at a dose of 150 mg, continuously, until the development of progressive disease or 
unacceptable adverse events.  Dose reductions can occur.  See Section 4.1.4.2.1.  Erlotinib 
should be taken the same time each day, always one hour before food intake and two hours 
after food intake.  Missed dose can be taken the same day at least one hour before or two 
hours after the ingestion of food.  If daily dose is missed entirely, the regularly prescribed 
dose should be taken the next day.  Do not double the dose of erlotinib.
For administrative reasons, treatment courses are 28 days (4 weeks).  At the beginning of 
each treatment course, patients will be provided either a bottle containing 30 tablets of 
150 mg or 100 mg erlotinib if the patients are receiving 150 mg or 100 mg of erlotinib, 
respectively,  or 2 bottles containing 30 tablets in each bottle of 25 mg of erlotinib if the 
patients are receiving erlotinib 50 mg; or blister packs containing 30 tablets of either 150 mg 
or 100 mg erlotinib if the patients are receiving 150 mg or 100 mg of erlotinib, respectively,  
or a blister pack containing 60 tablets of 25 mg erlotinib if the patient is receiving 50 mg of 
erlotinib daily.    Study treatment will be started at Course 1, visit 1 and will end when patient 
discontinues study drug due progressive disease progression or for any reasons detailed in 
Section 3.3.4.1.  Study drug will be prescribed by the investigator and may be dispensed 
either by the investigator, site staff or affiliated pharmacy.
4.1.4.2.1 Dose reduction and discontinuation of erlotinib
In the event of treatment toxicities, the treatment with erlotinib should be handled according 
to the schedule in Table 4.1.4.2.1: 1.


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Table 4.1.4.2.1: 1
Dose reduction and discontinuation scheme for erlotinib
AE type and CTCAE Grade
Action
Dose reduction scheme
Diarrhoea                            
Grade 2 persisting for 2 or more 
consecutive days (48 hours) 
despite adequate anti-diarrhoeal 
medication/hydration               
Ocular disorders
Onset of ocular disorders requiring 
treatment intervention or >CTCAE 
Grade 3 OR
worsening ocular disorders >1 
CTCAE Grade
Dermatology/skin
Any dermatology/skin CTCAE 
>Grade 3
Total bilirubin >3 x ULN and/or 
transaminases are >5 x ULN in pts 
with normal baseline
Total bilirubin >3 x ULN in pts 
with hepatic impairment (total 
bilirubin > ULN or Child Pugh 
A,B and C)
Dehydration in patients at risk for 
renal failure
Any drug related AE Grade ≥3
Pause 
treatment 
until 
patient has recovered to 
Grade ≤1 or baseline1.
Resume 
treatment 
at 
reduced dose according 
to schedule opposite.
If 
patient 
has 
not 
recovered to Grade ≤1 or 
baseline1 within 14 days 
study treatment must be 
permanently 
discontinued2.
If patient was receiving   
150 mg, resume 
treatment at a dose of 
100 mg.
If patient was receiving   
100 mg, resume 
treatment at a dose of 
50 mg.
If patient was receiving 
50 mg, discontinue 
erlotinib.
Hepatic failure or gastrointestinal 
perforation
Acute/ worsening ocular disorders
more severe than allowed above 
for dose reduction
Discontinue erlotinib


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Table 4.1.4.2.1: 1(continued) Dose reduction and discontinuation scheme for erlotinib
AE type and CTCAE Grade
Action
Dose reduction scheme
Acute onset and/or unexplained 
worsening of pulmonary systems 
(dyspnea, cough, fever)
Pause erlotinib 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 erlotinib at 
current dose.  If AEs 
are drug related, follow 
directions in row 
above.
If ILD is confirmed, 
discontinue erlotinib.
* Patients taking erlotinib with an inhibitor of both CYP3A4 and CYP1A2 and experiencing a severe 
adverse reaction should be evaluated for a dose reduction of erlotinib.
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 
judgement, further treatment with erlotinib will be decided in agreement between the sponsor and the 
investigator.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This open-label trial will be treated as blinded by the sponsor until primary analysis database 
lock.
The Data Monitoring Committee (DMC) will be provided with unblinded data in order to 
ensure the ongoing safety and efficacy of the trial. Data unblinding as required for the DMC 
review will be conducted on an ongoing basis by a data manager or CRO not involved in the 
trial in order to keep the trial team blinded.
For the primary analysis of PFS, the trial team will complete the aggregate analysis.
4.1.5.2
Procedures for emergency unblinding
Not applicable.


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4.1.6
Packaging, labelling, and re-supply
Details of packaging and sample labels will be found in the Investigator Study File (ISF). 
Trial drug packages will have unique medication numbers which will be used for tracking 
purposes only. The medication numbers will not be linked to randomisation numbers.
Afatinib will be supplied as film-coated Tablets. Available dosage strength will be 20 mg, 
30 mg, 40 mg, and 50 mg. Tablets will be supplied in 
, 
child-resistant, tamper-evident bottles.
Erlotinib will be supplied as film-coated Tablets.  Available dosage strength will be 25 mg, 
100 mg, and 150 mg.  Tablets will be supplied in child-resistant bottles in the US and 
Canada.  For all other countries, erlotinib will be supplied in polyvinyl chloride (PVC) blister 
sealed with aluminium foil.
Resupply of all study medication will be managed by the IXRS system.  Details are provided 
in the ISF and IXRS User Guides.
4.1.7
Storage conditions
Trial medication, which will be provided by the sponsor and/or a CRO appointed by the 
sponsor, must be kept in a secure, limited access storage area under the storage conditions 
defined below until supplied/administered to patient. Temperature logs must be maintained to 
make certain that the drug supplies are stored at the correct temperature. In case temperature 
would be out of range, this has to be reported in the ISF and the sponsor be notified.
4.1.7.1
Storage conditions for afatinib
Afatinib 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 instructions on the label.
Patients should be instructed to keep the bottles tightly closed to protect from moisture.
4.1.7.2
Storage conditions for erlotinib
Erlotinib must be stored in the original packaging according to the instructions on the label.
If the erlotinib storage conditions are found to be outside the specified range, contact the local 
clinical monitor as provided in the list of contacts.
4.1.8
Drug accountability
Drug supplies, which will be provided by the sponsor or CRO appointed by the sponsor, must 
be kept in a secure, limited access storage area under the storage conditions defined by the 
sponsor. A temperature log (documenting at least a weekly min/max temperature reading) at 


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the study site must be maintained to make certain that the drug supplies are stored at the 
correct temperature.
The investigator /pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor or CRO when the following requirements are 
fulfilled:

approval of the study protocol by the IRB / ethics committee,

availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre,

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,  if permitted by local regulations.

All other local requirements are met (i.e. submission of completed, signed Form 1572 
in the US)
The investigator / pharmacist / 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). 
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational product(s) and trial patients. The 
investigator / pharmacist / 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 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 treatments
Rescue medication
Rescue medications to reverse the actions of afatinib are not available. There is no specific 
antidote for overdosage with afatinib. Potential adverse events should be treated 
symptomatically. Common adverse events of treatment with afatinib include diarrhoea, 
nausea, vomiting, rash/acne and stomatitis. 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 below.
Concomitant treatments


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Concomitant medications or therapy to provide adequate supportive care may be given as 
clinically necessary. 
After randomization, palliative radiotherapy may be initiated 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. The irradiated area can not be used for 
tumour response assessment. During palliative radiotherapy, study treatment should be held 
and may be resumed once the patient has recovered from any radiation associated toxicity. If 
the medication is interrupted for more than 14 days, the decision to continue will be made by 
the investigator in agreement with the BI Clinical Monitor. Continuous dose interruption of 
>28 days due to palliative radiotherapy is not allowed.
All concomitant therapy, including anaesthetic agents, vitamins, homeopathic/herbal
remedies, nutritional supplements, must be recorded in the eCRF during the screening and 
treatment period, starting with any medications taken within 4 weeks of the screening visit, 
and ending at the EOT visit. After the EOT visit, only concomitant therapy indicated for 
treatment of an AE has to be reported. 
In case of major surgery (as judged by the investigator), it is recommended to stop treatment 
with afatinib around one week prior to the surgery, and to restart treatment after complete 
wound healing. If the medication is interrupted for more than 14 days, the decision to 
continue medication will be made by the investigator in agreement with the BI Clinical 
Monitor.
Refer to the Tarceva® SPC/PI included in the site ISF for management of AEs due to 
treatment with erlotinib.
Emergency procedures
For patients receiving either afatinib or erlotinib, 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). Study drugs should be 
interrupted pending investigation of these symptoms. If interstitial lung disease is diagnosed, 
study drug must be permanently discontinued and appropriate treatment instituted as 
necessary. Refer to Tables 4.1.4.1.2: 1 and 4.1.4.2.1:1 for details.
Emergency contact information is provided in the ISF.
4.2.2
Restrictions 
4.2.2.1
Restrictions regarding concomitant treatment
Concomitant medications, or therapy to provide adequate supportive care, may be given as 
clinically necessary. 
Palliative radiotherapy may be given as described in Section 4.2.1.


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Patients receiving erlotinib and taking warfarin or other coumarin-derivative anticoagulants 
should be monitored regularly for changes in PT and INR.
Additional experimental anti-cancer treatment and/or standard chemo-, immunotherapy, 
hormone treatment; with the exception of bisphosphonates (denosumab is excluded), 
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 study treatment. 
 
 
Erlotinib
Erlotinib is metabolized predominantly by CYP3A4, and inhibitors of CYP1A2 would be 
expected to increase exposure to the drug.  Caution should be used during co-treatment with 
erlotinib and CYP3A4 inhibitors, and in some situations a decreased dose of erlotinib may be 
required.  CYP3A4 inducers may increase clearance of erlotinib.  See Appendix 10.6 for a list 
of common CYP3A4 inhibitors and inducers.  Alternate treatments should be considered.  If 
an alternate treatment is not possible, erlotinib dose modifications should considered.  
Grapefruit and grapefruit juice can reduce the availability of CYP3A4 enough to significantly 
increases the bioavailability of drugs metabolized by CYP3A4 (P04-06229).
St. John’s Wort increases the activity of CYP3A4, effectively decreasing the bioavailability 
of drugs metabolized by the same system.
Erlotinib is metabolized to a lesser extent by CYP1A2.  Caution should be used during 
co-treatment with erlotinib and CYP1A2 inhibitors, and in some situations a decreased dose 
of erlotinib may be required (R11-1186).  
Co-administration of erlotinib with omeprazole, a proton pump inhibitor, decreased the 
erlotinib AUC. The concomitant use of proton pump inhibitors should be avoided if possible.
Co-administration of erlotinib with ranitidine, an H2 receptor antagonist, decreased the 
erlotinib AUC.  Erlotinib and any H2 receptor antagonist should be taken in a staggered 
manner.  Erlotinib must be taken once a day 10 hours after the H2 receptor antagonist dosing 
and at least 2 hours before the next dose of H2 receptor antagonist.
Refer to Appendix 10.6 and the Tarceva® SPC or PI included in the ISF for more 
information.


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4.2.2.2
Restrictions on diet and life style
Patients receiving either afatinib or erlotinib should be advised to avoid intense irradiation 
with UV light and harsh detergents to prevent skin related adverse events.
Patients receiving afatinib or erlotinib should be advised to avoid any foods known to 
aggravate diarrhoea.
Suggest patients receiving afatinib or erlotinib use a thick, alcohol-free cream on dry areas of 
the body.
4.2.2.3
Women of child-bearing potential and pregnancy prevention
Patients who are not of child-bearing potential due to being postmenopausal (1 year without 
menstruations and at least 2 years without menstruation following chemotherapy) (R11-1406) 
or surgical sterilization (oophorectomy, hysterectomy and/or tubal ligation) do not need to 
use contraception to be eligible for participation in this trial.
All other patients are considered to have child-bearing potential and must use adequate 
contraception while participating in this trial (from screening until end of trial participation or 
2 months after last dose of trial medication, whichever is later).
Acceptable methods of birth control include surgical sterilization or double barrier method, 
and must be in accordance with local regulations where applicable.  Double barrier method of 
contraception is defined as two barrier methods used simultaneously each time the patient has 
intercourse.  Acceptable 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).  Those using hormonal contraceptives, or with 
partners using hormonal contraceptives, must also be using an additional approved method of 
contraception (as described above). Partner vasectomy, natural “rhythm”, and spermicidal 
jelly/cream are not acceptable methods of contraception.
Women who become pregnant while participating in the study must discontinue study 
medication immediately.  The pregnancy must be reported following procedures detailed in 
Section 5.2.2.2.
4.2.3
Management of expected adverse events
Dermatologic adverse events and diarrhoea are the most common side-effects associated with 
treatment with afatinib. Treatment of these side-effects should be proactive and should be 
started as early as possible after onset of symptoms.
The most common adverse events in NSCLC patients receiving erlotinib are rash and 
diarrhoea, anorexia, fatigue, dyspnea, cough, nausea, infection and vomiting (R11-1186).  
Refer to the Tarceva package insert for management of these events. 


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4.2.3.1
Management of diarrhoea and hydration status
Diarrhoea occurs at a high frequency and generally begins within 2 weeks of exposure to 
afatinib. Although usually mild to moderate, diarrhoea may lead to dehydration and compel 
treatment modification or discontinuation, so early management is essential 
(Table 4.2.3.1: 1). At the time of initiation of treatment with afatinib, site staff should ensure 
patients are counseled on prompt reporting of any diarrhoea and instituting corrective 
measures such as hydration and treatment with antidiarrhoeals.  Sites should confirm that a 
patient has ready access to antidiarrhoeal medication.
Patients must be advised to drink an adequate amount of fluids to make up for the fluid lost 
through diarrhoea. 


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Table 4.2.3.1: 1
Grade specific treatment of study-drug related diarrhoea
Severity 
(CTCAE Grading)
Description 
Intervention concerning 
afatinib 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 clear fluids per day;
4 mg (2 Tablets) of loperamide 
to be taken immediately, 
followed by 2 mg (1 Tablet) 
after each loose stool until 
bowel movements cease for 12 
hours
Moderate (Grade 2)
Increase of 4-6 stools per 
day over baseline; iv. 
fluids indicated < 24 
hours; moderate increase 
in ostomy output 
compared with baseline; 
not interfering with ADL
Continue same dose 
unless Grade 2 
diarrhoea continues for 
≥ 2 days (48 hours) in 
which case treatment 
must be interrupted 
until recovered to ≤
Grade 1 followed by 
dose reduction
Continue loperamide; 
assess for dehydration and 
electrolyte imbalance;
consider iv 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
Dose interruption until 
recovered to ≤Grade 1 
followed by dose 
reduction1
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) 
Dose interruption until 
recovered to ≤Grade 1 
followed by dose 
reduction1
See Grade 3
1If despite optimal supportive care and a treatment interruption, diarrhoea does not resolve to CTC AE Grade ≤1 
within 14 days, treatment with afatinib must be permanently discontinued. 
4.2.3.2
Management of dermatological AEs
Dermatologic AEs of afatinib include rash, acne, dermatitis acneiform, and dry skin. General 
recommendations for prophylaxis are summarized in Table 4.2.3.2: 1 and grade-specific 
treatment recommendations are summarized in Table 4.2.3.2: 2. For dose adjustment of 
afatinib and erlotinib refer to Section 4.1.4.  
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).


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Table 4.2.3.2: 1
General recommendation for prophylaxis while receiving study drug
Personal hygiene
Use of gentle soaps and shampoos for the body, e.g. pH 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. It is recommended that cuticles not 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, PABA 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 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.
Table 4.2.3.2: 2
Grade specific treatment recommendations of skin reactions
Severity 
(CTCAE Grading)
Description
Specific intervention
ACNEIFORM RASH
Mild (Grade 1)
Macular or papular eruptions or 
erythema without associated 
symptoms
Consider topical antibiotics, e.g. 
clindamycin 2% or topical erythromycin 1% 
cream of metronidazole 0.75% 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 treatment as for Grade 1 
plus short term topical steroids, e.g. 
prednicarbate cream 0.02% plus
an oral antibiotic (for at least 2 weeks) e.g. 
Doxycycline 100mg b.i.d. or Minocycline 
hydrochloride 100mg b.i.d.


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Table 4.2.3.2: 2(continued)
Grade specific treatment recommendations of skin reactions
Severity 
(CTCAE Grading)
Description
Specific intervention
ACNEIFORM RASH
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.
Consider referral to dermatologist.
Consider systemic steroids.
Life threatening 
(Grade 4)
Generalized exfoliative, ulcerative, 
or bullous dermatitis
See Grade 3.
Systemic steroids are recommended.
EARLY AND LATE XEROTIC SKIN REACTIONS - PRURITUS
Mild (Grade 1)
Mild or localized
Topical polidocanol cream.
Consider oral antihistamines (e.g. 
diphenhydramine, dimethindene, cetirizine, 
levocetirizine, desloratidine, fexofenadine 
or clemastine).
Moderate (Grade 2)
Intense or widespread
See Grade 1 plus oral antihistamines;
Consider topical steroids, e.g. topical 
hydrocortisone.
Severe (Grade 3)
Intense or widespread and interfering 
with activities of daily living (ADL)
See Grade 2.
XEROSIS (DRY SKIN)
Mild (Grade 1)
Asymptomatic
Soap-free shower gel and/or bath oil.
Avoid alcoholic solutions and soaps.
Urea- or glycerin-based moisturizer.
In inflammatory lesions consider topical 
steroids (e.g. hydrocortisone cream).
Moderate (Grade 2)
Symptomatic, not interfering with 
ADL
See Grade 1.
In inflammatory lesions consider topical 
steroids (e.g. hydrocortisone cream).
Severe (Grade 3)
Symptomatic,
interfering with ADL
See Grade 2.
Topical steroids of higher potency (e.g. 
prednicarbate, mometasone furoate)
Consider oral antibiotics.


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Table 4.2.3.2: 2(continued)
Grade specific treatment recommendations of skin reactions
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 (e.g. 
potassium permanganate therapeutic baths, 
final concentration of 1:10,000, or 
povidone-iodine baths).
Topical application of aqueous silver nitrate 
solutions to fissures.
Moderate (Grade 2)
Symptomatic, not interfering with 
ADL
See Grade 1. 
Consider oral antibiotics.
Severe (Grade 3)
Symptomatic,
Interfering with ADL
See Grade 2.
4.2.3.3
Management of mucositis/stomatitis
General and grade specific recommendations are described in Table 4.2.3.3: 1. For dose 
adjustment refer to Section 4.1.4 and for restrictions on concomitant therapies refer to 
Sections 4.2.3, 10.5 and 10.6.
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 manuovers 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, chillies, 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 4.2.3.3: 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 4.2.3.3: 1
Grade specific treatment recommendations of study-drug related 
mucositis/stomatitis
Severity 
(CTCAE grading)
Description 
Treatment recommendations
Intervention concerning 
afatinib 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.
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
4.3
TREATMENT COMPLIANCE
The study medication will be given in accordance with the protocol and the instructions of
the site investigator. 
The appropriate number of study medication for one cycle, or 4 weeks, of treatment will be 
provided to patients to be self-administered at home.
Patients will be asked to bring the remaining trial medication at the end of each cycle to the 
investigator site for a compliance check. The remaining film-coated tablets will be counted 
by the investigator/site staff and recorded at the investigator site. Discrepancies between the 
number of tablets remaining and the calculated number of tablets the patients should have 
taken must be documented and explained. At the end of each cycle any remaining medication 
will be collected. If the patient is eligible for further treatment, a new bottle of study 
medication must be dispensed. 
The investigator and/or the sponsor can withdraw a patient from the study in the event of 
serious and persistent non-compliance which jeopardizes the patient’s safety or render study 
results for this patient unacceptable. Patients repeatedly missing scheduled on-treatment 
study visits, unless due to exceptional circumstances, are considered non-compliant. A 
maximum of 20% of doses of study drug may be missed for other reasons than drug-related 
AEs. Patients who miss taking study drug more frequently are considered non-compliant.  
The BI clinical monitor must be contacted and these patients will be discussed.


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Non-compliant patients will be included in the efficacy analysis (as part of all patients 
randomized) and the safety analysis (as part of all patients treated).


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY
5.1.1
Endpoints of efficacy
The primary endpoint of this study is progression-free survival, as determined by RECIST 
1.1(R09-0262).
The key secondary endpoint of this trial is:

Overall survival
Other secondary endpoints of this trial are: 

Objective response (CR, PR) according to RECIST 1.1 (R09-0262)

Disease control (CR, PR, SD) according to RECIST 1.1 (R09-0262) 

Tumour shrinkage

Health-related Quality of Life (HRQoL)
5.1.2
Assessment of efficacy
5.1.2.1
Tumour Assessment
Response and progression will be evaluated in this study using Response Evaluation Criteria 
in Solid Tumours (RECIST) guideline version 1.1(R09-0262). Tumour response will be 
assessed by investigator for clinical management of the patient and by a retrospective central 
review.  Progression free survival will be defined as time from the date of randomization to 
the date of progression or to the date of death, whichever occurs first.
Full details of imaging procedures and RECIST 1.1 assessment can be found in Appendix
10.1
5.1.2.1.1 Central imaging
All image data will be sent to a central imaging unit to obtain an independent blinded 
confirmation of tumour response assessment based on a uniform interpretation of 
radiographic image data for all patients enrolled in the trial. Upon receipt, the central imaging 
unit will log all image data into a tracking system and perform quality control of digitised 
radiographic images. An independent review of radiographic images including (i) sequential 
lesion selection and measurement and (ii) incremental radiological response assessment 
followed by (iii) global review of tumour response or progression will be performed by two 
blinded (with regard to patient, treatment, and visit) radiologists. In the case of disagreement 
on the radiological assessment at any timepoint between the two primary reviewers, a third 


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adjudicating radiologist will select one of the primary reviewer’s interpretations for all 
timepoints. The data will also be reviewed by an oncologist who will provide a final 
assessment for each patient.
The review of the image data will be performed by independent radiologists, who are not
affiliated with the study. All procedures will be done according to the specifications provided 
in the investigator site file. The purpose of the blinded reading is to independently assess 
patient response to therapy and disease progression.
Modifications of the conventional RECIST 1.1 lesion measurement criteria will be introduced 
into the measurement process in an attempt to reduce variability in the measurements for the 
independent central imaging review.
Eligibility and treatment decisions will be based on the assessment of disease by the 
investigator. Central imaging will not be used for this purpose and the results of the central 
imaging review will not be communicated to the investigator.
After approval of Protocol Version 3.0, the independent imaging review will be discontinued
and sites will no longer require to send images to the central imaging unit.
5.2
SAFETY
5.2.1
Endpoints of safety
Safety of afatinib and erlotinib will be evaluated by intensity and incidence of adverse events, 
graded according to NCI CTCAE version 3.0 (R04-0474).  Safety endpoints include:
The overall incidence and intensity of adverse events
Gastrointestinal events (vomiting, nausea, diarrhoea)
Skin reactions (rash, acne)
Tolerability of afatinib and erlotinib will be assessed based on dosage reduction and 
discontinuation due to adverse events.
5.2.2
Assessment of adverse events
A diagram of the Adverse event/Serious Adverse events reporting requirements is presented 
in Appendix 10.7.
5.2.2.1
Definitions of adverse events
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.


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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 

Planned hospitalizations required by the protocol

Hospitalization planned prior to informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration)

Hospitalization for administration of study drug 
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. 
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 underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
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 “neoplasm 
progression (grade 5, outcome fatal).” 


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Changes in vital signs, ECG, physical examination, and laboratory test results 
Changes in vital signs, ECG, physical examination and laboratory tests will be recorded as an 
AE in the eCRF, if they are judged clinically relevant by the investigator.
Adverse Events of Special Interest (AESIs)
Although rare, drug-induced liver injury is under constant surveillance by sponsors and 
regulators and is considered as AESI.  Timely detection, evaluation, and follow-up of 
laboratory alterations of selected liver laboratory parameters to distinguish an effect of the 
underlying malignancy on liver function from other causes are important for patient safety.  
The following are considered as AESIs:
Hepatic injury defined by the following alterations of liver parameters: Hepatic injury defined 
by the following alterations of liver parameters:
o
For patients with normal liver function (ALT, AST and bilirubin within normal limits) 
at baseline an elevation of AST and/or ALT >3 fold ULN combined with an elevation 
of bilirubin >2 fold ULN measured in the same blood draw sample. Patients showing 
these lab abnormalities need to be followed up according to Appendix 10.9 of this 
clinical trial protocol and the "DILI checklist" provided in the ISF.
o
For patients with abnormal liver function at baseline an elevation of AST and/or ALT 
>5 fold ULN combined with an elevation of bilirubin >2 fold ULN measured in the 
same blood draw sample. Patients showing these lab abnormalities need to be 
followed up according to Appendix 10.9 of this clinical trial protocol and the "DILI 
checklist" provided in the ISF.  
AESIs are to be reported in an expedited manner similar to Serious Adverse Events, even if 
they do not meet any of the seriousness criteria - for details please see Chapter 5.2.2.2.
If the investigator determines any AESI is related to study drug, the administration of the 
study drug must be managed according to Section 4.1.4 of the protocol.
5.2.2.2
Adverse event and serious adverse event reporting
All adverse events, serious and non-serious, occurring during the course of the clinical trial 
(i.e., from signing the informed consent through to the Follow-up) will be collected, 
documented and reported to the sponsor by the investigator on the appropriate CRF(s) / 
eCRFs / SAE reporting forms. Serious AEs and AESIs occurring later than 28 days after the 
last administration of study drug will only be reported if deemed to be related to study drug.
Following approval of Protocol Version 3.0 and after the individual patient’s end of trial, the 
investigator does not require to actively monitor the patient for AEs but should only report 
relevant SAEs and AESIs that the investigator may become aware of. Reporting will be done
according to the specific definitions and instructions detailed in the ‘Adverse Event 


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Reporting’ Section of the Investigator Site File. A diagram of the reporting requirements is 
provided in Appendix 10.7.
For each adverse event, the investigator will provide the onset date, end date, intensity, 
treatment required, outcome, seriousness, and action taken with the investigational drug. The 
investigator will determine the relationship of the investigational drug to all AEs as defined in 
Section 5.2.2.1. 
The investigator also has the responsibility to report AEs according to the table below and 
Appendix 10.7:
Table 5.2.2.2: 1
AE/SAE Reporting
Time period
Reporting requirements
From signing of informed consent through to 
28 days after last trial drug administration
Report all AEs, SAEs and AESIs regardless 
of relatedness or whether the trial drug was 
administered. This includes all deaths.
Post-treatment (>28 days after last trial drug 
administration)
Report only SAEs and AESIs which are 
considered related to trial treatment that the 
investigator may become aware of.
Death should be reported as an SAE only 
when considered related to trial treatment 
(because death is an endpoint and will be 
followed-up separately).
Any AEs reported to the sponsor during this phase must be documented in the safety 
database.  
The investigator must report the events via telephone/fax using the SAE form immediately 
(within 24 hours) to the sponsor: SAEs, AESIs and non-serious AEs occurring at the same 
time as an SAE or AESI and/or which are medically related to the SAE or AESI. With receipt 
of any further information to these events, a follow-up SAE report has to be provided. SAEs, 
AESIs and non-serious AEs must include a causal relationship assessment made 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.


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The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU 
(country-specific contact details will be provided in the Investigator Site File). This 
immediate report is required irrespective of whether the investigational product has been 
administered or not and irrespective of causal relationship. It also applies if new information 
to existing SAEs becomes available. 
Pregnancy
In rare cases, pregnancy might occur in clinical trials. Once a female subject has been 
enrolled into the clinical trial, after having taken study 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 or next business day 
whichever is shorter) 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).
5.2.3
Assessment of safety laboratory parameters
Safety laboratory samples will be analyzed at a central laboratory (Quest Diagnostics). Safety 
laboratory examinations will include haematology, biochemistry and urine examinations. 
Table 5.2.3: 1 presents the laboratory tests to be performed.
After approval of Protocol Version 3.0, the safety laboratory samples will be analyzed in a 
laboratory facility at or nearby the investigational site; provided that the laboratory is 
appropriately certified and reference ranges are available.


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Table 5.2.3: 1
Clinical laboratory tests
Category
Parameters 
Hematology
haemoglobin, haematocrit, platelet count, white 
blood cell count (WBC). At screening only:  
neutrophils
Coagulation
International Normalized Ratio (INR), activated 
Partial Thromboplastin Time (aPTT)
Chemistry
Electrolytes
sodium, potassium, calcium, magnesium
Liver function tests
alkaline phosphatase, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), γ-
glutamyltransferase (GGT), total  bilirubin
Renal function parameters
blood urea/blood urea nitrogen (BUN), creatinine; 
Glomerular Filtration Rate (GFR) will be 
estimated utilising serum creatinine values (see 
Appendix 10.3)
Other
glucose, albumin
Urinalysis
pH, protein, glucose, blood, 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 
childbearing potential ( WOCBP)
The investigator should complete additional evaluations of laboratory tests as clinically 
indicated.  Any abnormal findings from these investigations need to be reported as an 
Adverse Event.
5.2.4
Electrocardiogram
12-lead ECGs will be taken at the time points specified in the flow chart if clinically 
indicated. ECGs will be completed locally at the study sites. 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, Performance Status
A full physical exam must include cardiopulmonary examination, examination of the regional 
lymph nodes, examination of the abdomen, and an assessment of the mental and neurological 


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status. Additional symptoms which have not been reported during a previous examination 
must be clarified. Wherever possible the same investigator should perform this examination.
A complete physical examination will be done as indicated on the flow chart. A 
symptom-directed examination is to be performed at all other visits as indicated in the flow 
chart. 
5.2.5.2
Vital Signs
Vital sign measurements- blood pressure [systolic blood pressure, diastolic blood pressure], 
pulse rate, respiratory rate, temperature, measurement of height (in cm, at screening) and 
body weight (in kg), and the evaluation of the ECOG performance status will be performed at 
the times specified in the flow chart.  
5.2.5.3
Left ventricular function
Left Ventricular Ejection Fraction (LVEF) as measured by ECHO or MUGA (ECHO only in 
Germany) will be assessed at time points specified in the flow chart if clinically indicated. 
The same method of measurement must be used throughout the trial.
5.3
OTHER
5.3.1
Other endpoints
Patient-reported outcomes will be measured with the following multidimensional
questionnaires included in Appendix 10.8.  

EQ-5D health status self-assessment questionnaire (R96-2382)

EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer
(EORTC) Quality of Life Questionnaire (QLQ-C30) (R99-1213, R07-2064)

EORTC Lung cancer specific supplementary module (EORTC QLQ-LC13) 
(R07-2060, R07-2065)
All three questionnaires will be completed at the time points specified in the Flow Chart.
After approval of Protocol Version 3.0, the completion of EQ-5D, EORTC QLQ-C30 and 
EORTC QLQ LC-13 questionnaires will no longer be required.
Questionnaires should be completed by patients prior to seeing the clinician, prior to clinical
assessment, prior to any treatment at the clinic, and before provision of any new information
about their disease status so that the responses are not influenced (biased). The questionnaires 
represent source documents. Validated translations exist for all questionnaires for all 
countries participating in the study and patients will receive the questionnaires in their native 
language.
Any unsolicited information provided by the patient on the questionnaire and any safety 
related data obtained from the patient’s responses to the standard questions on the 
questionnaires will be immediately reported to the investigator. The investigator will review 
the patient’s responses against the clinical assessment which corresponds to the timepoint the 


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questionnaire was completed for any potential AEs not captured during the clinical 
assessment.  If the investigator determines a new AE has occurred, this will be appropriately 
reported in the eCRF.
If local regulations require the completed questionnaires to be confidential (i.e. not seen by
the site staff) appropriate arrangements will be made to ensure confidentiality.
The patient perspective is considered a supportive contribution to inform physicians on the
clinical utility of afatinib compared to erlotinib in the NSCLC population under investigation.
In addition, the EQ-5D, HRQoL assessment will inform a later health economic 
(cost-effectiveness) analysis.
EQ-5D
The EQ-5D is a disease generic instrument that has been widely used and has been found to
capture HRQOL changes in NSCLC (R07-2129, R07-2130). The EQ-5D comprises the
following two questionnaires:
1. The EQ-5D comprises 5 dimensions of health (mobility, self-care, usual activities,
pain/discomfort, anxiety/depression). Each dimension comprises three levels (no 
problems, some/moderate problems, extreme problems).
2. The EQ VAS records the respondents self-rated health status on a vertical graduated 
(0- 100) visual analogue scale.
For the EQ-5D the respondent is asked to indicate his/her health state by placing a cross in
the box against the most appropriate statement in each of the 5 dimensions. Additional
instructions are provided in the ISF.
QLQ-C30 and LC-13
The QLQ-C30 is comprised of 30 questions. The QLQ-C30 incorporates both multi-items
scales and single-item measures. These include one global health status/HRQoL scale, five
functional scales, three symptoms scales and six single items to assess dyspnea, insomnia,
appetite loss, constipation, diarrhoea and financial difficulties. Each of the multi-item scales
includes a different set of items – no item occurs in more than one scale (R07-2064). The
QLQ-LC13 module comprises 13 questions. The module is designed for use in patients
receiving treatment with chemotherapy and / or radiotherapy. The QLQ-LC13 incorporates
one multi-item scale to assess dyspnoea, and a series of single items assessing pain,
coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and haemoptysis 
(R07-2064).
 
 


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planned visits specified in the flow chart for homecare use. Resource use collection will 
 
5.3.2
Other assessments
5.3.2.1
Demographics and history
Demographics (sex, birth date, race), alcohol history, and histological subtype will be 
collected during the screening 1 visit. The smoking history will be documented as follows:

Smoking status: smoker vs. non-smoker

Number of pack years = (number of cigarettes smoked per day x number of years 
smoked)/ 20 (R08-4072)

Date of last cigarette
History of NSCLC will be obtained during screening and reported in the eCRF:

The date of first histological diagnosis

The primary tumour site

The number and location of metastatic sites (bone, brain, liver, pleural effusion, other)

Tumour Stage according to the TNM-classification at initial diagnosis and study entry 
(i.e. re-staging of TNM).

Previous surgery and radiotherapy for NSCLC

Previously administered chemotherapy including start and end dates and the outcome
 
 
 
 
 
 
 
 
 


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5.4
APPROPRIATENESS OF MEASUREMENTS
All clinical assessments are standard measurements commonly used in studies of advanced 
solid tumours. RECIST version 1.1 is used for assessment of the change in tumour burden. 
These criteria are well established and well received by the regulatory authorities and 
scientific community. 
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.
The HRQoL questionnaires used in the present trial are recommended by and/or acceptable to 
multiple national authorities. 
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Pharmacokinetic analyses are not planned to be part of this trial.
5.6
BIOMARKERS
There are no approved predictive tumour- or serum-derived biomarkers for patients with 
advanced squamous cell carcinoma of the lung using erbB directed agents as second-line 
therapy following first-line platinum-based chemotherapy. Consequently, there is a strong 
rationale to identify predictive markers which are features at baseline that may predict 
responsiveness to ErbB TKI in this population. For the purpose of this trial, all patients are 
required to have archival tissue available and should consent blood samples for biomarker 
analyses.
If archival tumour tissue is available from more than one occasion the latest obtained sample
should be used wherever possible. The site of biopsy (primary tumour or metastatic site) 
should be recorded in the eCRF.
Tumour tissue derived biomarker
An optimal of 10 slides (minimum 5) from archival tumour tissue will be required for each 
patient randomized into the study.  Based on volume of tumour tissue in the submitted 
sample, testing will be conducted by a laboratory(s) designated by BI to evaluate diagnostics 
related to EGFR signalling pathways and/or cancer related genes (non-germline) which could 
impact the anti-tumor activity of afatinib.  These may consist of tests to detect gene 
amplification (e.g. FISH), genomic sequencing (e.g. EGFR mutation analysis) and/or 


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immunohistochemical expression (e.g. H-score). Further details will be provided in the 
laboratory manual. These tests are considered investigational and the results will not be 
available to the PI or patient while a patient is receiving study drug. Results will be available 
upon request of the PI for patients who have discontinued study drug.  Details of the request 
process will be provided in the ISF.
Serum derived biomarkers
The analyses will include determination of biomarkers similar to those previously described 
(R11-1316). Serum samples will be collected at baseline, at 4 weeks from the start of 
treatment and upon progression (EOT). All the analyses will be done by a central laboratory.  
Further details are provided in the laboratory manual.
5.6.1
Endpoints based on biomarkers
No endpoints in this trial are based on biomarkers.
5.6.2
Methods of sample collection
Detailed instructions for the collection and shipping of all tissue samples will be provided in 
the laboratory manual in the ISF.
5.6.3
Analytical determinations
See section 5.6 BIOMARKERS.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients must provide written informed consent (ICF) before any study related screening 
procedures can be used.  A diagram of the stages of a patient’s participation in this trial is 
included in Section 3.1, and allowable time windows for visits are included in the flow chart.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening
Refer to the Flow Chart for procedure details.
Tumour assessments at screening must be completed within 21 days of randomization.  All 
other screening assessment must be completed within 28 days of randomization. Assessments
required for study participation which were completed as part of Standard of Care before the 
patient signed the ICF can be used for the screening assessments if they were completed 
within the allowed timeframe.
6.2.2
Treatment period
Course 1, Visit 1 (Day 1 of 1st treatment course)
All procedures must be completed on Day 1 of Course 1. Refer to the flow chart for details.
Study medication must be administered as soon as possible after randomization, but within 
2 days at the latest.  Sites are strongly encouraged to have the patient take the first dose of 
study medication while he/she is still at the investigative site, and to document this in the site 
source documentation.
Course 1, Visit 2 (8 +2 days after start of study drug)
Refer to the flow chart for details.
Course 2 (Day 1, -3 to +2 days) and all subsequent visits
Refer to the flow chart for details.
In case a patient misses the scheduled study visit but reports to the investigative site before 
the next scheduled study visit, the missed visit should be performed.  The current date and 
reason for the delayed visit should be noted in the source documentation.  All subsequent 
study visits should take place at the start of the next treatment cycle per the flow chart.  In the 
event of any study drug interruption or delay of treatment, the tumour assessment schedule 
will not be changed.


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6.2.3
End of trial and follow-up period
End of Treatment
Refer to the flow chart for details.
Follow-up (28 +7 days after discontinuation of study drug)
Refer to the flow chart for details.
Observation Period (Every 28 +7 days after FUP)
Collect vital status of patient.  Refer to flow chart for details.
Once Protocol Version 3.0 is final (and where required locally, approvals are obtained by the 
site as per Section 8.1), the collection of vital status data will be ceased. 
End of Trial
The end of trial will be defined as when both of the following are met:
1. All events, for both PFS and OS analysis, have occurred
AND
2. All randomized patients have completed the Follow Up visit 28 days after 
discontinuation study drug


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a randomized, open-label Phase III trial to evaluate the efficacy and safety of afatinib 
versus erlotinib in patients with squamous cell NSCLC eligible to receive therapy in the 
second-line setting. Patients will be randomized to afatinib or erlotinib in a 1:1 ratio. 
Randomization will be stratified with respect to race (Eastern Asian vs. non-Eastern Asian).
An interim analysis will be performed as described in Section 7.3.4.
Overall survival is the key secondary endpoint. OS will be tested only if the primary endpoint 
of PFS shows statistical significance (p<0.05, two-sided). 
7.2
NULL AND ALTERNATIVE HYPOTHESES
The alternative hypothesis of the primary analysis is that the progression-free survival time
for patients treated with afatinib is different from that of patients who receive erlotinib.  That 
is
HA: Safatinib(t)≠Serlotinib(t), for t>0
The null hypothesis tested by this trial is:
H0: Safatinib(t)= Serlotinib(t), for t>0
where S(t) is the probability that a patient passes time t without dying or experiencing disease 
progression. The subscripts represent the two treatment groups of either afatinib or erlotinib. 
The null hypothesis will be tested at the two-sided 0.05 level with any adjustment necessary 
for the interim analysis.
7.3
PLANNED ANALYSES
Two analysis datasets will be used:
Randomized Set (RS):  this dataset includes all patients who are randomised, regardless of 
taking investigational treatment.
Treated Set (TS):  the dataset includes all randomised patients who take at least one dose of 
investigational treatment.
7.3.1
Primary analyses
The primary efficacy analysis will include all randomised patients regardless of taking 
investigational treatment (RS) and patients will be analysed as randomised.


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7.3.1.1
Primary endpoint PFS
The primary analysis of PFS will be conducted after 372 patients have progressed or died.
Disease progression will be evaluated according to the RECIST 1.1 criteria (R09-0262).  The 
analysis will be based upon the evaluation of tumour imaging as determined by central 
imaging. Clinical deterioration without image-based progression will be excluded from the 
primary analysis, but will be examined as part of a sensitivity analysis. 
For patients with known date of progression (or death):

PFS [days] = date of progression or death – date of randomisation + 1.
Patients with unknown disease progression status or date, or who are treated with new 
anti-cancer therapy will be handled as described in Section 7.4.
A stratified log-rank test will be used to compare afatinib to erlotinib. The test will be 
stratified by race (Eastern Asian vs. non-Eastern Asian).
A stratified Cox proportional-hazards model will be used to derive the hazard ratio and 95% 
confidence interval (CI) between the two randomised regimens. Kaplan-Meier estimates and 
95% CI will be calculated at landmark time points.
7.3.2
Secondary analyses
OS will be tested only if the primary endpoint of PFS shows statistical significance. The 
treatment regimens will be compared in terms of time to death as the key secondary endpoint, 
but treatment after progression is expected to obscure any effect of afatinib relative to 
erlotinib.  
The analysis of OS will estimate the hazard ratio and the corresponding 95% confidence 
interval based on a Cox-PH model. Additionally, a stratified log-rank test will be performed.  
Kaplan-Meier estimates of OS will be tabulated and K M estimates will be presented 
graphically.
OS will be analysed twice. The first analysis will be performed at the time of the primary PFS 
analysis using a Haybittle-Peto stopping boundary (p-value <0.0001). The primary analysis 
of survival is planned at 632 deaths.  However, if the futility analysis curtails accrual at 
500 patients, the primary analysis of OS will be performed after 80% of the randomized 
patients have died.
 
 


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7.3.2.1
Other secondary analyses
  
 
 
 
 
 
 
A descriptive analysis of PFS will be performed at the time of the final analysis.
7.3.2.1.2 Best RECIST assessment
Each patient will be assigned to one of the following RECIST categories, irrespective of 
protocol violations or missing data: 


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
CR (complete response)

PR (partial response)

SD (stable disease)

PD (progressive disease)

unknown (not assessable, insufficient data)
Objective response is defined as CR or PR. Time to objective response is the time from 
randomization to the date of first documented CR or PR. The duration of objective response 
is the time from first documented CR or PR to the time of progression or death. Disease 
control is defined as CR, PR, or SD. 
Logistic regression will be used to test for a difference between regimens for objective 
response and for disease control. The statistical model will include the same stratification 
factors that will be used for the analysis of PFS. Nominal significance levels will be reported.
Descriptive statistics will be calculated for the duration of objective response and duration of 
disease control.
7.3.2.1.3 Tumour shrinkage
The two treatment groups will be compared in terms of the minimum sum of target lesion 
diameters recorded for each patient after randomisation. 
The analysis will compare the treatments using analysis of covariance (ANCOVA) for 
minimum sum of diameters, using baseline sum of diameters as a covariate. The 
randomization strata will be included as classification factors.
Waterfall plots will display the maximum percentage reduction from baseline sum of target 
lesion diameters.
7.3.2.1.4 Patient-reported Outcomes
The analyses will focus on cough, dyspnea, and pain measured on the EQ-5D, EORTC QLQ-
C30 and QLQ-LC13 questionnaires.
For each of the summary scales and items measuring cough, dyspnea, and pain, the 
randomized treatments will be compared in terms of:

The proportion of patients that are improved
Improvement is defined as scores that improve by at least 10 points at any 
time during the study. All randomized patients will be included in the 
denominator. 

Time to deterioration 


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Time to deterioration will be defined as the time to a 10-point worsening 
from the baseline score.
Patients who die before deteriorating will be analysed as having deteriorated 
at the time of death. Disease progression without scale deterioration will be 
censored at the time of the last scale measurement. Patients with no HRQoL 
assessments will be censored at day of randomisation. 
Time to deterioration will be analysed similarly to PFS i.e. log-rank test 
stratified by the stratification factors used at randomisation will be used to 
test for the effect of afatinib.

Change in cough, dyspnea and pain scores over time 
The change in cough, dyspnea and pain will be assessed using a mixed-
effects growth curve model with the average profile over time for each 
endpoint described by a piecewise linear.
The results of the time to deterioration analyses and the longitudinal analysis will be 
displayed using Forest plots.
In addition, similar analyses will be summarized for all QLQ-C30 and QLQ-LC13
subscales/items (where a single item is scored).
Finally, the usage of cough, dyspnea and pain medication will be described. 
 
7.3.3
Safety analyses
All patients who receive afatinib or erlotinib will be included in the analysis of safety. 
The analysis of adverse events will include events that start within the period defined by the 
first treatment administration until 28 days after the last administration.  
Adverse events and laboratory parameters will be graded according to CTCA , Version 3.0 
(R04-0474). 


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Standard tabulations arranged by MedDRA SOC and PT will include: 
the overall incidence and intensity of adverse events, 
AE judged to have been related to afatinib
AE leading to dosage reduction
AE leading to permanent treatment discontinuation
SAE
These standard Tables will be supplemented with Tables in which MedDRA SMQ and HLT 
(with some modifications) will be used to group MedDRA PT for the following:

rash/acne

stomatitis 

ocular effects 

lip effects

nail effects

fatigue
Tables that describe the frequency, intensity, time to onset, and clinical consequences will be 
produced for the following AE of special interest:

diarrhea 

rash/acne
Listings will be prepared of patients who are identified as having experienced any of the 
following AE.  For AE other than the single PT dehydration, identification will be based 
upon modified MedDRA SMQ and HLT groupings. If sufficient events occur within the trial, 
analyses similar to those for diarrhea and rash may be performed.  

dehydration

renal insufficiency

hepatic impairment

ILD-like events

heart failure
Primary laboratory tests are defined as:
Low values (-): haemoglobin, total WBC, platelets, neutrophils, potassium,
magnesium, sodium, and GFR
High values (+): AST, ALT, alkaline phosphatase, aPTT, INR, creatinine, and total 
bilirubin
The following analyses will be presented for the primary laboratory tests:


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
descriptive statistics at each planned assessment, 

frequency of patients with transitions in CTCAE grade from baseline to worst and last 
values during treatment, and 

frequency of patients with possible clinically significant abnormalities.
Possible clinically significant abnormalities are defined as CTCAE grade of 2 or greater, with 
an increase of at least one grade from baseline.
Additional, more in-depth analyses will be performed as needed. These analyses will examine 
the influence of extent of exposure and time to event onset.
7.3.4
Interim analyses
An interim analysis will be performed after at least 300 but not more than 500 patients have 
been randomized and when 130 patients have experienced PD or death, as determined by 
assessment at the study sites, among the first 176 patients randomized into the trial. (In the 
event that the 130 PD events occur before 300 patients are randomized, a decision on when to 
complete the analysis will be made in discussion with the DMC.)  A Heybittle-Peto 
boundary (p-value <0.0001) will be used for stopping for superiority. Screening will be 
stopped when recruitment is expected to reach 500 patients if any required actions from the 
DMC Data Review Meeting have not been implemented. This analysis will lead to one of the 
three following decisions:
(1) No change- Accrual will continue until 800 patients have been randomized.
(2) Partial curtailment- Accrual will be stopped after the 500 patients needed for the 
analysis of PFS have been randomized.
(3) No further accrual- The trial will be stopped for superiority or futility.
While waiting for 130 PFS failures to occur, accrual of patients will continue, as described 
above, but only the first 176 patients will be included in the interim analysis.  Additional 
details of the interim analysis are contained in the data monitoring committee charter.
7.4
HANDLING OF MISSING DATA
Table 7.4: 1 describes how patients will be classified for the analysis of PFS.


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Table 7.4: 1
Rules to determine events and censoring for PFS
Rule #
Situation
Outcome 
(event or 
censored)
Date of PFS event or 
censoring
1
No baseline tumour assessment (no death 
before second scheduled assessment)
censored
Date of randomisation
2
Progressed from central imaging (no missed 
radiologic assessments)
event
Date of PD
3a
Non-PD from central imaging1, death before 
next scheduled assessment
event
Date of death
3b
Non-PD from central imaging1, one missed 
assessment, death or progression after date 
of missed assessment, but before a second 
scheduled assessment
event
Date of PD or death
3c
Non-PD from central imaging1, more than 
one consecutive missed assessment, death or 
progression after date of second missed 
assessment
censored
Date of last imaging before 
missed assessment
3d
Non-PD from central imaging1, more than 
one consecutive missed assessment, non-PD 
according to imaging after missed 
assessments
censored
Date of last non-PD imaging
4
New anti-cancer medication before 
progression or death
censored
Date of last imaging before 
new anti-cancer medication
5
Death before the scheduled date of first 
imaging
event
Date of death
6a
No imaging performed post-baseline, patient
dies between first and second scheduled 
assessments
event
Date of death
6b
No imaging performed post-baseline, patient 
dies after second scheduled assessment
censored
Date of randomisation
6c
No imaging performed post-baseline, vital 
status is unknown or patient known to be 
alive
censored
Date of randomisation
7
Alive and not progressed from central 
imaging (no missed assessments)
censored
Date of last imaging
  1 - From the last assessment at which CR, PR or SD was assessed.
7.5
RANDOMISATION
Equal proportions of patients will be randomised to afatinib and to erlotinib. Randomization 
will be performed in blocks and stratified by race (Eastern Asian vs. non-Eastern Asian). The 
process of randomisation will be performed as described in Section 4.1.2.
7.6
DETERMINATION OF SAMPLE SIZE
Table 7.6: 1 shows the number of PFS events required for the primary analysis. The Table
indicates that 372 PFS events would be expected to provide 90% power for the log-rank test, 


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presuming a hazard ratio of 0.714 for afatinib relative to erlotinib (corresponding to median 
PFS times of 14 vs. 10 weeks, respectively). Data on file (R10-6208).
Table 7.6: 1
Number of PFS events required for 80% and 90% power1
80% Power
90% Power
Median PFS for afatinib 
14 weeks
14 weeks
Median PFS for erlotinib
10 weeks
10 weeks
Hazard ratio of afatinib vs erlotinib
0.714
0.714
Number of events required for both 
groups2
278
372
Total Number of randomised patients
350
500
1 log-rank test, alpha = 0.05, two-sided
2 The number of required events was calculated using EAST-5 software excluding interim analysis, with patients randomised 
in a 1:1 ratio at a rate of 6 patients per week. 
Table 7.6: 2 indicates that 632 deaths would be expected to provide 80% power for the log-
rank test, presuming a hazard ratio of 0.800 for afatinib relative to erlotinib (corresponding to 
median survival times of 8.75 vs. 7.00 months, respectively).
Table 7.6: 2
Number of deaths required for 80% and 90% power1
80% Power
90% Power
Median OS for afatinib
8.75 months
8.75 months
Median OS for erlotinib
7.00 months
7.00 months
Hazard ratio of afatinib vs erlotinib
0.80
0.80
Number of events required for both 
groups2
632
845
Total Number of randomised patients
800
1040
1 log-rank test, alpha = 0.05, two-sided
2 The number of required events was calculated using EAST-5 software excluding interim analysis, with patients randomised 
in a 1:1 ratio at a rate of 36 patients per month. 


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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 (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory authorities.


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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.
8.3
RECORDS
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, either on 
paper or via remote data capture. 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 entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the 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. 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 fulfil 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 afatinib, this is the current version of the Investigator’s Brochure (U03-3218).  For 
erlotinib this is the EU SPC. The current versions of these reference documents are to be 
provided in the ISF. No AEs are classified as listed for study design or invasive procedures.


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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 
ISF.
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
P04-06229
Huang SM, Lesko LJ. Drug-drug, drug-dietary supplement, and drug-citrus 
fruit and other food interactions:  what have we learned? J Clin Pharmacol
2004;44(6):559-569.
P07-11507
Moy B, Goss PE. Lapatinib-associated toxicity and practical management 
recommendations.  Oncologist 2007;12(7):756-765.
P10-09678
Yap TA, Vidal A, Adam J, Stephens P, Spicer J, Shaw H, et al. Phase I trial 
of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients 
with advanced solid tumours.  J Clin Oncol 2010:28(25);3965-3972.
P10-09976
Yang CH, Shih JY, Su WC, Hsia TC, Tsai CM, Ou SHI, et al. A Phase II 
study of BIBW 2992 in patients with adenocarcinoma of the lung and 
activating EGFR mutations (LUX-Lung 2). 46th Ann Mtg of the American 
Society of Clinical Oncology (ASCO), Chicago, 4 - 8 Jun 2010 (Poster) 2010.
P10-12524
Yang CH, Shih JX, Su WC, Hsia TC, Tsai CM, Ou SHI, et al.  A Phase II 
study of afatinib (BIBW 2992) in patients with adenocarcinoma of the lung 
and activating EGFR/HER1 mutations (LUX-Lung 2).  35th Ann Cong of the 
European Society for Medical Oncology (ESMO), Milan, 8-12 Oct 2010 
(Poster) 2010.
P10-12525
Seiwert TY, Fayette J, Campo JM del, Clement PM, Hitt R, Cupissol D, et al. 
Updated results of a randomized, open-label Phase II study exploring BIBW 
2992 versus cetuximab in patients with platinum-refractory 
metastatic/recurrent head and neck cancer (SCCHN).  35th Ann Cong of the 
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Seiwert T, Fayette J, Campo JM del, Clement P, Hitt R, Cupissol D, et al.  A 
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(LUX-Lung 1).  35th Ann Cong of the European Society for Medical Oncology 
(ESMO), Milan 8-12 Oct 2010 (Oral Presentation).


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a quality-of-life instrument for use in international clinical trials in oncology. J 
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9.2
UNPUBLISHED REFERENCES


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10.
APPENDICES
10.1
RECIST 1.1 CRITERIA
The criteria below are based on RECIST 1.1 (R09-0262).
The preferred method of assessment is a spiral CT scan with IV and oral contrast, unless IV 
and/or oral contrast are medically contraindicated. CT scans of the chest, abdomen and other 
areas of known or newly suspected disease must be performed. Scans of the abdomen, pelvis 
and other areas of the body, but not chest, may be done with MRI instead of CT. 
Skin lesions followed as target lesions must be documented by colour digital photography 
and must include in the image a ruler with millimetre subdivisions and a label that includes 
the patients ID and date. 
Bone scans (using 99m-technetium polyphosphonate scintigraphy) are recommended at 
baseline if the patient has any signs and symptoms consistent with bone metastasis or a 
history of bone metastasis. Bone metastasis identified at baseline must be documented and 
assessed according to RECIST 1.1 at the times of the other tumour measurements indicated in 
the flow chart. During the study bone scans should be repeated as clinically indicated in 
patients without bone metastasis at Baseline. 
For the purposes of this study, patients should be re-evaluated for response at weeks 8, 12, 
16, and every 8 weeks thereafter. In the event of a treatment delay, interruption or 
discontinuation of treatment, tumour assessment should continue to follow the original 
schedule. 
After approval of protocol version 3, tumour assessment will be performed every 18 weeks 
unless clinically indicated until progression or start of further treatment.
Follow-up tumour assessments must utilize the same CT/MRI/photographic method and 
acquisition technique (including use or non-use of IV contrast) as were used for screening 
assessments to ensure comparability. A chest x-ray or skeletal x-ray which clearly 
demonstrates a new metastatic lesion may be used to document progression in lieu of 
CT/MRI/bone scan.   
Only those patients who have measurable disease present at baseline, have received at least
3 weeks of therapy, and have had their disease re-evaluated will be considered evaluable for 
response.  These patients will have their response classified according to the definitions stated 
below.  
Measurability of tumour at baseline
Measurable lesions
Lesions that can be accurately measured in at least one dimension with longest diameter 
≥10 mm (by CT scan, MRI, caliper measurement) or ≥20 mm (by chest X-ray).  


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Pathological lymph nodes, defined as lymph nodes with a short axis >15mm are also 
measurable.
Measurable disease
Measurable disease requires the presence of at least one measurable lesion. 
Non-measurable disease
Non-measurable lesions are all other lesions, including small lesions (longest diameter 
<10 mm with CT scan, MRI or caliper measurement or <20 mm with chest X-ray or 
pathological lymph nodes with shortest axis ≥10 and <15 mm) as well as truly non-
measurable lesions. Lesions considered truly unmeasurable include leptomeningeal disease, 
ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/ abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques.
New lesions in irradiated fields
Previously irradiated lesions should not be used as indicator lesions. However, new lesions 
occurring in previously irradiated fields can be used to assess the antitumour response.
Methods of measurement
All measurements must be recorded in metric notation, using a ruler or calipers. All baseline 
evaluations must be performed as close as possible to the treatment start and never more than 
4 weeks before the beginning of the treatment. If a lesion is considered too small to measure, 
a default measurement of 5mm should be applied. If the lesion is not visible, a default 
measurement of 0mm should be applied.
The same method of assessment and the same technique must be used to characterise each 
identified and reported lesion at baseline and during follow-up.
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes). In the case of skin lesions, documentation by colour 
photography including a ruler to estimate the size of the lesion is obligatory.
CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed 
with cuts of 5 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm. This applies to the chest, abdomen and 
pelvis.
Ultrasound, endoscopy and laparoscopy should not be used to measure tumour lesions or 
evaluate tumour response. However, these techniques can be useful to supplement 
information from other techniques.


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Cytology and histology can be used to differentiate between PR and CR in rare cases (for 
example, residual lesions in tumour types such as germ cell tumours where known residual 
benign tumours can remain).
Baseline Documentation of Target and Non-target Lesions
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs should be identified as target lesions and will be 
recorded, measured (longest diameter = LD) and numbered at baseline. Target lesions should 
be selected on the basis of their size (lesions with the longest diameter) and their suitability 
for accurate repetitive measurements (either by imaging techniques or clinically). Lymph 
nodes must be ≥15mm in order to be considered as target lesions. 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD. The baseline sum LD will be used as reference to further characterise 
the objective tumour response of the measurable dimension of the disease (see Table 10.1: 1).
Table 10.1: 1
Evaluation of target lesions
Complete Response 
(CR)
Disappearance of all target lesions.
Partial Response 
(PR)
At least a 30% decrease in the sum of LD of target lesions taking as 
reference the baseline sum LD.
Progression (PD)
At least a 20% increase in the sum of LD of target lesions taking as 
reference the smallest sum LD recorded since the treatment started, 
together with an absolute increase in the sum of LD of at least 5mm.
OR
The appearance of one or more new lesions.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR, taking as reference 
the baseline SoD, nor sufficient increase to qualify for PD taking as 
reference the smallest SoD since the treatment started.
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements are not required and these lesions should be 
followed as “present” or “absent” (see Table 10.1: 2).


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Table 10.1: 2
Evaluation of non-target lesions and new lesions
Complete Response 
(CR)
Disappearance of all non-target lesions and normalisation of 
tumour marker level.
Non-CR/ Non-PD
Persistence of one or more non-target lesions or/and maintenance 
of tumour marker level above normal limits.
Progression (PD)
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.
Although a clear progression of non-target lesions only is 
exceptional, in such circumstances, the opinion of the treating 
physician should prevail and the progression status should be 
confirmed later by the review panel (or study chair).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status.
Confirmation
In the case of SD, follow-up measurements must have met SD criteria at least once after 
study entry at a minimum interval of six weeks.
Evaluation of Best Response to Study Treatment
The best response to study treatment (Table 10.1: 3) is the best response recorded from the 
start of treatment until disease progression or start of further anti-cancer treatment (taking as 
reference for progressive disease the smallest measurements recorded since the treatment 
started). In general, the patient’s best response assignment will depend on the achievement of 
both measurements and confirmation criteria (Table 10.1: 3).
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment.


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Table 10.1: 3
Algorithm for evaluation of overall best response*
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/ Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not 
evaluated
No
PR
SD
Non-PD or not 
evaluated
No
SD
Not evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
* In the case of SD, follow-up measurements must have met the SD criteria at least once after study entry at a minimum 
interval of six (6) weeks.


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10.2
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS*
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5
Dead
* As published in Am. J. Clin. 
R01-0787


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10.3
FORMULA FOR ESTIMATED CREATININE CLEARANCE RATE
The following formula may be used for estimated creatinine clearance rate (eCCR) using 
Cockcroft-Gault formula.  On-line calculators or formulas which are institution standards for 
the calculation of estimated creatine clearance may also be used.  The calculation and result 
must be filed in the patient’s chart.
When serum creatinine is measured in mg/dL;







mg/dL
in 
Creatinine
Serum
72
85
.0
kilograms
in 
Mass
Age
140
eCCR





Female
if
When serum creatinine is measured in µmol/L;






µmol/L
in 
Creatinine
Serum
Constant
kilograms
in 
Mass
Age
140
eCCR




Where Constant is 1.23 for men and 1.04 for women.


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10.4
NYHA 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 dyspnea 
(shortness of breath).
Class II (Mild)
Slight limitation of physical activity. Comfortable at rest, but 
ordinary physical activity results in fatigue, palpitation, or 
dyspnea.
Class III 
(Moderate)
Marked limitation of physical activity. Comfortable at rest, 
but less than ordinary activity causes fatigue, palpitation, or 
dyspnea.
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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10.5
LIST OF POTENT INHIBITORS AND INDUCERS OF P-GLYCOPROTEIN 
(MDR1)
Inhibitors
Inducers
Cyclosporine A
Ketoconazole
Itraconazole
Erythromycin
Verapamil
Quinidine
Tacrolimus
Nelfinavir
Ritonavir
Saquinavir
Amiodarone
Azithromycin
Captopril
Carvedilol
Clarithromycin 
Conivaptan
Diltiazem
Dronedarone
Felodipine
Lopinavir
Ranolazine
Ticagrelor
Rifampicin
St John’s Wort
Carbamazepine
Phenytoin
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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10.6 LIST OF STRONG CYP3A4 INHIBITORS INDUCERS
The following lists the more frequently used CYP3A4 inhibitors, but is not intended to be 
all-inclusive:
atazanavir
troleandomycin (TAO)
indinavir
itraconazole
nelfinavir
ketoconazole
ritonavir
voriconazole
saquinavir
nefazodone
clarithromycin
grapefruit
telithromycin
grapefruit juice
The following lists the more frequently used CYP3A4 inducers, but is not intended to be 
all-inclusive:
rifabutin
phenobarbitol
rifampicin
phenytoin
rifapentine
St. John’s Wort
carbamazepine
(R11-1186)


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10.7
ADVERSE EVENT/SERIOUS ADVERSE EVENT REPORTING
No
Yes
Adverse Event that is not a  Pre-existing 
condition documented during screening
Do not 
report
Complete 
SAE Form 
and eCRF
Complete
SAE
Complete
eCRF only
Yes
No
Other
SAE 
(including 
those with 
fatal 
outcomes)
Death 
d/t PD
Disease
Progression
(PD)
If Serious
Did event occur from date ICF 
was signed through to the FUP
If Nonserious
Is Event Serious?*
If not during this 
period, was event 
related to Study 
Drug?
 *Resulted in Death
    Life-threatening
    Hospitalization/prolongation of hospitalization
    Persistent/significant disability
    Congenital anomaly/birth defect
   Important medical event
Disease progression 
does not need to be 
filed as SAE; 
however, if signs and 
symptoms of Disease 
progression meet SAE 
criteria, report signs 
and symptoms as 
SAEs.
If during this period, 
patient experienced:
Complete
eCRF
Did event occur from date ICF 
was signed through to the FUP ?
Do not 
report


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10.8 QOL QUESTIONNAIRES


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The following page was added in protocol version 2


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10.9
CLINICAL EVALUATION OF LIVER INJURY
10.9.1
Introduction
Alterations of liver parameters, as described in Section 5.2.2.1 (AESIs), are to be further 
evaluated using the following procedures:
10.9.2
Procedures
Any elevation of ALT/AST and bilirubin qualifying as laboratory alert would be confirmed 
by local laboratory on initial sample if possible. If, due to technical error, the laboratory is 
not able to complete the confirmatory testing, an alert will be generated.
If a site receives a potential DILI alert notice from the local laboratory, the following must be 
completed:
1.) Evaluate patient within 48 hours and
2.) Perform following laboratory tests locally for confirmation
1.
Repeat of AST, ALT, bilirubin (with fractionation to total and direct) 
2.
Haptoglobin
3.
Complete blood count and cell morphology
4.
Reticulocyte count
5.
Creatinine kinase (CK)
6.
Lactate dehydrogenase (LDH)
7.
Alkaline Phosphatase
If the initial alert values (i.e. AST,ALT, and bilirubin) are confirmed on the second sample 
described as above, then an abdominal ultrasound or clinically appropriate alternate imaging  
(to rule out biliary tract, pancreatic or intrahepatic pathology, e.g. bile duct stones or 
neoplasm) must be completed within 48 hours 
The findings from the hepatic imaging (including comparison to prior imaging if available) 
must be made available as soon as possible as part of the adverse event reporting process.  In 
the event the etiology of the abnormal liver tests results is not identified based on the imaging 
(e.g. biliary tract, pancreatic or intrahepatic pathology), then the “DILI checklist” must be 
completed.  Details of the “DILI checklist” are provided in the ISF.  The following 
assessments need to be performed in order to complete the “DILI checklist” and results will 
be reported via the eCRF:
o
obtain a detailed history of current symptoms and concurrent diagnoses and 
medical history according to the “DILI checklist” provided in the ISF;
o
obtain history of concomitant drug use (including non-prescription 
medications, herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets according to the “DILI checklist” 
provided in the ISF;


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o
obtain a history of exposure to environmental chemical agents (consider 
home and work place exposure) according to the “DILI checklist” provided 
in the ISF;
o
complete the following laboratory tests as detailed in the DILI checklist 
provided in the ISF:

Clinical chemistry
alkaline phosphatase, cholinesterase (serum)*, albumin, PT or INR, CK, 
CK-MB, coeruloplasmin*, α-1 antitrypsin*, transferrin*, amylase, lipase, 
fasting glucose, cholesterol,triglycerides

Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), 
Hepatitis C (Anti-HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-
IgM, Anti-IgG), Hepatitis E (Anti-HEV, Anti-HEV IgM, RNA if Anti-
HEV IgM positive), Anti-Smooth Muscle antibody (titer), Anti-nuclear 
antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, Anti-
mitochondrial antibody, Epstein Barr Virus (VCA IgG, VCA IgM), 
cytomegalovirus (IgG, IgM), herpes simplex virus (IgG, IgM)*, varicella 
(IgG, IgM)*, parvovirus (IgG, IgM)*

Hormones, tumormarker
Thyroid-stimulating hormone(TSH)*

Haematology
Thrombocytes, eosinophils
*If clinically indicated (e.g. immunocompromised patients)
-
Long term follow-up
o
Initiate close observation of subjects by repeat testing of ALT, AST, and 
bilirubin (with fractionation to total and direct) at least weekly until the 
laboratory ALT and or AST abnormalities stabilize or return to normal, 
then according to the protocol. Depending on further laboratory changes, 
additional parameters identified e.g. by reflex testing will be followed up 
based on medical judgement and Good Clinical Practices (GCP).
and report these via the eCRF.


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11. DESCRIPTION OF GLOBAL AMENDMENTS
Number of global amendment
1
Date of CTP revision
24 Oct 2012
EudraCT number
2011-002380-24
BI Trial number
1200.125
BI Investigational Product
Afatinib, BIBW 2992
Title of protocol
LUX-Lung 8:  A randomized, open-label Phase III trial of 
afatinib versus erlotinib in patients with advanced squamous 
cell carcinoma of the lung as second-line therapy following 
first-line platinum-based chemotherapy
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
FLOW CHART
Description of change
Change in footnote *** from afatinib to study drug
Rationale for change
The discontinuation visits apply to either study drug.
Section to be changed
1.1 MEDICAL BACKGROUND 
Description of change
Added hyperlink
Rationale for change
Omitted in error in previous version.
Section to be changed
1.2 Drug Profile
Description of change
 
.
Rationale for change
 
Section to be changed
3.3.2 Inclusion criteria
Description of change
Modified inclusion criterion 2.
Rationale for change
Clarify this criterion.
Section to be changed
3.3.3  Exclusion criteria
Description of change
Added exclusion criterion 21.


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Number of global amendment
1
Rationale for change
Align the criterion with the language in 3.3.1, specifying 
patients need to have disease progression after completion 
of 1st line treatment.
Section to be changed
3.3.4.1.1 Patient discontinuation of study participation
Description of change
Clarification of assessments to be completed for patients 
who discontinue therapy without disease progression.
Rationale for change
Clarification of language.
Section to be changed
4.1.5.1 Blinding
Description of change
Changed language clarifying the timing of trial team 
unblinding will be at the time of the snapshot used for the 
primary analysis.
Rationale for change
The previous protocol stated the trial team will remain 
unblinded for as long as feasible.  This threshold will be at 
the time of the aggregate data reviews of the database 
snapshot used for primary analysis.
Section to be changed
4.2.1 Rescue medication, emergency procedures, and 
additional treatments/
Description of change
Added:  There is no specific antidote for overdosage with 
afatinib.
Rationale for change
Provide clarification.
Section to be changed
4.2.2.1  Restrictions regarding concomitant treatment
Description of change
 
Rationale for change
  
.
Section to be changed
4.2.3.3  Management of mucositis/stomatitis
Description of change
Added hyperlink.
Rationale for change
Required due to new break in page.
Section to be changed
5.2.3.1  Assessment of safety laboratory parameters
Description of change
Added hyperlink.
Rationale for change
Required due to new break in page.
Section to be changed
 
Description of change
Rationale for change
Align protocol language with ongoing data collection.
Section to be changed
5.6.3 Analytical determinations
Description of change
Added section.
Rationale for change
Omitted in error in previous version and required for 
sponsor SOPs.
Section to be changed
7.2 NULL AND ALTERNATIVE HYPOTHESES
Description of change
Changed title.
Rationale for change
Error in previous version and to align with sponsor SOPs.
Section to be changed
 
Description of change
Added and deleted medications; and added statement.
Rationale for change
Align the protocol with IB v13 and to provide updated 
information and disclosure on assessing medications not 
listed.


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Number of global amendment
1
Section to be changed
10.8  QOL QUESTIONNAIRES
Description of change
Added last page of the EQ-5D
Rationale for change
Omitted in error in previous version.


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Number of global amendment
2
Date of CTP revision
25 May 2016
EudraCT number
2011-002380-24
BI Trial number
1200.125
BI Investigational Product
Afatinib, BIBW 2992
Title of protocol
LUX-Lung 8:  A randomized, open-label Phase III trial of 
afatinib versus erlotinib in patients with advanced squamous 
cell carcinoma of the lung as second-line therapy following 
first-line platinum-based chemotherapy
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Title page
Description of change
Change in BI product name and Sponsor contacts.
Rationale for change
To provide current and up-to-date information.
Section to be changed
Protocol Synopsis
Description of change
Change in BI Product name and number of patients entered.
Rationale for change
To provide current and up-to-date information.
Section to be changed
Flow chart
Description of change
Follow-up visit: update visit allowed window to +7days.
Footnote numbers:
- 4: change to frequency and review of ECG
- 6: change to frequency and review of ECHO/MUGA
- 9: no longer required to complete QOL questionnaires
-
- 12: change to imaging assessment frequency
- 14: no longer required to collect Observation Period data
Rationale for change
Follow-up visit: to be in lined with the current BI guideline.
Footnote: following the database lock for the primary 
analysis of OS data, patients would have been on treatment 
for more than 2 years and as such: sufficient vital status and
health related QOL, 
data have been collected and 


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Number of global amendment
2
therefore no longer required; and a more frequent ECG, 
ECHO/MUGA and imaging assessment is no longer 
considered necessary.
Section to be changed
1.2 Drug profile
Description of change
Afatinib is now approved by both EMA & FDA.
Rationale for change
To provide current and up-to-date information.
Section to be changed
3.1 Overall Trial Design and Plan
Description of change
Discontinue central imaging review and cease the collection 
of vital status data.
Update the visit window for the Follow-up visit to +7days.
Rationale for change
Following the database lock for the primary analysis of OS 
data:
- There is no longer the requirement for central analysis of 
imaging as the primary endpoint of PFS has been assessed 
and reported; 
- Sufficient vital status data have been collected and 
therefore no longer required. 
Update the Follow-up visit window to be in lined with the 
current BI current guideline for reporting SAE/AESI.
Section to be changed
3.3.4. Removal of patients from therapy or assessments
Description of change
Further clarify the option in allowing patients to access 
study treatment via an alternative source and that collection 
of vital status will no longer be required for these patients. 
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
5.1.2.1.1 Central imaging
Description of change
Discontinue central imaging review and sending images to 
Central Imaging Unit will no longer be required.
Rationale for change
Following the database lock for the primary analysis of OS 
data, there is no longer the requirement for central analysis 
of imaging as the primary endpoint of PFS has been 
assessed and reported.
Section to be changed
5.2.2 Assessment of Adverse Events
Description of change
Update the terminology for protocol-specified significant 
events to AESIs.
Update the reporting timeline and requirements for SAE 
and AESIs.
Rationale for change
To be in lined with BI current guideline for reporting 
SAE/AESI.
Section to be changed
5.2.3 Assessment of safety laboratory parameters
Description of change
Safety lab samples will no longer be sent to central lab for 
analysis but will be done at local lab instead. 
Rationale for change
Following the database lock for the primary analysis, there 
is no longer the requirement for sending blood samples to 
central lab for analysis.
Section to be changed
5.2.4 Electrocardiogram
Description of change
ECG will be performed at the time points specified in the
flow chart only if clinically indicated.
Rationale for change
Following the data base lock for the primary analysis,
sufficient ECG data has been collected for analysis.


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Number of global amendment
2
Section to be changed
5.2.5.3 Left ventricular function
Description of change
LVEF will be performed at the time points specified in the
flow chart only if clinically indicated.
Rationale for change
No safety signals in terms of the effect on cardiac 
contractility have been identified for afatinib in the context 
of this trial and using a larger safety database. Therefore 
routine monitoring of left ventricular (LVEF) is not 
warranted.
Section to be changed
5.3.1 Other endpoints
Description of change
Discontinue the collection of QOL questionnaires and the 
Rationale for change
Following the database lock for the primary analysis of OS 
data, sufficient health related QOL and 
 have 
been collected and therefore no longer required.
Section to be changed
6.2.3 End of trial and follow-up period
Description of change
Cease the collection of Observation Period data.
Rationale for change
Following the database lock for the primary analysis of OS 
data, sufficient vital status data have been collected and 
therefore no longer required.
Section to be changed
Appendix 10.1 RECIST 1.1 criteria
Description of change
Reduce imaging assessment frequency.
Rationale for change
Since patients have been on treatment for more than 2 years, 
therefore such frequent imaging assessment is no longer 
considered necessary.
Section to be changed
Appendix 10.9 Clinical Evaluation of Liver Injury
Description of change
Further evaluations of liver parameters will be performed at 
local lab. 
Rationale for change
It is no longer required to send blood samples to central lab 
for analysis and this will instead be performed at local lab.

SAP_001.pdf: 
 
SIGNATURE INFORMATION 
 
Document: 
                               
                           
Document No.:                                                                                                                        
 
Title 
                             
 
 
 
 
 
 
                         
 
SIGNATURES  (ELECTRONICALLY OBTAINED)  
 
Meaning of Signature: 
Signed by: 
Date signed: (GMT) 
                                   
 
 
 
                               
                                                                                                          
                                   
 
 
 
                               
                                                                                                   
                                   
 
 
 
                               
                                                                                                   
                                   
 
 
 
                               
                                                                                                           
                                   
 
 
 
                               
                                                                                                                     
                                  
 
 
 
                               
                                                                                                                     
                                   
 
 
 
                               
                                                                                                                       
1200-0125--tsap
T12-3007-01
LUX-Lung 8:  A randomized, open-label Phase III trial of afatinib versus
erlotinib in patients with advanced squamous cell carcinoma of the lung as
second-line therapy following first-line platinum-based chemotherapy
Author-Trial Statistician
5/15/2012 19:20:31
Author-Trial Clinical Monitor
5/15/2012 20:17:35
Approval-Project Statistician
5/16/2012 07:21:38
Verify Paper Signature Completion
5/16/2012 19:36:12


 
SIGNATURE INFORMATION (continued) 
Document 
                              
                          
Document No.:                                                                                                                        
 
Title 
                             
 
 
 
 
 
 
                         
SIGNATURES  (ELECTRONICALLY OBTAINED)  
(There are no entries on this page if there are up to seven signatures.) 
Meaning of Signature: 
Signed by: 
Date signed: (GMT) 
                                   
 
 
 
                               
                                                                                                                      
                                   
 
 
 
                               
                                                                                                                      
                                   
 
 
 
                               
                                                                                                                      
                                     
 
 
 
                                 
                                                                                                                      
                                     
 
 
                                 
                                                                                                                      
                                     
 
 
                               
                                                                                                                       
                                     
 
 
                                
                                                                                                                       
                                     
 
 
                                 
                                                                                                                     
 
1200-0125--tsap
T12-3007-01
LUX-Lung 8:  A randomized, open-label Phase III trial of afatinib versus
erlotinib in patients with advanced squamous cell carcinoma of the lung as
second-line therapy following first-line platinum-based chemotherapy


 
 
TITLE PAGE 
 
 
Trial Statistical Analysis Plan  
 
T12-3007-01 
BI Trial No.: 
1200.125 
Title: 
LUX-Lung 8:  A randomized, open-label Phase III trial of afatinib 
versus erlotinib in patients with advanced squamous cell 
carcinoma of the lung as second-line therapy following first-line 
platinum-based chemotherapy 
Investigational 
Product: 
Afatinib, BIBW 2992 
Responsible trial 
statistician: 
Telephone: 
 
Fax: 
 
Date of statistical 
analysis plan: 
18 APR 2012 SIGNED  
Version: 
Final 
Page 1 of 27
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Boehringer Ingelheim  
TSAP for BI Trial No: 1200.125 
Page 2 of 27
 
1. 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................... 1 
1. 
TABLE OF CONTENTS ...................................................................... 2 
LIST OF TABLES .............................................................................................. 4 
2. 
LIST OF ABBREVIATIONS ............................................................... 5 
3. 
INTRODUCTION .................................................................................. 7 
4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ...... 8 
5. 
ENDPOINTS .......................................................................................... 9 
5.1 
PRIMARY ENDPOINT ...................................................................................... 9 
5.2 
SECONDARY ENDPOINTS .............................................................................. 9 
5.2.1 
Key secondary endpoint .................................................................................. 9 
5.2.2 
Other secondary endpoints ............................................................................. 9 
.................................................................................. 9 
.................................................................................. 9 
6. 
GENERAL ANALYSIS DEFINITIONS ........................................... 10 
6.1 
TREATMENTS .................................................................................................. 10 
6.2 
IMPORTANT PROTOCOL VIOLATIONS .................................................. 10 
6.3 
PATIENT SETS ANALYSED .......................................................................... 12 
.................................................................................................... 13 
6.5 
POOLING OF CENTRES ................................................................................ 13 
6.6 
HANDLING OF MISSING DATA AND OUTLIERS ................................... 14 
6.7 
BASELINE, TIME WINDOWS AND CALCULATED VISITS .................. 14 
7. 
PLANNED ANALYSIS ....................................................................... 15 
7.1 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........ 15 
7.2 
CONCOMITANT DISEASES AND MEDICATION .................................... 15 
7.3 
TREATMENT COMPLIANCE ....................................................................... 15 
7.4 
PRIMARY ENDPOINT .................................................................................... 15 
7.5 
SECONDARY ENDPOINTS ............................................................................ 18 
7.5.1 
Key secondary endpoint ................................................................................ 18 
7.5.2 
Other Secondary endpoints .......................................................................... 19 
7.5.2.1 
Best RECIST assessment ............................................................................ 19 
7.5.2.2 
Tumour shrinkage ....................................................................................... 20 
7.5.2.3 
Patient-reported Outcomes ......................................................................... 20 
 .................................................................................. 22 
7.7 
EXTENT OF EXPOSURE ................................................................................ 22 
7.8 
SAFETY ANALYSIS ......................................................................................... 22 
7.8.1 
Adverse events ............................................................................................... 22 
7.8.2 
Laboratory data ............................................................................................. 24 
7.8.3 
Vital signs ....................................................................................................... 24 
7.8.4 
ECG ................................................................................................................ 25 
7.8.5 
Others ............................................................................................................. 25 
8. 
REFERENCES ..................................................................................... 26 
............................................................... 27 


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Page 3 of 27
 
10. 
HISTORY TABLE ............................................................................... 27 
 
 


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LIST OF TABLES 
Table 6.2: 1 
Important protocol violations .......................................................................... 11 
Table 7.4: 1 
Rules to determine events and censoring for PFS ........................................... 16 
Table 10: 1 
History table .................................................................................................... 27 
 
 


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2. 
LIST OF ABBREVIATIONS 
Term 
Definition / description 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
BRPM 
Blinded Report Planning Meeting 
CI 
Confidence Interval 
CR 
Complete Response 
CTC 
Common Terminology Criteria   
CTP 
Clinical Trial Protocol 
CTR 
Clinical Trial Report 
DM&SM 
Boehringer Ingelheim Data Management and Statistics Manual 
DMC 
Data Monitoring Committee 
EMEA 
European Agency for the Evaluation of Medicinal Products 
HLT 
High Level Term 
HRQoL 
Health-Related Quality of Life 
ICH 
International Conference on Harmonisation 
MedDRA 
Medical Dictionary for Regulatory Activities 
NE 
Not Evaluable 
NN 
Non-CR/Non-PD 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
PSTAT 
Project Statistician 
PR 
Partial Response 
PT 
Preferred Term 
PV 
Protocol Violation 
Q1 
Lower Quartile 
Q3 
Upper Quartile 
s.d. 
Standard Deviation 
SD 
Stable Disease 
SMQ 
Standardised MedDRA query 


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Term 
Definition / description 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event  
TOC 
Table of Contents 
TMW 
Trial Medical Writer 
TSAP 
Trial Statistical Analysis Plan 
 


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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 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 will be used for all analyses. 
 


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4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY 
Tumour shrinkage measurement is changed to the maximum decrease of sum of target lesion 
diameters (i.e. the minimum sum of target lesion diameters after randomisation minus 
baseline) for better interpretability. 


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5. 
ENDPOINTS 
5.1 
PRIMARY ENDPOINT 
The primary endpoint of this study is progression-free survival, as determined by RECIST 
1.1 (1). 
5.2 
SECONDARY ENDPOINTS 
5.2.1 
Key secondary endpoint  
The key secondary endpoint is overall survival. 
5.2.2 
Other secondary endpoints 
Refer to Section 5.1.1 of the CTP. 
Other secondary endpoints of this trial are:  
• 
Objective response (CR, PR) according to RECIST 1.1 (1) 
• 
Disease control (CR, PR, SD) according to RECIST 1.1 (1)  
• 
Tumour shrinkage 
• 
Health-related Quality of Life (HRQoL) 


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6. 
GENERAL ANALYSIS DEFINITIONS 
6.1 
TREATMENTS 
For reporting purposes, all randomised patients will be classified into either ‘Afatinib’ or 
‘Erlotinib’ as randomised.  For efficacy analyses patients will be analysed as randomised.  
For safety analyses, treated patients will be analysed according to the initial treatment taken. 
The following study periods based on actual start and stop dates of study treatment 
administration are defined: 
• Pre-screening: for any data recorded prior to day of informed consent. 
• Screening: day of informed consent to day prior to starting study treatment. 
• On-treatment: day of first administration of study treatment to the 28th day after last 
administration of study treatment. 
• Post-treatment: day after last administration of study treatment to the 28th day after last 
administration of study treatment. 
• Post-study: on or after the 29th day after last administration of study treatment. 
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 post-treatment periods 
defined above will be combined into one ‘on treatment’ analysing treatment), unless 
otherwise specified according to the protocol Section 5.2.2.2 and protocol Appendix 10.7. 
6.2 
IMPORTANT PROTOCOL VIOLATIONS 
No per protocol set (PPS) will be defined 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 
A 
 
Entrance criteria not met 
 
 
A1 
Diagnosis of NSCLC 
questionable 
Refer to IN 1 
 
A2 
Prior treatment for NSCLC 
does not meet entrance 
criteria 
Refer to IN 2,3, EX 1,2 
 
A3 
No measurable disease 
according to RECIST 1.1 at 
screening 
Refer to IN4   
 
A4 
Abnormal screening values  
Refer to IN7 
 
A5 
Other deviation from 
entrance criteria 
 
Refer to in/exclusion criteria 
B 
 
Informed consent 
 
 
B1 
Informed consent not 
available  
Signed informed consent not 
available 
 
B2 
Inadequate informed consent 
Informed consent obtained but 
not adequately done (e.g., 
obtained after the study 
specific activities were done, 
patient signed the wrong 
version of the ICF, version 
signed did not receive prior 
IRB/EC approval). 
C 
 
Trial medication & 
randomization 
 


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C1 
Incorrect medication dose 
taken 
e.g., starting dose is not 40 mg 
for afatinib or 150 mg for 
erlotinib; dose was not 
paused, resumed, reduced, or 
discontinued according to 
protocol, including incorrect 
dose interruptions during 
concomitant treatment 
 
C2 
Randomization not followed 
e.g., randomized to afatinib 
but received erlotinib or vice 
versa. 
 
C3 
Non-compliance  
Check MQRM listings for 
extreme non-compliance only 
D 
 
Concomitant medication 
 
 
D1 
Use of prohibited 
concomitant medications   
 
Review concomitant 
medications for prohibited 
medication use. 
E 
 
Trial specific 
 
 
E1 
Procedures not performed 
according to protocol 
Check applicable data. 
 
E2 
Prohibited on study 
interventions given 
Patient received therapeutic 
radiation or another anti-
cancer treatment during on 
study period 
 
6.3 
PATIENT SETS ANALYSED 
• Randomised set: 
This patient set includes all randomised patients, whether the patient received study 
medication or not. 
• Treated set: 
This patient set includes all patients who received at least one dose of investigational 
treatment.  


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Ranomised set will be used for all efficacy analyses and treated set will be used for all safety 
analyses. 
6.5 
POOLING OF CENTRES 
This section is not applicable because centre/country is not included in the statistical model.  
 


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6.6 
HANDLING OF MISSING DATA AND OUTLIERS 
In general missing efficacy data will not be imputed and all reasonable efforts will be taken 
during the study to obtain such data.  Patients with unknown vital status, missing tumour 
imaging data and missing HRQOL assessments will be censored for time to event analyses; 
further details are provided in Section 7.   
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”). (2) 
 
6.7 
BASELINE, TIME WINDOWS AND CALCULATED VISITS 
Baseline values will be the measurements taken most recently prior to first administration of 
study drug. 
Study day will be calculated relative to the date of the first administration of study drug.  The 
day prior to first administration of study drug will be ‘Day -1’ and the day of first 
administration of study drug will be ‘Day 1’; therefore ‘Day 0’ will not exist. 
For the presentation of tumour response data which will follow a calculated visit approach 
based on the protocol specified tumour imaging schedule.  Imaging will be performed at 
week 8, 12 and 16, and in 8-weekly intervals thereafter from the date of randomisation; 
images will be slotted to Week 8, 12, 16, 24, … XX based on their relative day and using a ± 
2, ±4 week window as appropriate (images taken in the first 4 weeks from randomisation will 
be slotted to Week 8).  If two or more images for a patient are assigned to one interval then 
the last assessment will be used to ensure progressive disease is not missed.  Note German 
sites only will have an X-ray completed instead of a CT or MRI for the week 12 assessment. 
If disease progression is suspected, a follow-up CT or MRI will then be completed. In the 
case where a CT or MRI is not completed for the week 12 assessment, it will be handled as 
missing assessment.  
 


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7. 
PLANNED ANALYSIS 
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Median 
/ Max. For appendix tables, the set of summary statistics is: N / Mean / s.d. / Min / Q1 (lower 
quartile) / Median / Q3 (upper quartile) / Max. 
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 specified, all patients in the respective patient 
set whether they have non-missing values or not). 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. 
7.2 
CONCOMITANT DISEASES AND MEDICATION 
Descriptive statistics using standard summary tables for the randomised set of patients are 
planned for this section of the report. 
7.3 
TREATMENT COMPLIANCE 
Descriptive statistics using standard summary tables for the treated set of patients are planned 
for this section of the report.  A summary of whether patients took their treatment according 
to the protocol and whether they missed any doses will be produced for each planned visit.  In 
addition a summary of overall percentage compliance will be produced using visit dates and 
the total number of doses missed during the study. 
7.4 
PRIMARY ENDPOINT 
The primary endpoint of this study is PFS, defined as the time (weeks) from the date of 
randomisation to the date of disease progression, or date of death whichever is earlier, 
subjected to the censoring rule (see Table 7.4: 1).  The date of progression for the primary 
analyses will be determined based on an independent central imaging review incorporating 
both radiologist and oncologist reviews, blinded to treatment assignments.  The primary 
endpoint analysis will be performed on the randomised set of patients. 
A stratified log-rank test will be used to test the effect of afatinib on PFS compared to 
erlotinib.  The test will be stratified by race (Eastern Asian and Non-Eastern Asian). An 
interim analysis is planned using Haybittle-Peto stopping boundary (p-value < 0.0001). The 
details of the interim analysis are described in the DMC SAP. The final significance level 
need not be adjusted in the case of one interim look. The final significance level will be 
adjusted as necessary in case additional interim looks are requested by the DMC. 
A Cox proportional hazard model, stratified by race will be used to estimate the hazard ratio 
and 95% confidence interval (CI) between the two treatment groups.  Kaplan-Meier estimates 
and 95% CIs (using Greenwood’s standard error estimate) will be tabulated at time points of 


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every 12 weeks and will include a comparison of the treatment groups using a z-test 
(approximation of the normal distribution).  Kaplan-Meier curves for the two treatment 
groups will also be produced. 
A descriptive analysis of PFS will be performed at the time of the final analysis. 
The rules to determine whether or not patients have had a PFS event (progression or death) 
along with the date of event or date of censoring (for those with no event) are specified in 
Table 7.4: 1.  These rules will be applied to both the independent central review and 
investigator assessed data prior to analysis.  A summary table of the reasons for censoring 
will be produced by treatment group. 
Table 7.4: 1 
Rules to determine events and censoring for PFS 
Rule # 
Situation 
Outcome  
(event or 
censored) 
Date of PFS event or 
censoring 
1 
No baseline tumour assessment (no death 
before second scheduled assessment) 
censored 
Date of randomisation 
2 
Progressed from central imaging (no missed 
radiologic assessments) 
event 
Date of PD 
3a 
Non-PD from central imaging1, death before 
next scheduled assessment 
event 
Date of death 
3b 
Non-PD from central imaging1, one missed 
assessment, death or progression after date 
of missed assessment, but before a second 
scheduled assessment 
event 
Date of PD or death 
3c 
Non-PD from central imaging1, more than 
one consecutive missed assessment, death or 
progression after date of second missed 
assessment 
censored 
Date of last imaging before 
missed assessment 
3d 
Non-PD from central imaging1, more than 
one consecutive missed assessment, non-PD 
according to imaging after missed 
assessments 
censored 
Date of last non-PD imaging 
4 
New anti-cancer medication before 
progression or death 
censored 
Date of last imaging before 
new anti-cancer medication 
5 
Death before the scheduled date of first 
imaging 
event 
Date of death 
6a 
No imaging performed post-baseline, patient 
dies between first and second scheduled 
assessments 
event 
Date of death 
6b 
No imaging performed post-baseline, patient 
dies after second scheduled assessment 
censored 
Date of randomisation 
6c 
No imaging performed post-baseline, vital 
status is unknown or patient known to be 
alive 
censored 
Date of randomisation 
7 
Alive and not progressed from central 
imaging (no missed assessments) 
censored 
Date of last imaging 
  1 - From the last assessment at which CR, PR or SD was assessed. 


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7.5 
SECONDARY ENDPOINTS 
7.5.1 
Key secondary endpoint 
Overall survival, defined as the time from randomization to death, is the key secondary 
endpoint.  
A Cox proportional hazard model, stratified by race, will be used to estimate the hazard ratio 
and the corresponding 95% confidence interval. Additionally, a stratified log-rank test will be 
performed.  Kaplan-Meier estimates of OS and 95% CIs (using Greenwood’s standard error 
estimate) will be tabulated at 12-week interval and compared at each time point with z-test. 
Kaplan- Meier curves will be presented graphically. 
OS will be analysed twice. The first analysis will be performed at the time of the primary PFS 
analysis using a Haybittle-Peto stopping boundary (p-value <0.0001). The primary analysis 
of survival is planned at 632 deaths.   However, if the futility analysis of PFS curtails accrual 
at 500 patients, the primary analysis of OS will be performed after 80% of the randomized 
patients have died. 
 
 
 
 
 
 
 
 
 


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7.5.2 
Other Secondary endpoints 
7.5.2.1 Best RECIST assessment 
Each patient will be assigned to one of the following RECIST categories, CR, PR, SD, 
Non-CR/Non-PD (NN), PD or Not Evaluable (NE), irrespective of protocol violations or 
missing data. 
Objective response is defined as CR or PR. Time to objective response is the time from 
randomization to the date of first documented CR or PR. The duration of objective response 
is the time from first documented CR or PR to the time of progression or death. Disease 
control is defined as CR, PR, SD or NN. The duration of disease control is the time from 
randomization to progression or death defined only for those patients with disease control. 
Logistic regression, stratified by the same stratification factors used for the analysis of PFS, 
will be used to test for a difference between regimens for objective response and for disease 
control based on central imaging assessment. Nominal significance levels will be reported. 
Time to response will be summarised by the planned imaging time points. Descriptive 
statistics will be calculated for the duration of objective response and duration of disease 
control, where applicable patients will be censored as for the PFS primary analysis. 
A summary of objective response rate and disease control rate using the investigator 
assessment of best overall response will also be produced, along with a table comparing the 
investigator best overall RECIST assessment with the corresponding central imaging 
assessment. 
The impact on objective response for each of the subgroups defined in Section 6.4 will be 
explored.  The logistic model detailed above but without the stratification factors will be 
used.  A ‘forest plot’ will be provided presenting the odds ratio (Afatinib vs. Erlotinib) and 
corresponding 95% CI for each subgroup category.  Subgroup analyses will only be 
performed on the independent central imaging assessments. 
The RECIST 1.1 guidelines state that confirmation of response is not required for randomized 
Phase III studies that have PFS as the primary endpoint; hence the above summaries will be 
produced without the requirement for confirmation.  However, for completeness all the above 


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summaries and analyses will be repeated with the requirement for confirmation, these will be 
considered secondary in nature. 
7.5.2.2 Tumour shrinkage 
Tumour shrinkage for each patient, measured (via central imaging review) as the maximum 
decrease from baseline (i.e. minimum sum of target lesion diameters after randomisation 
minus baseline), will be compared for the two treatment groups.  An analysis of covariance 
(ANCOVA) for the minimum sum of diameters, with the baseline sum of diameters fitted as 
a covariate and the randomisation strata fitted as factors will be performed. 
In addition waterfall plots of the maximum percentage reduction from baseline sum of target 
lesion diameters will be presented for each treatment group. 
7.5.2.3 Patient-reported Outcomes 
HRQOL questionnaires as measured by the EORTC QLQ-C30 and QLQ-LC13 at baseline, 
during treatment and follow-up will be included in the analysis.  All scoring of the symptom 
scales/items will follow the EORTC scoring algorithm. 
The analyses will focus on cough, dyspnea and pain; specifically: 
• Cough: Q31 - How much did you cough? (QLQ-LC13) 
• Dyspnoea: Composite of: Q33 - Were you short of breath when you rested? Q34 - 
Were you short of breath when you walked? Q35 - Were you short of breath when 
you climbed stairs? (QLQ-LC13).  Individual item from QLQ-C30, Q8 - Were you 
short of breath? 
• Pain: Composite of: Q9 - Have you had pain? Q19 - Did pain interfere with your daily 
activities? (QLQ-C30).  Individual items from QLQ-LC13, Q40 - Have you had pain 
in your chest? Q41 - Have you had pain in your arm or shoulder? Q42 - Have you had 
pain in other parts of your body? 
For each of the summary scales and items measuring the above the treatment groups will be 
compared for the following: 
Distribution of patients improved, stable or worsened 
Improvement will be defined as a score that improves from baseline by at least 10 points (on 
the 0-100 point scale) at anytime during the study.  If a patient has not improved, worsening 
will be defined as a 10 point worsening at anytime during the study.  Otherwise, a patient will 
be considered as stable. 
The number and percentage of patients falling into each of these three categories will be 
summarised by treatment group.  All randomized patients will be included in the 
denominator. A logistic regression model, stratified by stratification factor race will be used 


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to compare the distribution of patients improving/not improving across the two treatment 
groups. 
Time to deterioration 
Time to deterioration (months) is defined as the time from randomisation to an increase 
(worsening) from the baseline score of at least 10 points on the 0-100 point scale. Patients 
who die before deteriorating and before the end of follow-up will be analysed as having 
deteriorated at the time of death. Disease progression without scale deterioration will be 
censored at the time of the last scale measurement. Patients with no HRQoL assessments will 
be censored at day of randomisation. Patients who are alive with no disease progression and 
no scale deterioration at the end of the follow-up will be censored at the date of last 
questionnaire. 
This time to event data will be analysed and summarised using the same methodology as for 
the primary efficacy endpoint, refer to Section 7.4.  The hazard ratios will be displayed using 
Forest plots. 
Change in scores over time 
Changes in scores over time will be assessed using longitudinal models; these will be mixed-
effects growth curve models with the average profile over time for each endpoint described 
by a piecewise linear model adjusted for the fixed effects race.  The models will allow the 
slope to change at 8, 12, and 16 weeks.  Each model will also include the two random effects 
of intercept and slope (time from randomisation).  The area under the estimated growth curve 
(AUC) up to the median follow-up time will be calculated as a summary measure for each 
treatment group; this will be divided by the median follow-up time so that it can be 
interpreted as the mean HRQOL score up to the median follow-up time.  The treatment effect 
will be estimated as the average difference between the treatment group means scores, 
together with a 95% confidence interval and associated p-value based on a t-statistic with 
degrees of freedom calculated using the Kenward-Roger method.  The results of the analyses 
will be displayed using Forest plots. 
 
 
 
 
 
In addition, all single items and subscales (functional and symptom) from both questionnaires 
will be analysed in a similar fashion to summarise the impact of therapy over the entire 
profile of the measures, and to examine the consistency of component items with the 
composite measures. 
Note as higher scores represent a ‘better’ level of functioning; deterioration in scales/items 
related to functioning will be defined as a decrease from baseline score of at least 10 points. 
Finally, the usage of cough, dyspnoea and pain medication will be described. 


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7.7 
EXTENT OF EXPOSURE 
Total treatment time (days and number of courses) will be calculated for each patient; 
off-drug periods due to non-compliance or toxicity prior to permanent discontinuation will be 
included as treatment time.  In addition the total treatment time will be summed over all 
patients and transformed to patient years.  Standard descriptive summaries, by treatment 
group, of these data will be provided for the treated set of patients. 
A Kaplan-Meier plot showing the number of patients at risk (exposed) during the study 
treatment period will also be produced. 
Further summaries will also be produced: 
• Treatment time (days) broken down by each dose level (50 mg, 40 mg, 30 mg and 
20 mg for afatinib; 150 mg, 100 mg and 50 mg for erlotinib). 
• Number and proportion of patients on each dose level over time. 
• Time to first dose reduction and duration (days) of off-drug periods prior to first dose 
reduction. 
• Plot of proportion of patients with the first dose reduction over time 
Summary of time to dose escalation will be produced only for afatinib treatment group. 
7.8 
SAFETY ANALYSIS 
All safety analyses will be performed on the treated set.  
7.8.1 
Adverse events 
The analyses of adverse events 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 applies: 
• 
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) 


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• 
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 
AE episodes will be condensed into AE records provided that the episodes were reported with 
the same term on the respective MedDRA level and that the episodes are assigned to the same 
treatment. For further details on summarization of AE data, please refer to the guideline 
'Handling and summarization of adverse event data for clinical trial reports and integrated 
summaries'. (7) 
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events (TEAE). That means that all adverse events occurring between first drug intake till  
28 days after last drug intake will be assigned to the randomised treatment. All adverse events 
occurring before first drug intake will be assigned to ‘screening’ and all adverse events 
occurring after last drug intake + 28 days will be assigned to ‘post-treatment’ (for listings 
only). For details on the treatment definition, see Section 6.1. 
An overall summary of adverse events will be presented. This summary will include the first 
5 categories from the list below and AEs by highest CTC grade.  
The frequency of patients with adverse events will be summarised by highest CTC grade 
(grade 3, 4, 5 and all grades to allow both treatment groups to fit on one page), treatment, 
primary system organ class and preferred term. Separate tables will be provided for patients 
with each of the following AE categories: 
• All AEs. 
• Drug related AEs. 
• AEs leading to dose reduction. 
• AEs leading to treatment discontinuation. 
• Serious AEs. 
• Drug related serious AEs. 
• AEs leading to death. 
• AEs in Afatinib patients who dose escalate from 40 mg to 50 mg. 
The system organ classes will be sorted according to the standard sort order specified by 
EMEA, preferred terms will be sorted by frequency (within system organ class). 
In order to most accurately characterize those adverse events related to different mechanism, 
MedDRA SMQ and HLT (with some modification) will be used to group MedDRA PT for 
rash/acne, stomatitis, ocular effects, lip effects, nail effects and fatigue. As a first step in the 
analysis of grouped AE, all constituent PT will be presented in a separate table for each 
grouped AE. The first 5 standard tables will be supplemented with tables using the grouped 
AE. Groupings will follow the project standard and details 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 
project defined groupings and MedDRA PTs within each grouping will also be produced. 


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Additional tables will be produced to describe the frequency, intensity, time to onset, and 
clinical consequences for AE of special interest, diarrhea and rash/acne. 
Separate listings will be prepared for patients who are identified as having experienced any of 
the following AE.  For AE other than the single PT dehydration, identification will be based 
upon modified MedDRA SMQ and HLT groupings. If sufficient events occur within the trial, 
analyses similar to those for diarrhea and rash/acne may be performed.   
• dehydration 
• renal insufficiency 
• hepatic impairment 
• ILD-like events 
• heart failure 
7.8.2 Laboratory data 
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (8). CTCAE version 3.0 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’ (9). 
Primary laboratory tests are defined as: 
• Low values (-): haemoglobin, total WBC, platelets, neutrophils(only at baseline), 
potassium, magnesium, sodium, and GFR 
• High values (+): AST, ALT, alkaline phosphatase, aPTT, INR, creatinine, and total 
bilirubin 
The following analyses will be presented for the primary laboratory tests: 
• descriptive statistics at each planned assessment,  
• frequency of patients with transitions in CTCAE grade from baseline to worst and last 
values during treatment, and  
• frequency of patients with possible clinically significant abnormalities. 
 
Possible clinically significant abnormalities are defined as CTCAE grade of 2 or greater, with 
an increase of at least one grade from baseline. 
Frequency and time of onset of liver enzyme elevations will be tabulated. Additional, more 
in-depth analyses will be performed as needed. These analyses will examine the influence of 
extent of exposure and time to event onset. 
7.8.3 
Vital signs 
Only descriptive statistics are planned for this section of the report. 
A summary table of left ventricular ejection fraction (LVEF) values will be produced by each 
scheduled visit along with the change from baseline.  An additional summary will be 


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produced of the baseline along with the minimum on treatment value, change from baseline 
to minimum value, last LVEF on treatment and the change from baseline to last LVEF on 
treatment.  The number of patients with a significant LVEF event will also be presented; a 
significant event is defined as a decrease of ≥20% relative to baseline that is also below the 
institutional lower limit of normal or 50%. 
7.8.4 
ECG 
Not applicable. 
7.8.5 
Others 
ECOG performance score: 
A descriptive summary of ECOG performance score will be produced by each scheduled visit 
along with the change from baseline.   
 
 
 


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8. 
REFERENCES 
1 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D et al., New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 
1.1). Eur J Cancer 2009; 45:228-247 [R09-0262]. 
2 
 
3 
P Korhonen and J Palmgren 'Effect modification in a randomized trial under non-
ignorable non-compliance: an application to the alpha-tocopherol beta-carotene 
study', Applied Statistics (2002) 51, Part 1: 115-133 [R10-4999] 
4 
P Korhonen, N Laird and J Palmgren 'Correcting for non-compliance in 
randomized trials: An application to the ATBC study', Statistics in Medicine 
(1999). 18, 2879-2897 [R10-5000] 
5 
J Robins and D Finkelstein 'Correcting for Noncompliance and Dependent 
Censoring in an AIDS Clinical Trial with Inverse Probability of Censoring 
Weighted (IPCW) Log-Rank Tests', Biometrics (Sept 2000), 56, 779-788  
[R10-4487] 
6 
J Robins 'Information recovery and bias adjustment in proportional hazards 
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[R10-4484] 
7 
 
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim  
TSAP for BI Trial No: 1200.125 
Page 27 of 27
 
 
10. 
HISTORY TABLE 
Table 10: 1 
History table 
Version 
Date 
(DD-Mmm-YY) 
Author 
Sections 
changed 
Brief description of change 
Final 
18-APR-12 
 
None 
This is the final TSAP without any 
modification