A Multicentre, Cohort Study to Assess the Impact on SYMptom Burden and Patient Health-related Quality of Life of Afatinib Treatment in Advanced Non-small Cell Lung Cancer in a Real World Setting in Greece.
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Boehringer Ingelheim

ABCD
TITLE PAGE
Non-interventional Study Protocol
Document Number:
c03517862-03
BI Study Number:
1200.247
BI Investigational
Product(s):
Afatinib (GIOTRIF®)
Title:
A multicentre, cohort study to assess the impact on 
SYMptom burden and patient health-related quality of Life 
of afatinib treatment in advanced non-small cell lung cancer 
in a real world setting in Greece. The ‘SYM-Less’ study
Protocol version identifier:
2.0 (incorporating protocol amendment 1)
Date of last version of 
protocol:
31 July 2018
PASS:
No
EU PAS register number:
Study not registered
Active substance:
Afatinib 
Medicinal product:
GIOTRIF 20mg, 30mg, 40mg and 50mg film-coated tablets
Product reference:
Not applicable
Procedure number:
Not applicable
Joint PASS:
No
Research question and 
objectives:
The study primarily aims at assessing the impact of afatinib 
therapy on the patient-reported lung cancer-specific 
symptom burden, after 6 months of therapy. The main 
secondary objectives include the evaluation of the impact of 
afatinib on total symptomatic distress, functional activity,
HRQoL, as well as the assessment of adherence with 
treatment and the description of patterns of use of afatinib in 
routine clinical practice in terms of treatment modifications, 
and reasons for these modifications, in a representative 
sample of Greek subjects with advanced NSCLC in real-life 
clinical settings.
Country(-ies) of study:
Greece
Author:
Marketing authorisation 
holder(s):
Date:
31 July 2018
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TITLE PAGE

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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS.................................................................................................2
2.
LIST OF TABLES...........................................................................................................4
3.
LIST OF FIGURES .........................................................................................................4
4.
LIST OF ABBREVIATIONS..........................................................................................5
5.
RESPONSIBLE PARTIES..............................................................................................8
6.
ABSTRACT.....................................................................................................................9
7.
AMENDMENTS AND UPDATES...............................................................................18
8.
MILESTONES...............................................................................................................28
9.
RATIONALE AND BACKGROUND..........................................................................29
9.1
MEDICAL BACKGROUND ...................................................................................29
9.2
TARGETED THERAPIES FOR NSCLC ................................................................30
9.2.1
Afatinib drug profile..........................................................................................30
9.3
RATIONALE FOR PERFORMING THE STUDY .................................................31
10.
RESEARCH QUESTION AND OBJECTIVES ...........................................................33
10.1
PRIMARY OBJECTIVE ..........................................................................................33
10.2
SECONDARY OBJECTIVES..................................................................................33
11.
RESEARCH METHODS ..............................................................................................34
11.1
STUDY DESIGN......................................................................................................34
11.1.1
Synoptic study assessment schedule .................................................................34
11.1.2
Baseline and post-baseline timepoint definitions..............................................36
11.1.3
Study primary and secondary endpoints ...........................................................36
11.1.3.1
Primary endpoint/outcome measure ..........................................................36
11.1.3.2
Secondary endpoints/outcome measures ...................................................36
11.2.1
Site selection .....................................................................................................37
11.2.2
Study time period ..............................................................................................37
11.2.3
Projected duration of patient participation in the study ....................................38
11.2.4
Selection of population......................................................................................38
11.2.4.1
Inclusion criteria ........................................................................................38
11.2.4.2
Exclusion criteria.......................................................................................38
11.2.4.3
Withdrawal criteria ....................................................................................39

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11.2.4.4
Discontinuation of the study by the sponsor..............................................40
11.3
STUDY TREATMENT ............................................................................................40
11.3.1
Dosing/method of administration......................................................................40
11.3.2
Dose adjustment due to adverse events.............................................................41
11.3.3
Special warnings and precautions for use .........................................................41
11.4
VARIABLES ............................................................................................................42
11.4.1
Primary outcome variable .................................................................................42
11.4.2
Secondary outcome variables............................................................................42
11.4.3
Other variables ..................................................................................................43
11.4.4
Confounding/effect modification variables.......................................................44
11.5
DATA SOURCES.....................................................................................................44
11.5.1
Administration of patient-reported outcome questionnaires.............................46
11.5.2
Data collection schedule and study flow chart..................................................46
11.6
STUDY SIZE............................................................................................................51
11.7
DATA MANAGEMENT..........................................................................................51
11.8
DATA ANALYSIS...................................................................................................52
11.8.1
Study populations..............................................................................................52
11.8.2
Analysis for the primary endpoint.....................................................................53
11.8.3
Analysis for the secondary endpoints................................................................53
11.8.4
Analyses for the safety data ..............................................................................54
11.8.5
Drug exposure ...................................................................................................54
11.8.6
Additional analyses ...........................................................................................54
11.8.7
Interim analysis .................................................................................................55
11.9
QUALITY CONTROL.............................................................................................55
11.10 LIMITATIONS OF THE RESEARCH METHODS................................................56
11.11 OTHER ASPECTS ...................................................................................................57
11.11.1
Informed consent, data protection, study records .............................................57
11.11.1.1
Study approval, patient information, and informed consent......................58
11.11.1.2
Data quality assurance ...............................................................................58
11.11.1.3
Records ......................................................................................................58
11.11.1.4
Statement of confidentiality.......................................................................59
11.11.1.5
Completion of study ..................................................................................59
12.
PROTECTION OF HUMAN SUBJECTS ....................................................................61
13.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS.................................................................................................................62

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13.1
DEFINITIONS OF ADVERSE EVENTS................................................................62
13.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING ............................................................................................................63
13.3
TIME WINDOWS ....................................................................................................65
13.4
REPORTING TO HEALTH AUTHORITIES..........................................................66
14.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ...67
15.
REFERENCES ..............................................................................................................68
15.1
PUBLISHED REFERENCES...................................................................................68
15.2
UNPUBLISHED REFERENCES.............................................................................72
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS........................................................73
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS (REVISION 2)..................74
ANNEX 3. ADDITIONAL INFORMATION........................................................................79
2.
LIST OF TABLES
Table 1:
Study Milestones..............................................................................................28
Table 3:
Grading Scale for Toxicities Not Included in the NCI CTCAE ......................64
Table 4:
List of Stand-Alone Documents.......................................................................73
Table 5:
ECOG Performance Status Grading.................................................................79
3.
LIST OF FIGURES
Figure 1: 
Synoptic Study Diagram ..................................................................................35

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4.
LIST OF ABBREVIATIONS
AE
Adverse Event
ADR
Adverse Drug Reaction
ALK
Anaplastic Lymphoma Kinase
ΑESI 
Adverse Event of Special Interest 
ASBI
Average Symptom Burden Index
ATC
Anatomical Therapeutic Chemical
BI
Boehringer Ingelheim 
BMI
Body Mass Index
CA
Competent Authority
CD-ROM
Compact Disc, read-only-memory
CI
Confidence Interval
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Clinical Research Organisation
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
DCF
Data Clarification Form
DMP
Data Management Plan
EAIR
Exposure Adjusted Incidence Rates
ECOG
Eastern Cooperative Oncology Group
ECOG PS
ECOG Performance Status
eCRF
electronic Case Report Form
EDC
Electronic Data Capture
EGFR
  Epidermal Growth Factor Receptor 
EMA
European Medicines Agency
EORTC
European Organisation for Research and Treatment 
EORTC QLQ-C
EORTC Quality of Life Questionnaire – Cancer

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LIST OF ABBREVIATIONS (Continued) 
FACT-L
Functional Assessment of Cancer Therapy – Lung 
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HR
Hazard Ratio
HRQoL
Health-Related Quality of Life
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
ILD
Interstitial Lung Disease 
IRB
Institutional Review Board
ISF
Investigator Site File
MAH
Marketing Authorisation Holder 
MedDRA
Medical Dictionary for Drug Regulatory Activities
NCI
National Cancer Institute
NIS
Non Interventional Study
NSCLC
Non-Small Cell Lung Cancer 
OS
Overall Survival
pDCF
paper Data Clarification Forms
PPS
Per Protocol Set
PRO
Patient Reported Outcome
PT
Preferred Term
QoL
Quality of Life 
RCT
Randomized Clinical Trial
RSE
Relative Standard Error
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SD
Standard Deviation
SDV
Source Data Verification

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  LIST OF ABBREVIATIONS (Continued)
SFEE
Hellenic Association of Pharmaceutical Companies
SmPC
Summary of Product Characteristics
SOC
System Organ Class
SOP
Standard Operating Procedure
TKI
Tyrosine Kinase Inhibitor
VAS
Visual Analogue Scale
VEGF
Vascular Endothelial Growth Factor
WBDC
Web Based Data Capture
WHO
World Health Organisation
WHOCC
WHO Collaborating Centre 

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5.
RESPONSIBLE PARTIES
Study Sponsor
 
Address: 
Contract Research Organisation 
Name: 
Address:
Participating Investigators
The list and contact details of all investigators will be kept in a stand-alone document and will 
be available upon request.

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6.
ABSTRACT
Name of company:
Tabulated
Clinical Study Protocol
Boehringer Ingelheim
Name of finished medicinal 
product:
GIOTRIF film-coated tablets
Name of active ingredient:
Pharmacotherapeutic group: 
Antineoplastic agents, protein kinase 
inhibitors, 
ATC code: L01XE13 
Active substance: Afatinib
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
02 April 2015
1200.247
2.0
31 July 2018
Title of study:
A multicentre, cohort study to assess the impact on SYMptom burden 
and patient health-related quality of Life of afatinib treatment in 
advanced non-small cell lung cancer in a real world setting in Greece.
The ‘SYM-Less’ study
Original protocol version and date:
V.1.0 -  02 April 2015
Name and affiliation of main author: 
Rationale and 
background:
The incidence of lung cancer in developed countries is growing. 
Moreover, despite a wealth of therapies, prognosis of advanced stage 
non-small cell lung cancer (NSCLC) is poor, with a median overall 
survival 
(OS) 
approaching 
10 
months 
with 
platinum-based 
chemotherapy and 2 years with targeted therapies. 
NSCLC bears not only significant mortality but also morbidity as 
patients suffer from debilitating symptoms, such as cough, chest pain, 
dyspnea, anorexia, fatigue and hemoptysis. Symptoms are at the 
cornerstone of patients’ well-being, as in a recent survey patients 
reported that prolongation of progression-free survival (PFS) is the 
most important factor for choosing a treatment only when disease-
specific symptoms are mild, while PFS plays a less central role when 
considering a treatment choice in the presence of severe symptoms. It 
is thus not surprising that alleviation of symptom burden has been 
added to the core of disease management, making it imperative to 
evaluate not only treatment effectiveness but also quality of life (QoL) 
and symptom burden in both clinical research and routine patient care 
settings.
There is a broad array of questionnaires used in the field of NSCLC for 
the assessment of health-related QoL (HRQoL). Among them, the 
most commonly used generic instruments assessing global health 

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status are the Euro QoL EQ-5D and the cancer-generic European 
Organization for Research and Treatment (EORTC) Quality of Life 
Questionnaire – Cancer (EORTC QLQ-C30). Moreover, disease-
specific instruments assessing HRQoL have been developed for 
patients with NSCLC including the Functional Assessment of Cancer 
Therapy – Lung (FACT-L), the EORTC QLQ – Lung Cancer (EORTC 
QLQ-LC13) and the Lung Cancer Symptom Scale (LCSS). 
For patients with NSCLC tumors harbouring mutations of the 
epidermal growth factor receptor (EGFR), targeted treatments, 
including the first generation tyrosine kinase inhibitors (TKIs), 
erlotinib and gefinitib, have shown benefits in terms of prolongation of 
survival and increased response rates and improvement of HRQoL. 
However, resistance to therapy commonly develops, which has led to 
the development of the irreversible EGFR TKI, afatinib, which targets 
and blocks signalling from dimers of all ErbB family members, EGFR 
(ErbB1), HER 2 (ErbB2), ErbB3 and ErbB4. Afatinib (GILOTRIF™/ 
GIOTRIF®) was approved in 2013 by the FDA and EMA based on 
results of the pivotal phase 3 studies LUX-Lung 3 and LUX-Lung 6. In 
the US afatinib is indicated for the first-line treatment of patients with 
metastatic non-small cell lung cancer (NSCLC) whose tumors have 
epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 
(L858R) substitution mutations as detected by an FDA-approved test. 
While in Europe, afatinib as monotherapy is indicated for the treatment 
of Epidermal Growth Factor Receptor (EGFR) TKInaïve adult patients 
with locally advanced or metastatic non-small cell lung cancer 
(NSCLC) with activating EGFR mutation(s). 
In the LUX-Lung 3 randomized controlled trial (RCT) patients were 
randomised (2:1) to receive afatinib 40 mg once daily or up to 6 cycles 
of premetrexed/cisplatin. According to the results of the study, for the 
subgroup of patients with common mutations (Del 19, L858R) (204 on 
afatinib and 104 on chemotherapy) the median PFS was 13.6 vs. 6.9 
months [Hazard Ratio (HR) 0.47; 95% CI 0.34-0.65; p<0.0001] and 
the median OS was 30.3 vs. 26.2 months, demonstrating a clear benefit 
of afatinib treatment. In addition to the Del19, L858R mutations, 
certain less common mutations have also been shown to be sensitive to 
afatinib treatment. Moreover, compared to chemotherapy first-line 
afatinib was associated with better control of cough (HR, 0.60; 95% 
CI, 0.41 to 0.87; P=0.007) and dyspnea (HR, 0.68; 95% CI, 0.50 to 
0.93; P=0.015), as well as improved global health status/QoL 
(P=0.015), and functional scale scores as assessed with the use of 
EORTC QLQ-C30 and the EORTC-QLQ-L13. The results of the 
pivotal LUX-Lung 3 RCT have been supported by the LUX-Lung 6 
phase 3 RCT.
The LUX-Lung 6 phase 3 trial was the largest conducted in Asian 
patients with EGFR mutation-positive advanced lung cancer (n=364). 
The study compared first line afatinib with gemcitabine/cisplatin 
chemotherapy. In the afatinib arm mean PFS was 11.0 months vs. 5.6 
months for those in the chemotherapy arm (HR 0.28; P<0.0001). Side-
effects seen with afatinib were manageable through dose reductions 
and supportive care; treatment-discontinuation rate due to adverse 
events was 5.9% in the afatinib compared to 39.8% in the 

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gemcitabine/cisplatin arm. Regarding symptom improvement and 
HRQoL, patients treated with afatinib in the LUX-Lung 6 study,
demonstrated improvement of cough  (P<0.0001), dyspnea (P<0.0001) 
and pain (P=0.03), as well as decreased time to deterioration of these 
symptoms compared to those treated with chemotherapy. Global health 
improvement was also demonstrated by a higher proportion of patients 
in the afatinib group than in the gemcitabine/cisplatin group (62.7% 
versus 32.7%; P<0.0001). Notably, prolongation of PFS was 
associated with improved HRQoL and significantly longer control of 
disease-related symptoms. 
Mature survival data from the LUX-Lung 3 and LUX-Lung 6 studies 
have indicated that with a median follow-up of 41 months in the LUX-
Lung 3, and 33 months in the LUX-Lung 6, afatinib offered a 
significant improvement in OS among patients with Del 19-positive 
tumors (median 33.3 vs. 21.1 months with chemotherapy, P=0.0015 in 
LUX-Lung 3; and 31.4 vs. 18.4 months, P=0.023 in LUX-Lung 6).
On the ground of the aforementioned evidence, afatinib represents a 
great advance in the therapeutic armamentarium of advanced NSCLC 
with activating EGFR mutations. Taking into consideration the limited 
real-world evidence that is attributed to the recent advent of afatinib in 
the market, this field non-interventional study aims primarily at 
assessing the impact of the therapy on patients’ disease-related 
symptom burden and HRQoL. In addition, it represents an attempt 
towards gaining experience on the routine use of afatinib in daily 
clinical practice in a representative sample of Greek subjects with 
advanced NSCLC in real-life clinical settings. The study will 
complement the evidence available from the RCTs and assist in the 
decision-making process of the medical professionals that provide care 
to this heavily burdened population. 
Research question 
and objectives:
Primary Objective
To evaluate the impact of afatinib therapy on the patient-reported 
lung cancer-specific symptom burden, using the Average Symptom 
Burden Index (ASBI) of the LCSS in eligible patients, over 6 
months of therapy, in a real world clinical setting in Greece.
Secondary Objectives   
To evaluate the effect of afatinib therapy on the patient-reported 
lung cancer-specific symptom burden, total symptomatic distress, 
functional activity status and global quality of life, using the LCSS 
total score and domain subscores, at the post baseline predefined 
timepoints (i.e., at 2-month intervals during the first 12 months of 
therapy and at 6-month intervals thereafter until the end of the
patient’s participation in the study);
To assess the impact of afatinib treatment on the HRQoL of the 
study population using the EQ-5D-3L questionnaire at the post 
baseline predefined timepoints; 
To assess the impact of afatinib therapy on patient’s ECOG 
performance status (PS) at the post baseline predefined timepoints;
To record patient adherence to treatment with afatinib during the 
study observation period as well as the reasons for missing doses;
To assess the patterns of use of afatinib in routine clinical practice 

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in terms of treatment modifications (permanent discontinuations, 
temporary interruptions, dose changes), and reasons for these 
modifications.
Study design:
This is a non-interventional, multicentre, cohort study, based on new 
data collection, which will include a representative sample of patients 
with advanced/metastatic NSCLC in Greece. 
Patients will be treated according to the local prescribing information 
of the study medication (afatinib, GIOTRIF®) and routine medical 
practice in terms of visit frequency and types of assessments 
performed. Since this is purely non-interventional study, primary data 
obtained prospectively during the study visits through patients’ 
interview and patient reported outcomes (PROs) or as performed per 
standard clinical practice will mainly be employed.
The overall study duration period is expected to be 60 months, 
including a 48-month enrollment period and a minimum 12-month 
follow-up period. During the observation period, data will be collected 
at routine clinical visits at 2-month intervals for the first 12 months and 
at 6-month intervals thereafter until the end of study participation. The 
end of study participation is defined as a maximum of 48 months after 
afatinib treatment intiation or disease progression, death, withdrawal of 
consent, unacceptable toxicity, study completion or physician’s 
decision whichever occurs earlier. The maximum 48-month length of 
participation in the study pertains to the patients enrolled during the 
first 12 months of recruitment, while the maximum observation period 
for the last patient enrolled is 12 months.
Population:
A total of 128 patients are planned to be enrolled by seven (7) 
Oncology and Pulmonology hospital centres/clinics in Greece 
specialized in lung cancer. Physicians will originate from a random 
pool of specialists in lung cancer and will be recruited from various 
geographic regions in Greece in order for variations in clinical practice 
to be reflected. Investigators’ selection will be performed by the means 
of a documented and constructed feasibility assessment process that 
will account, among others, for physicians’ qualifications, previous 
participation and experience in similar clinical studies and recruitment 
potential and retention capability. 
Patients who will be considered as eligible for participation in this 
study must meet ALL the following inclusion criteria and NONE of 
the exclusion criteria presented below:
Inclusion Criteria

Adult outpatients (18 years and older) of either gender;

Histologically or cytologically confirmed locally advanced or 
metastatic (IIIB/IV) NSCLC of any histological type with 
activating EGFR mutation(s) according to local laboratory EGFR 
testing;

EGFR-TKI naïve patients; 

Patients for whom the decision to prescribe therapy with afatinib 
(GIOTRIF®) according to the locally approved product’s summary 
of product characteristics (SmPC) has already been taken prior to 

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their enrolment in the study and is clearly separated from the 
physician’s decision to include the patient in the current study;

Patients must be able and willing to provide written informed 
consent and to comply with the requirements of this study protocol;

Patients must have signed an informed consent document;

Patients must be able to read, understand and complete the study 
specific questionnaires.
Exclusion Criteria

Patients who have initiated treatment with afatinib more than 7 
days prior to their enrolment into the study; 

Patients that meet any of the contraindications to the administration 
of the study drug according to the approved SmPC;

Patients currently receive treatment with any investigational 
drug/device/intervention or have received any investigational 
product within 1 month or 5 half-lives of the investigational agent 
(whichever is longer) before the commencement of therapy with 
afatinib.
Variables:
Primary Variable:

ASBI score of LCSS -defined as the mean of the score of the 6 
major lung cancer symptoms, i.e. loss of appetite, fatigue, cough, 
dyspnea, pain, and hemoptysis- at enrollment and at 2-month 
intervals over the initial 6-month observation period.
Secondary Variables: 
Patient-rated ASBI score of LCSS at the post-baseline predefined 
timepoints;
Patient-rated total LCSS score -defined as the average of the 
aggregate score of all 9 items that comprise the LCSS- at 
enrollment and at the post-baseline predefined timepoints;
Patient-rated individual LCSS domain scores at enrolment and at 
the post-baseline predefined timepoints;
Proportion of patients with reported problems for each level for 
each dimension of EQ-5D and proportion of patients with ‘no 
problems’ (i.e., level 1) and ‘with problems’ (i.e., level 2 & 3) at 
enrolment and at the post-baseline predefined timepoints; 
EQ-VAS score at enrolment and at the post-baseline predefined 
timepoints; 
ECOG PS score at baseline and at the post-baseline predefined 
timepoints;
Ratio of doses actually taken to doses prescribed over the study 
participation period and reasons for discrepancies;  
Proportions of patients with treatment discontinuations, temporary 

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interruptions, or dose change(s) and reasons for treatment 
modifications.
Confounding/Effect Modification Variables
  The following variables will be considered as potential confounders or 
effect modifiers of the main association between treatment with 
afatinib and change in disease-specific symptom burden: Age; Gender; 
Body Mass Index (BMI); Educational/marital/employment status; 
Baseline 
comorbidity 
count 
with 
particular 
emphasis 
on 
gastrointestinal, psychiatric, and musculoskeletal and connective tissue 
disorders; Concomitant medications both at baseline and at the time of 
symptom burden assessment with particular emphasis among others on 
analgesics, 
antitussives, 
antidepressants, 
antiemetics, 
and 
antidiarrheals; Disease stage at baseline; Baseline ECOG PS; Baseline 
smoking status and lifetime tobacco exposure; Lung cancer histologic 
classification; EGFR mutation subtype; Sites of metastases; Adherence 
to afatinib treatment.    
Data sources:
The study will mainly involve new data collection, by means of a web 
based data capture (WBDC) system. Data will be collected by the 
study physicians as generated according to the standard clinical 
practice and by the patients as captured with the use of PROs. No 
further laboratory tests and examinations are required apart from those 
recommended by the study medication SmPC.
Patient source data pertaining to medical- and lung cancer-related 
history will be abstracted from patient medical charts/records by the 
investigators and will be recorded in the relevant section of the 
WBDC. 
All afatinib treatment modifications, concomitant medications, study-
related routine clinical assessments, vital signs and adverse events 
(AEs) will also be collected.
Concomitant or prior disease-related medications entered into the 
database will be coded using the Anatomical Therapeutic Chemical 
(ATC) WHO Collaborating Centre for Drug Statistics Methodology 
(WHOCC) Drug Reference List. 
Medical history/comorbidities and adverse events will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA) terminology.
PROs (LCSS patient scale and EQ-5D-3L) will be collected via self-
administered paper questionnaires completed by the patients 
themselves at study enrolment and periodically throughout study 
participation, according to the study visit frequency.
For the measurement of the adherence to therapy, a patient diary will 
be used which the patient will be requested to fill in only with the date 
and reasons for missed pills. 
In addition, physicians will be requested to assess the patients’ 
performance status using the ECOG PS instrument.
Study size:
Sample size calculation has been based on study's primary endpoint, 
which involves the determination of the proportion of study population 

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with clinically meaningful improvement in LCSS ASBI score after a 6-
month treatment period. 
Due to the lack of published data on the effect of afatinib on symptom 
burden using the LCSS, the worst case scenario has been taken into 
account, i.e., that the proportion of patients experiencing symptom 
improvement after 6 months of therapy will be approximately 0.50. 
Consequently, the assessment of 96 patients is required to estimate the 
aforementioned proportion with a margin of error not exceeding 0.10
which represents a scientifically acceptable level of precision of the 
estimate [95% CI: 0.40-0.60; α: 0.05; Relative Standard Error (RSE): 
10.21%]. This means that for any proportion between 0.05 and 0.95,
the precision will range from 0.04 to 0.10 at a 95% confidence limit.
In order to control for an estimated 25% drop out/non-evaluable rate, 
128 patients are finally required in order to ensure the aforementioned 
sample size for the final statistical analysis.
Data analysis:
This study is not aimed to confirm or reject any pre-defined 
hypotheses; therefore statistical analyses will be of explorative and 
descriptive nature. 
Continuous variables will be summarized with the use of descriptive 
statistical measures (mean value, standard deviation, median and 
extreme values) and categorical/distinct variables will be displayed as 
frequency tables (N, %). The normality of distribution of continuous 
variables will be examined using Shapiro-Wilk test in order to 
determine whether or not to use parametric methods for the analysis of 
the sample data.
Pertaining to the primary endpoint the proportion of patients 
experiencing a minimum clinically important symptom improvement 
(i.e., decrease in the ASBI from enrolment ≥10 in two subsequent 
measurements) over 6 months of treatment will be calculated along 
with the respective 95% confidence interval.
The symptom improvement rate throughout the study observation 
period will also be calculated in patient-years. 
With regard to the secondary endpoints pertaining to the LCSS 
outcome measures: the mean change of the total LCSS, the LCSS 
domain subscores and the ASBI subscore, will be calculated from 
enrolment to all available subsequent study visits and will be examined 
for statistical significance with the use of the paired t-test or its non-
parametric analogue. Pertaining to the change of the mean LCSS as 
well as the mean ASBI through the observation period, linear mixed 
models will be applied.
The distribution of patients by level (‘level 1: no problems’, ‘level 2: 
some problems’ and ‘level 3: extreme problems’) for each dimension 
as well as the distribution of patients in the dichotomized EQ-5D levels 
[‘no problems’ (level 1) and ‘problems’ (levels 2 and 3)] will be 
presented in frequency tables (N, %) for all patients with available 
data. Descriptive statistical measures will be calculated for the EQ-
VAS score at each predefined study timepoint along with the observed 
changes in the EQ-VAS from enrolment, while the paired t-test or the 
Wilcoxon signed rank test will be used to assess the statistical 
significance of the change.   

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The McNemar’s test will be used in order to evaluate the change in the 
levels (‘with problems’/‘no problems’) of each dimension between 
enrolment and the post-baseline visits.
The distribution of patients in the different ECOG performance status 
levels at every study time-point will be presented in frequency tables 
(N, %). Additionally, changes in the status of patients from baseline to 
post-baseline evaluations will be depicted in shift tables.
Adherence to study treatment along with proportion of patients who 
discontinued permanently or temporarily treatment, dose modifications 
and reasons for treatment discontinuations will be analysed in 
descriptive manner.  
In order to examine the impact of baseline and other characteristics 
including 
among 
others, 
gender, 
age, 
BMI, 
educational/marital/employment status, disease stage, histological 
subtype, sites of metastases, EGFR mutation subtype, smoking status, 
ECOG PS, type of concomitant medications and comorbidity count, as 
well as adherence to therapy at 6 months on the study primary 
endpoint, generalized linear models will be applied. 
In addition, the number and proportion of patients experiencing any 
serious AE (SAE) and the number and proportion of patients 
experiencing any non-serious AE (NSAE) will be calculated and 
presented in frequency tables by MedDRA system organ class (SOC) 
and preferred (PT) while frequency tables will be presented pertaining 
to the National Cancer Institute (NCI) Common Toxicity Criteria for 
Adverse Events (CTCAE) toxicity grade classification of AEs.
All the aforementioned statistical tests will be two-sided and will be 
performed at a 0.05 significance level.
Statistical analysis will be conducted using a validated statistical 
software package (e.g., SAS).
Taking into consideration the long-term study duration as well as the 
current limited evidence on the real-world clinical outcomes of 
treatment with afatinib in patients with NSCLC, an interim analysis is 
planned to be performed after the first enrolled 40 patients have 
completed the 6-month study observation period.
The main purpose of the interim analysis is to gain preliminary 
information on the impact of afatinib in the study key outcome 
measures. No resultant decisions and actions will be taken in terms of 
the study progress as a consequence of the interim analysis. The 
interim analysis does not involve any stopping boundary for early stop 
due to efficacy or for sample size adjustment, thus no multiplicity 
adjustment will be performed.
Milestones:
Start of data collection*:           01 March 2016
End of data collection**:          01 March 2021
Interim report of study results: 4 months after the data cut-off date for 
the purposes of interim analysis (i.e., 
when the first enrolled 40 patients 
complete 
the 
6-month 
study 
observation period)
Final report of study results**: 30 September 2021

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*
This date corresponds to the actual date of the start of data collection.
** These milestones are subject to change depending on the actual date of the 
“Last Patient Out”.

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7.
AMENDMENTS AND UPDATES
The main scope of Amendment #1 is: (a) to decrease the required sample size from 160 to 
128; (b) to increase the length of the recruitment period by 12 months, i.e., from 36 to 48 
months; (c) to increase the allowable time window of the study visits from ±1 week for Visits 
2-7, and ±2weeks for Visits 8-13 to ±3weeks for all; and (d) to include an interim analysis. 
The sections of the protocol that are affected, the description of the amendment and the 
reason for change are displayed in the following table, where deleted text is indicated by 
strikethrough and added text in bold characters:

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Number
Date
Section of 
study protocol
Amendment or update
Reason
1
19 June 2018
Section 11.1 
(Study 
Design), 4th
paragraph 
Text changed from: 
“Follow-up visit frequency 
will be determined by the 
treating physician, however 
study-related data will be 
collected at 2-month (±1 
week) intervals during the 
first 12 months of study 
participation and every 6 
months (±2 weeks) 
thereafter until the end of
the study observation 
period.” 
to:  
“Follow-up visit frequency 
will be determined by the 
treating physician, however 
study-related data will be 
collected at 2-month (±13 
weeks) intervals during the 
first 12 months of study 
participation and every 6 
months (±23 weeks) 
thereafter until the end of 
the study observation 
period.”  
To widen the 
time window 
for the 
scheduled 
study visits in 
order to allow 
for a data 
collection 
schedule that 
better mirrors 
the patterns of 
routine clinical 
care.
Section 11.1.2    
(Baseline and 
post-baseline 
timepoint 
definitions), 
2nd  bullet
Text changed from: 
“Post-baseline predefined 
timepoints for study-
specific assessments are 
defined as: every 2 months 
(±1 week) during the first 
12 months of therapy and 
every 6 months (±2 weeks) 
thereafter until the end of 
patient’s participation in the 
study.”
to:  
“Post-baseline predefined 
timepoints for study-
specific assessments are 
defined as: every 2 months 
(±13 weeks) during the first 
12 months of therapy and
every 6 months (±23 weeks) 
thereafter until the end of 
To widen the 
time window 
for the 
scheduled 
study visits in 
order to allow 
for a data 
collection 
schedule that 
better mirrors 
the patterns of 
routine clinical 
care.

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Number
Date
Section of 
study protocol
Amendment or update
Reason
patient’s participation in the 
study.”
Section 11.2.1 
(Site 
selection), 1st
paragraph  
Text changed from: 
“A total of 160 patients are 
planned to be enrolled by 
ten (10) Oncology and 
Pulmonology hospital 
centres/clinics in Greece 
specialized in lung cancer.”
to:
“A total of 160 128 patients 
are planned to be enrolled 
by ten (10) seven (7) 
Oncology and Pulmonology 
hospital centres/clinics in 
Greece specialized in lung 
cancer.”
To decrease 
the originally 
planned 
required 
sample size 
from 160 to 
128 due to the 
lower than 
expected 
recruitment 
rate at the time 
of drafting this 
amendment, 
and the 
participation 
of fewer than 
projected 
study sites.   
Section 11.2.2 
(Study time 
period), 1st
paragraph  
Text changed from: 
“The overall study duration 
period is expected to be 48 
months, including a 36-
month enrollment period 
and a minimum 12-month 
follow-up period.”
to:
“The overall study duration 
period is expected to be 48
60 months, including a 36 
48-month enrollment period 
and a minimum 12-month 
follow-up period.”
To extend the 
originally 
planned 
recruitment 
period by 12 
months in 
order to 
facilitate the 
recruitment of 
the required 
sample size.   
Section 11.2.3    
(Projected 
duration of 
patient 
participation in 
the study), 1st
paragraph  
Text changed from: 
“In the context of this study, 
each participant will be 
treated with afatinib until 
disease progression, death, 
withdrawal of consent, 
unacceptable toxicity, study 
completion or physician’s 
decision whichever occurs 
earlier. Thus the maximum 
To reflect the 
change in the 
overall study 
duration from 
48 to 60 
months due to 
the 12-month 
recruitment 
period 

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Number
Date
Section of 
study protocol
Amendment or update
Reason
length of participation in the 
study pertaining to the first 
enrolled patient is 48 
months while the maximum 
observation period for the 
last patient enrolled is 12 
months.” 
to: 
In the context of this study 
which is planned to have 
an overall duration of 60 
months, each participant 
will be treated with afatinib 
and observed in the 
context of the study until 
the end of study 
participation defined as a 
maximum of 48 months 
after afatinib treatment 
initiation or until disease 
progression, death, 
withdrawal of consent, 
unacceptable toxicity, study 
completion or physician’s 
decision whichever occurs 
earlier. Thus the The 
maximum 48-month length 
of participation in the study 
pertaining to pertains to 
the patients enrolled 
during the first enrolled 
patient is 48 12 months of 
recruitment, while the 
maximum observation 
period for the last patient 
enrolled is 12 months.” 
extension, and 
to clarify that 
the maximum 
observation 
period remains 
48 months and 
has become 
applicable to 
patients 
enrolled over 
the first 12 
months of 
recruitment. 

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Number
Date
Section of 
study protocol
Amendment or update
Reason
Table 2 (Study 
Flow Chart 
and 
Assessments), 
“Visit 
Window” row
For Follow-up Visits V2 
to V7, the visit window 
was changed from ± 1 
week to ± 3 weeks; and 
for Follow-up Visits V8 
to V13, the visit window 
was changed from ± 2 
weeks to ± 3 weeks.
To widen the 
time window 
for the 
scheduled 
study visits in 
order to allow 
for a data 
collection 
schedule that 
better mirrors 
the patterns of 
routine clinical 
care.
Section 11.6       
(Study Size), 
2nd and 3rd  
paragraphs  
Text changed from: 
“…Consequently, the 
assessment of 120 patients 
is required to estimate the 
aforementioned proportion 
with accuracy (confidence 
interval) of ± 0.09 at the 
study population [95% CI: 
0.41-0.59; α: 0.05; Relative 
Standard Error (RSE): 
9.1%]. 
In order to control for an 
estimated 25% drop 
out/non-evaluable rate, 160 
patients are finally required 
in order to ensure the 
aforementioned sample size 
for the final statistical 
analysis.”  
to:
“…Consequently, the 
assessment of 120 96 
patients is required to 
estimate the 
aforementioned proportion 
with accuracy (confidence 
interval) of ± 0.09 at the 
study population [95% CI: 
0.41-0.59; α: 0.05; Relative 
Standard Error (RSE): 
9.1%]. with a margin of 
error not exceeding 0.10 
To reduce the 
originally 
planned 
evaluable 
study size 
from 120 to 96 
patients which 
represents the 
minimum 
required size 
for estimating 
the primary 
outcome 
measure with 
the highest 
scientifically 
acceptable 
margin of 
error. 

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Number
Date
Section of 
study protocol
Amendment or update
Reason
which represents a 
scientifically acceptable 
level of precision of the 
estimate [95% CI: 0.40-
0.60; α: 0.05; Relative 
Standard Error (RSE): 
10.21%]. This means that 
for any proportion 
between 0.05 and 0.95, the 
precision will range from 
0.04 to 0.10 at a 95% 
confidence limit. The 
sample size determination 
has been performed using 
the statistical software 
package SAS v9.4 (SAS 
Institute, Cary, NC).
In order to control for an 
estimated 25% drop 
out/non-evaluable rate, 160
128 patients are finally 
required in order to ensure 
the aforementioned sample 
size for the final statistical 
analysis.” 

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Number
Date
Section of 
study protocol
Amendment or update
Reason
Section 11.7       
(Data 
Management), 
last paragraph  
Text changed from: 
“Prior to the onset of data 
management activities, a 
detailed data management 
plan (DMP) will be issued 
describing the procedure to 
be followed for processing 
all collected study data in 
order to ensure they are 
valid, complete and accurate 
for statistical analysis. In 
addition, aiming at ensuring 
the expected quality of data, 
a thorough data cleaning 
session will be applied.”
to:
“Prior to the onset of data 
management activities, a 
detailed data management 
plan (DMP) will be issued 
describing the procedure to 
be followed for processing 
all collected study data in 
order to ensure they are 
valid, complete and accurate 
for the interim and final
statistical analysis. In
addition, aiming at ensuring 
the expected quality of data, 
a thorough data cleaning 
session will be applied 
twice during the conduct 
of the study for the 
purposes of the interim 
and final analysis, 
respectively.”
To add text 
indicating that 
an interim 
analysis is 
planned to be 
conducted in 
the context of 
the study, and 
to update the 
relevant text 
pertaining to 
the data 
cleaning 
process to be 
applied.   
Section 11.8       
(Data 
Analysis), 5th
paragraph  
Text changed from: 
“A SAP comprising a 
comprehensive and detailed 
description of the statistical 
methodology applied for the 
purposes of the main 
analyses along with 
imputation methods for 
missing data will be 
prepared prior to database 
To add a 
clarification 
that the SAP 
will also 
include details 
on the interim 
analysis to be 
carried out.   

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Number
Date
Section of 
study protocol
Amendment or update
Reason
lock.”
to:
“A SAP comprising a 
comprehensive and detailed 
description of the statistical 
methodology applied for the 
purposes of the main 
analyses interim and final 
analysis along with 
imputation methods for 
missing data will be 
prepared prior to database 
lock.”
Section 11.8       
(Data 
Analysis),
Addition of new 
subsection #11.8.7 titled 
“Interim Analysis”
The text added under the 
new section follows:
“Taking into 
consideration the long-
term study duration as 
well as the current limited 
evidence on the real-world 
clinical outcomes of 
treatment with afatinib in 
patients with NSCLC, an 
interim analysis is planned 
to be performed after the 
first enrolled 40 patients 
(i.e., around one-third of 
the overall sample size) 
have completed the 6-
month study observation 
period (i.e., have attended 
the 6-month study visit 
[V4] or have discontinued 
study participation, 
whichever occurs first).
The main purpose of the 
interim analysis is to gain 
preliminary information 
on the impact of afatinib 
in the study key outcome 
measures. No resultant 
decisions and actions will 
be taken in terms of the 
To add a 
section 
indicating that 
an interim 
analysis is 
planned to be 
carried out in 
the context of 
this study, and 
to provide the 
rationale, the 
purpose and 
the process for 
handling the 
results of this 
analysis.   

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Number
Date
Section of 
study protocol
Amendment or update
Reason
study progress as a 
consequence of the interim 
analysis. The interim 
analysis does not involve 
any stopping boundary for 
early stop due to efficacy 
or for sample size 
adjustment, thus no 
multiplicity adjustment 
will be performed.
The confidentiality of the 
interim analysis data will 
be controlled by 
assignment of the analysis 
to a statistical group that 
is independent of the 
Sponsor and investigators, 
i.e. is not otherwise 
involved in the study 
design or conduct. After 
completion of the analysis 
the results will be 
summarized in a synoptic 
interim CSR and 
distributed to the study 
Sponsor. The detailed 
interim analysis results 
will not be disclosed to the 
participating investigators 
until the overall study 
completion in order to 
account for the avoidance 
of any bias that may result 
from the premature 
disclosure and subjective 
interpretation of the 
preliminary findings. 
However, the preliminary 
results may be announced 
in the form of an abstract 
or poster/presentation in a 
descriptive manner, as per 
the Sponsor’s decision; in 
such case, the minimum 
required information will 
be disclosed aiming at 
safeguarding the scientific 
integrity of the final study 

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Number
Date
Section of 
study protocol
Amendment or update
Reason
results.”
Section 8 
(Milestones), 
Table 1
Update of the study 
milestones taking into 
consideration the actual 
date of first patient 
enrolled, the 12-month 
recruitment period 
extension and the 
incorporation of the 
interim analysis.
To update the 
study 
milestones in 
order to reflect 
the extension 
in the 
recruitment 
period, 
considering 
also the actual 
date of the first 
patient 
enrolled. 
Section 6 
(Abstract)
Amendment of the 
relevant text that is 
affected by the 
aforementioned
amendments in the main 
body of the protocol.
To harmonise 
the abstract 
section with all 
changes 
performed in 
the main body 
of the protocol 
as a result of 
this 
amendment. 

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8.
MILESTONES
Table 1:
Study Milestones
Milestone
Planned Date
Start of data collection
01 March 2016*
End of recruitment 
01 March 2020 or until the planned sample size of 128 
patients has been enrolled, whichever occurs earlier
End of data collection**
01 March 2021
Data cut-off date for the 
purposes of interim analysis 
When the first enrolled 40 patients complete the 6-
month study observation period
Interim report (with results 
of the interim analysis)
4 months after the data cut-off date for the purposes of 
interim analysis
Final database lock** 
01 June 2021
Final report of study 
results**
30 September 2021
*
This date corresponds to the actual date of the start of data collection.
** These milestones are subject to change depending on the actual date of the “Last 
Patient Out”.

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9.
RATIONALE AND BACKGROUND
9.1
MEDICAL BACKGROUND
The incidence of lung cancer in developed countries is growing. According to 2012 
estimates, the age standardized rate of lung cancer (including the trachea and bronchus) was 
41.9 per 100,000 cases in Europe, while the respective rate for Greece was 41.6 [1]. 
Worldwide, lung cancer is the leading cause of cancer-related deaths among males and the 
second leading cause of cancer-related deaths among women. In Greece, the age-adjusted 
mortality rates for 2012 were estimated to be 67.7 and 11.8 per 100,000 cases among males 
and females, respectively [2]. Moreover, despite a wealth of therapies, prognosis of advanced 
stage non-small cell lung cancer (NSCLC) is poor, with a median overall survival (OS) 
approaching 10 months with platinum-based chemotherapy and 2 years with targeted 
therapies [3, 4]. NSCLC is the most common type of lung cancer, and in most cases is 
diagnosed at an unresectable, locally advanced (stage IIIB) or metastatic stage (IV) [5]. 
NSCLC bears not only significant mortality, but also morbidity as patients suffer from 
debilitating symptoms, such as cough, chest pain, dyspnoea, anorexia, fatigue and 
haemoptysis [4, 6]. Symptoms are at the cornerstone of patients’ well-being, as evidenced in 
a recent survey in which patients reported that prolongation of progression-free survival 
(PFS) is the most important factor for choosing a treatment only when disease-specific 
symptoms are mild, while PFS plays a less central role when considering a treatment choice 
in the presence of severe symptoms. In regards to the specific symptoms, patients ranked 
fatigue as the most important risk, followed by diarrhoea, nausea and vomiting [7]. In another 
study, the majority of the subjects (82%) reported that they would prefer supportive therapy 
alleviating disease-symptoms to chemotherapy, while 68% of those preferring chemotherapy 
reported that their choice was based on symptom improvement rather than on prolongation of 
survival [8]. Symptoms affect the patient’s physical and emotional well-being and lead to
distress not only to the patients but also to their families [9]. Importantly, depression has been 
considered as an independent prognostic factor in lung cancer cases, regardless of disease 
severity [10]. A recent study confirmed a positive association between patient-perceived 
health-related quality of life (HRQoL) after NSCLC treatment initiation and survival [11].
Moreover in another study, baseline HRQoL measured by the European Organisation for 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30-item 
[QLQ-C30] emerged as the strongest predictor of OS among advanced NSCLC patients, 
while the EORTC QLQ-Lung Cancer 13 [EORTC QLQ-LC-13] dyspnoea score was also an 
independent predictor of OS prolongation [12]. It is thus not surprising that alleviation of 
symptom burden has been added to the core of disease management, making it imperative to 
evaluate not only treatment effectiveness but also HRQoL and symptom burden in both 
clinical research and routine patient care settings [9, 13, 14, 15].  
There is a broad array of questionnaires used in the field of NSCLC for the assessment of 
HRQoL [16]. Among them, the most commonly used generic instruments assessing global 
health status are the Euro QoL EQ-5D [17] and the cancer-generic EORTC QLQ-C30 [18].
Moreover, disease-specific instruments assessing HRQoL have been developed for patients 
with NSCLC including the Functional Assessment of Cancer Therapy – Lung (FACT-L) [19], 
the EORTC QLQ-LC13 [18] and the Lung Cancer Symptom Scale (LCSS) [20]. Euro QoL 

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EQ-5D is one of the two most frequently used generic questionnaire in lung cancer clinical 
trials [16].
Apart from the generic and disease-specific tools used for the assessment of HRQoL, the 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) developed in 1982 
[21], has been used in numerous trials as a tool to evaluate how the disease affects the 
patients’ daily living abilities, while its association with effectiveness outcomes is commonly 
evaluated. In the elderly with advanced NSCLC, ECOG PS was found to be a significant 
independent factor for OS [22]. Furthermore, in a study of patients with metastatic NSCLC 
receiving chemotherapy, EGOG PS 2 versus 0 or 1 was found to be associated with a high 
number of adverse events and poor survival [23]. 
It is also worthwhile to mention that the World Health Organisation (WHO) cites non-
adherence to therapy as a very important, yet modifiable factor of anti-cancer therapy 
outcomes. Notably among the many factors linked to adherence to oral therapies, are the 
severity of disease-related symptoms, and the patients’ physical and psychological well-being 
[24] adding further support to the importance of examining symptom and HRQoL outcomes 
in clinical studies of heavily burdened populations, but also of capturing treatment adherence. 
9.2
TARGETED THERAPIES FOR NSCLC
Over the last decade, several targeted therapies have been added in the treatment 
armamentarium of NSCLC in an attempt to increase efficiency and reduce side effects of 
other agents. In the treatment of NSCLC, targeted agents have been developed against the 
vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR), 
and more recently against anaplastic lymphoma kinase (ALK) [25, 26].
For patients with NSCLC tumors harbouring activating mutations of the epidermal growth 
factor receptor (EGFR), targeted treatments, including the first generation tyrosine kinase 
inhibitors (TKIs), erlotinib and gefitinib, have shown benefits in terms of prolongation of 
PFS and increased response rates and improvement of HRQoL [27]. 
9.2.1
Afatinib drug profile
Resistance to the first-generation EGFR agents therapy commonly develops, which has led to 
the development of the irreversible EGFR TKI, afatinib, which targets and blocks signalling 
from dimers of all ErbB family members, EGFR (ErbB1), HER 2 (ErbB2), ErbB3 and 
ErbB4. Afatinib (GILOTRIF®/GIOTRIF®) was approved in 2013 by the FDA and EMA 
based on results of the pivotal phase 3 studies LUX-Lung 3 and LUX-Lung 6. Specifically, in 
the US afatinib is indicated for the first-line treatment of patients with metastatic NSCLC 
whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as 
detected by an FDA-approved test, while in Europe, afatinib as monotherapy is indicated for 
the treatment of EGFR TKI-naïve adult patients with locally advanced or metastatic NSCLC 
with activating EGFR mutation(s) [3, 4]. Afatinib is available in orally administered film-
coated tablets.
The severity of symptoms and HRQoL when treated with afatinib were examined in the 
LUX-Lung 1 phase IIb/III randomized controlled clinical trial (RCT), where outcomes of 
patients treated with afatinib were compared to patients receiving placebo with the use of the 
EORTC QLQ-C30, the EORTC QLQ-LC13 and the EQ-5D at baseline and every 21 days. 
Global health as assessed by the EQ-5D as well as global health status, physical functioning 

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and fatigue assessed by the EORTC QLQ-C30 significantly improved with afatinib 
treatment. In addition, a significantly higher proportion of patients in the afatinib arm 
compared to placebo demonstrated improvement in disease-related symptoms, such as cough 
(P<0.0001), dyspnea (P=0.006), and pain (P<0.0001). In addition, afatinib delayed the time 
to deterioration of cough (P<0.001) [28].
The positive effect of afatinib on symptoms and QoL compared to chemotherapy has been 
evaluated in the LUX-Lung 3 and LUX-Lung 6 RCTs, where outcomes were assessed using 
the EORTC QLQ-C30 and LC13 at baseline and every 21 days. 
In the LUX-Lung 3 RCT, patients were randomised (2:1) to receive afatinib 40 mg once daily 
or up to 6 cycles of pemetrexed/cisplatin. According to the results of the study, for the 
subgroup of patients with common mutations (Del 19, L858R) (204 on afatinib and 104 on 
chemotherapy) the median PFS was 13.6 versus 6.9 months [Hazard Ratio (HR) 0.47; 95% 
CI 0.34-0.65; P<0.0001] and the median OS was 30.3 versus 26.2 months, demonstrating a 
clear benefit of afatinib treatment. In addition to the Del 19, L858R mutations, certain less 
common mutations have also been shown to be sensitive to afatinib treatment [29].
Moreover, ccompared to chemotherapy first-line afatinib was associated with better control 
of cough (HR, 0.60; 95% CI, 0.41 to 0.87; P=0.007) and dyspnea (HR, 0.68; 95% CI, 0.50 to 
0.93; P=0.015), as well as improved global health status/QoL (P=0.015), and functional scale 
scores as assessed with the use of EORTC QLQ-C30 and the EORTC-QLQ-L13 [30].
Among the functional scale scores, physical (P<0.001), role (P=0.004), and cognitive 
(P=0.007) functioning were improved compared to chemotherapy.
The results of the pivotal LUX-Lung 3 RCT have been supported by the LUX-Lung 6 RCT 
conducted in 36 sites in China, Thailand and South Korea among 364 patients. The study 
compared first line afatinib with gemcitabine/cisplatin chemotherapy. In the afatinib arm, 
mean PFS was 11.0 months vs. 5.6 months for those in the chemotherapy arm (HR 0.28; 
P<0.0001). In addition, a significant higher proportion of patients demonstrated improvement 
of cough (P<0.0001), dyspnea (P<0.0001) and pain (P=0.03), while afatinib also delayed the 
time to deterioration of these symptoms. Global health improvement was also demonstrated 
by a higher proportion of patients in the afatinib group than in the gemcitabine and cisplatin 
group (62·7% versus 32·7%; P<0.0001). Notably, prolongation of PFS was associated with 
improved HRQoL and significantly longer control of disease-related symptoms [3]. 
Mature survival data from the LUX-Lung 3 and LUX-Lung 6 studies have recently been 
published. With a median follow-up of 41 months in the LUX-Lung 3, 62% (213/345) 
patients had died; in the LUX-Lung 6, with a median follow-up of 33 months in the OS rate 
was 68% (246/364). Among patients treated with afatinib, the median OS was 28.2 months 
(95% CI, 24.6 to 33.6) in the LUX-Lung 3 and 23.1 months (95% CI, 20.4 to 27.3) in the 
LUX-Lung 6, which did not significantly differ from the OS in the respective chemotherapy 
arms. However, OS was significantly longer in the afatinib group (33.3 and 31.4 months in 
the LUX-Lung 3 and LUX-Lung 6 trials, respectively) than in the chemotherapy group in 
both trials (21.1 and 18.4 months, in the chemotherapy group of LUX-Lung 3 and LUX-Lung 
6, respectively) among patients with Del 19-positive tumors [31].
9.3
RATIONALE FOR PERFORMING THE STUDY
On the ground of the aforementioned evidence, afatinib represents a great advance in the 
therapeutic armamentarium of advanced NSCLC with activating EGFR mutations. Taking 

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into consideration the limited real-world evidence that is attributed to the recent advent of 
afatinib in the market, this field non-interventional study (NIS with new data collection) aims 
primarily at assessing the impact of the therapy on patients’ disease-related symptom burden 
and HRQoL. These parameters are considered as very important for the evaluation of 
medicines, especially those aiming to treat complicated diseases that impose a heavy 
symptom burden, impaired quality of life and poor prognosis, such as NSCLC [9]. 
Importantly, patients’ adherence to this orally administered medication will also be assessed.
In addition, the study represents an attempt towards gaining experience on the routine use of 
afatinib in daily clinical practice in a representative sample of Greek subjects with advanced 
NSCLC in real-life clinical settings. The study will complement the evidence available from 
the RCTs and assist in the decision-making process of the medical professionals that provide 
care to this heavily burdened population. 

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10.
RESEARCH QUESTION AND OBJECTIVES
10.1
PRIMARY OBJECTIVE

To evaluate the impact of afatinib therapy on the patient-reported lung cancer-specific 
symptom burden, using the Average Symptom Burden Index (ASBI) of the LCSS in 
eligible patients, over 6 months of therapy, in a real world clinical setting in Greece.
10.2
SECONDARY OBJECTIVES

To evaluate the effect of afatinib therapy on the patient-reported lung cancer-specific 
symptom burden, total symptomatic distress, functional activity status and global 
quality of life, using the LCSS total score and domain subscores, at the post-baseline 
predefined timepoints (please refer to Section 11.1.2, for the definition of the post 
baseline timepoints);

To assess the impact of afatinib treatment on the HRQoL of the study population 
using the EQ-5D-3L questionnaire at the post baseline predefined timepoints;

To assess the impact of afatinib therapy on patient’s ECOG PS at the post baseline 
predefined timepoints;

To record patient adherence to treatment with afatinib during the study observation 
period as well as the reasons for missing doses;

To assess the patterns of use of afatinib in routine clinical practice in terms of 
treatment modifications (permanent discontinuations, temporary interruptions, dose 
changes), and reasons for these modifications.

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11.
RESEARCH METHODS
11.1
STUDY DESIGN
This is a non-interventional, multicentre, cohort study, based on new data collection, which 
will include a representative sample of patients with advanced/metastatic NSCLC in Greece. 
Patients will be treated according to the local prescribing information of the study medication 
(afatinib, GIOTRIF®) and routine medical practice in terms of visit frequency and types of 
assessments performed. The assignment of the patient to this therapeutic strategy is not 
decided in advance by the study protocol but falls within current practice and the prescription 
of afatinib is clearly separated from the physician’s decision to include the patient in the 
current study.
Since this is purely non-interventional study, primary data -which will be obtained 
prospectively during the study visits through patients’ interview and patient reported 
outcomes (PROs) or as performed per standard clinical practice- will mainly be employed.
Follow-up visit frequency will be determined by the treating physician, however study-related 
data will be collected at 2-month (±3 weeks) intervals during the first 12 months of study 
participation and every 6 months (±3 weeks) thereafter until the end of the study observation 
period.  
The main foreseen limitations for this study are attributed to its observational design and are 
discussed in the relevant Section 11.10. Notably, these limitations are outweighed by the 
essential role that studies of such design play in evaluating treatment outcomes for marketed 
products, particularly in heterogeneous patient populations with diseases of complex and 
heterogeneous biology, such as cancer. The study will provide clinically-relevant real-world 
data for a broad patient population that will serve as complementary evidence to that of 
RCTs. In addition, the study outcomes will reflect patient perceptions on symptom burden 
accounting for variations in local standards of care, treatment patterns and individuals’ 
characteristics. 
11.1.1
Synoptic study assessment schedule
A synoptic study diagram reflecting the assessments of interest and the suggested time 
schedule is presented in the following figure. 

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Figure 1: 
Synoptic Study Diagram

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11.1.2
Baseline and post-baseline timepoint definitions 
In the context of this study the following definitions apply for the baseline and post -baseline 
assessments:
-
Baseline assessments are defined as the assessments performed prior to or at afatinib 
treatment onset. For PROs (patient-reported LCSS and EQ-5D-3L), the scores that 
will be collected at the enrolment visit will serve as the baseline data. 
-
Post-baseline predefined timepoints for study-specific assessments are defined as: 
every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months 
(±3 weeks) thereafter until the end of patient’s participation in the study.
11.1.3
Study primary and secondary endpoints
11.1.3.1
Primary endpoint/outcome measure

6-month symptom improvement rate using the LCSS ASBI, i.e., proportion of patients 
who will experience a minimum clinically important improvement in symptoms 
(defined as a decrease in the ASBI from enrolment ≥10 in two consecutive 
assessments) over 6 months of treatment. 
Note: A patient will be categorized as having:
- an improved ASBI if the mean of any two consecutive post-baseline ASBI 
assessments for that patient is at least 10 points below the patient’s ASBI at 
enrolment; 
- a worsened ASBI if the mean of any two consecutive post-baseline ASBI 
assessments for that patient is at least 10 points above the value at enrolment; 
- a stable ASBI if the mean of any two consecutive post-baseline ASBI assessments 
for that patient is within 10 points of the value at enrolment.
A change of 10 points on a 0-100 scale is considered sufficient to indicate a clinically 
meaningful change [32, 33, 34]; this magnitude is about the same as the 0.5 standard 
deviation that has also reported as a universally acceptable minimum clinically 
important difference [35].
11.1.3.2
Secondary endpoints/outcome measures

Change in the total LCSS score, ASBI score and individual domain scores from
enrolment to each post-baseline predefined timepoints; in addition change throughout 
the study observation period will be examined using longitudinal analysis;

Proportion of patients (n, %) with reported problems for each level for each dimension 
of EQ-5D and proportion of patients with ‘no problems’ (i.e., level 1) and ‘with 

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problems’ (i.e., level 2 & 3) at enrolment and at the post-baseline predefined 
timepoints; 

EQ-visual analogue scale (VAS) score (mean ± SD) at enrolment and at the post-
baseline predefined timepoints; 

Change in the proportion of patients in each of the EQ-5D dimension levels (no 
problems, with problems) and change in the EQ-VAS score between enrolment and 
post-baseline predefined timepoints; 

Change in ECOG PS scores from baseline to post-baseline predefined timepoints;

Ratio of doses actually taken to doses prescribed over the study participation period 
and reasons for discrepancies;  

Proportions of patients with treatment discontinuations, temporary interruptions, or 
dose change(s) and reasons for treatment modifications.

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11.3
STUDY TREATMENT
11.3.1
Dosing/method of administration
Each afatinib film-coated tablet contains 50, 40, 30 or 20 mg active substance (as afatinib 
dimaleate) and lactose (as monohydrate) as known active ingredient. For the full list of 
excipients please read the Summary of Product Characteristics.
When assessing a patient's EGFR mutation status, it is important that a well-validated and 
robust methodology is used to avoid false negative or false positive results.
According to the Summary of Product Characteristics, the recommended afatinib dose in 
first-line therapy is 40 mg once daily taken orally. Afatinib should be taken without food. 
Afatinib should be taken 3 hours after and at least 1 hour a meal. Afatinib is taken orally. The 
tablets are swallowed in one piece with a glass of water. For patients who are unable to 
swallow the afatinib tablets in one piece, they can be dissolved in about 100 mL of non -
carbonated drinking water. Do not use any other liquids for this. The tablets are placed in one 
piece into the water without breaking them up beforehand. After that the contents of the glass 
is stirred occasionally for up to 15 minutes until the tablet has dissolved into very small 
particles. Drink the dispersed solution immediately, then rinse the glass with about 100 mL of 
water and also drink this water. The dispersed solution can also be administered via a gastric 
tube. A forgotten afatinib dose should be taken on the same day as soon as the patient 
remembers it. However, if the time until the next planned dose is less than 8 hours, the patient 
should not take the forgotten dose.
The treatment with afatinib should be continued until disease progression or until the patient 
no longer tolerates the medicinal product. A dose escalation to a maximum of 50 mg/day may 
be considered in patients tolerating the dose of 40 mg/day well in the first 3 weeks (i. e. 
absence of diarrhoea, rash, stomatitis and other drug-induced events of CTCAE grade >1). 
The dose should not be escalated in any patients with a prior dose reduction. The maximum 
daily dose is 50 mg.

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11.3.2
Dose adjustment due to adverse events
Symptomatic adverse reactions (e. g. severe/persistent diarrhea or skin-related adverse 
reactions) can usually be managed successfully by interrupting the treatment and reducing the 
dose or by discontinuing afatinib:
Adverse reactions according to CTC1Recommended afatinib dose:
Grade 1 or Grade 2
No interruption2
No dose adjustment
Grade 2 (prolonged3 or intolerable) or
Grade >3
Interrupt until grade 0/12
Resume with dose 
reduction in 10 mg 
decrements4
1. NCI Common Terminology Criteria for Adverse Events 
2. In case of diarrhoea, patients should take anti-diarrhoeal drugs immediately (e. g. loperamide) 
and continue to take these drugs in case of persistent diarrhoea until loose bowel movements 
abate.
3. >48 hours of diarrhoea and/or > 7 days of rash
4. If the patient cannot tolerate 20 mg/day, permanent discontinuation of the treatment with afatinib 
should be considered.
11.3.3
Special warnings and precautions for use
Diarrhoea, including severe diarrhoea, has been reported in patients treated with afatinib. 
Diarrhoea may result in dehydration (with or without renal impairment), which in rare cases 
has resulted in fatal outcomes. Diarrhoea usually occurred within the first two weeks of 
treatment; grade 3 diarrhoea most frequently occurred within the first six weeks of treatment. 
Proactive treatment of diarrhoea including adequate hydration combined with anti-diarrhoeal 
drugs especially within the first 6 weeks of the treatment is important and should start at first 
signs of diarrhoea. Anti-diarrhoeal drugs (e.g. loperamide) should be used and if necessary 
their dose should be escalated to the highest recommended approved dose. Anti-diarrhoeal 
drugs should be readily available to the patients so that treatment can be initiated at first signs 
of diarrhoea and continued until loose bowel movements cease for 12 hours. Patients with 
severe diarrhoea may require interruption of the treatment with afatinib, dose reduction or 
discontinuation of therapy. Dehydrated patients may require administration of intravenous 
electrolytes and fluids. Patients are therefore instructed to initiate treatment of diarrhoea with 
anti-diarrhoeal therapy independently and to inform the attending doctor of this immediately.
Rash/acne has been reported in patients treated with afatinib. In general, rash manifests as a 
mild or moderate erythematous and acneiformous rash, which may occur or worsen in areas 
exposed to sunlight. Early treatment (such as emollients, antibiotics) of dermatic reactions 
increases the probability of treatment continuation. Patients with severe skin reactions may 
also require temporary interruption of therapy, dose reduction, additional therapeutic 
intervention, or referral to a specialist with expertise in managing these adverse dermatic 
reactions.

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In the event of acute or aggravating respiratory symptoms, interstitial lung disease (ILD) must 
be considered and afatinib treatment should be interrupted until the cause of these symptoms 
has been clarified. If interstitial lung disease is confirmed, afatinib must be permanently 
discontinued and appropriate treatment initiated.
Afatinib is not recommended for use in patients with severe renal impairment (creatinine 
clearance < 30 mL/min) and hepatic impairment (Child-Pugh score C).
Higher plasma levels of afatinib have been observed in female patients, patients with lower 
body weight and those with underlying renal impairment. This could result in a higher risk of 
developing adverse reactions including diarrhoea, rash/acne and stomatitis. Closer monitoring 
is recommended in patients with these risk factors. For more information please read the 
respective 
Summary 
of 
Product 
Characteristics, 
in 
particular 
the 
sections 
on 
"Contraindications", "Warnings and precautions for use", "Interaction with other medicinal 
products and other forms of interaction" as well as "Fertility, pregnancy and breast-feeding".
Further information about afatinib can be found in the enclosed Summaries of Product 
Characteristics.
11.4
VARIABLES
11.4.1
Primary outcome variable

ASBI score of LCSS -defined as the mean of the score of the 6 major lung cancer 
symptoms, i.e. loss of appetite, fatigue, cough, dyspnea, pain, and hemoptysis- at 
enrollment and at the 2-month intervals until the study visit at 6 months.
11.4.2
Secondary outcome variables

Patient-rated ASBI score of LCSS at the post-baseline predefined timepoints (these 
timepoints are defined in Section 11.1.2);

Patient-rated total LCSS score -defined as the average of the aggregate score of all 9 
items that comprise the LCSS- at enrollment and at the post-baseline predefined 
timepoints; 

Patient-rated individual LCSS domain scores at enrolment and at the post-baseline 
predefined timepoints;

Proportion of patients with reported problems for each level for each dimension of 
EQ-5D and proportion of patients with ‘no problems’ (i.e., level 1) and ‘with 
problems’ (i.e., level 2 & 3) at enrolment and at the post-baseline predefined 
timepoints; 

EQ-VAS score at enrolment and at the post-baseline predefined timepoints; 

ECOG PS score at baseline and at the post-baseline predefined timepoints;

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
Ratio of doses actually taken to doses prescribed over the study participation period 
and reasons for discrepancies;  

Proportions of patients with treatment discontinuations, temporary interruptions, or 
dose change(s) and reasons for treatment modifications.
11.4.3
Other variables
Sociodemographic and anthropometric patient characteristics: 
-
Age (years)
-
Gender: males, females (n,%); male-to-female ratio
-
Race: Caucasian, Asian, African, other;
-
Place of residence: urban areas, semi-urban areas, rural areas;
-
Educational level: no education, primary education, secondary education, tertiary 
education;
-
Marital status: single, married, divorced, widowed;
-
Employment status: unemployed, employed, retired, household duties, other;
-
Smoking status: never smoker, former smoker, occasional smoker, current 
smoker; if former or current smoker: smoking pack-years, and if former smoker: 
years since quitting smoking;
-
Weight (kg);
-
Height (cm);
-
Body mass index (BMI in kg/m2);
-
Systolic and diastolic arterial pressure (mmHg);
-
Respiratory rate (bpm [breaths/minute]).
Disease & clinical characteristics 
-
Age at disease diagnosis;
-
Disease stage (IIIB, IV) at baseline;
-
Histologic classification (adenocarcinoma squamous-cell-carcinoma, other);
-
EGFR mutation subtype (exon 19 deletions, Leu858Arg, other);
-
Sites of metastases at baseline;
-
Previous disease-related treatment patterns;
-
Baseline comorbid conditions;
-
Change in disease status throughout the study period.   
Treatment characteristics 

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-
Time from diagnosis to afatinib treatment onset;
-
Length of exposure to afatinib treatment throughout study duration;
-
Starting dosage regimen;
-
Type of dose modifications over the study observation period;
-
Concomitant medications both at baseline and throughout the conduct of the study.
11.4.4
Confounding/effect modification variables
The following variables will be considered as potential confounders or effect modifiers of the 
main association between treatment with afatinib and change in disease-specific symptom 
burden. 
-
Age at baseline;
-
Gender;
-
BMI at baseline;
-
Educational/marital/employment status; 
-
Baseline comorbidity count with particular emphasis on gastrointestinal, 
psychiatric, and musculoskeletal and connective tissue disorders;
-
Concomitant medications both at baseline and at the time of symptom burden 
assessment with particular emphasis among others on analgesics, antitussives, 
antidepressants, antiemetics, and antidiarrheals;
-
Disease stage at baseline;
-
Baseline ECOG PS; 
-
Baseline smoking status and lifetime tobacco exposure;
-
Lung cancer histologic classification; 
-
EGFR mutation subtype;
-
Sites of metastases at baseline;
-
Adherence to afatinib treatment over the 6-month observation period and over the 
whole study participation duration.    
11.5
DATA SOURCES
The study will mainly involve new data collection, by means of a web based data capture 
(WBDC) system. Data will be collected by the study physicians as generated according to the 
standard clinical practice and by the patients as captured with the use of PROs. No further 
laboratory tests and examinations are required apart from those recommended by the study 
medication SmPC.

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Patient source data pertaining to medical- and lung cancer-related history will be abstracted 
from patient medical charts/records by the investigators and will be recorded in the relevant 
section of the WBDC. 
All afatinib treatment modifications, concomitant medications, study-related routine clinical 
assessments, adverse events (AEs) and vital status will also be collected. Regarding vital 
status, if a patient is prematurely withdrawn from the study, he/she will be contacted by 
telephone or other methods to assess vital status at the end of study unless the patient has 
actively withdrawn consent for all forms of contact (refer to section 11.2.4.3).
Concomitant or prior disease-related medications entered into the database will be coded 
using the Anatomical Therapeutic Chemical (ATC) WHO Collaborating Centre for Drug 
Statistics Methodology (WHOCC) Drug Reference List. 
Medical history/comorbidities and adverse events will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) terminology.
In addition, physicians will be requested to assess:
- Patients’ performance status using the ECOG PS instrument. (For a sample of the 
English version please refer to ANNEX 3: ECOG PERFORMANCE STATUS SCALE).
Furthermore, the following PROs will be collected via self-administered paper questionnaires 
completed by the patients themselves at study enrolment and periodically throughout study 
participation, according to the study visit frequency.
- Disease-specific symptoms will be measured using the self-administered patient-rated 
LCSS, a reliable and valid lung cancer-specific instrument that is comprised of two 
components, the patient-rated scale employed in the present study and the observer-rated 
[20, 36, 37]. 
The patient-rated LCSS questionnaire consists of nine items, each scored with a 100-mm 
VAS used to evaluate six symptoms associated with lung cancer (loss of appetite, fatigue, 
cough, dyspnea, pain, and hemoptysis) as well as three global items used to evaluate the 
interference with normal activities, distress from lung cancer symptoms, and overall QoL.
The mean of the 6 major lung cancer symptoms comprises the ASBI that reflects the 
primary outcome variable in this study. In addition, the LCSS total score defined as the 
mean of the 9 items of the scale will be determined.
The time for LCSS patient scale completion is 8 minutes initially for demonstration of the 
VAS and 3-5 minutes for subsequent administrations. 
Rationale for selecting LCSS: The LCSS has been selected as the main PRO in this study 
since it is focused on symptom burden which is the main objective of the study as well as 
is more patient-friendly, less time-consuming and provides less patient and staff burden (it 
comprises 9 items in total compared to the 43 items of EORTC_LC13) and thus is 
considered more suitable for use in the common clinical setting in the context of a NIS. In 
addition, it has demonstrated a good reliability and validity compared to the other PROs 
[10]. (For a sample of the English version please refer to ANNEX 3: LCSS PATIENT 
SCALE).

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- HRQoL: The Greek version of Euroqol EQ-5D-3L [38] will be used in order to measure 
patients’ HRQoL at the specific timepoints of the study. 
The EQ-5D-3L is a standardized disease-generic instrument for the measurement QoL that 
has been widely used in both general and specific disease populations. It is cognitively not 
demanding, taking only a few minutes to complete. It consists of the EQ-5D descriptive 
system and the EQ VAS. EQ-5D is designed for self-completion by respondents and is 
ideally suited for use in clinics, and in face-to-face interviews. The EQ-5D-3L descriptive 
system comprises the following 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some 
problems, extreme problems. 
The EQ VAS records the respondent’s self-rated health on a vertical, visual analogue 
graduated (0–100) scale [17, 39]. (For a sample of the English version please refer to 
ANNEX 3: EQ-5D-3L).
- Adherence to therapy with afatinib: A patient diary will be used which the patient will 
be requested to fill in only with the date and reasons for missed pills. The diary will 
contain both predefined reasons and free text fields. 
Patient diary is among the accepted methods for estimating treatment adherence. This 
method has been selected as the less burdensome for the patient (compared with any
compliance-specific PRO) and the most accurate in terms of avoiding recall biases [40]. 
11.5.1
Administration of patient-reported outcome questionnaires
For the purposes of the current study, the validated Greek versions of the LCSS and EQ-5D-
3L instruments will be administered to the patients via a paper-and-pencil self-administered 
format. 
The questionnaires shall be provided to the patients before completing any other procedures 
or clinical exam at the study visit. This ensures that the interaction between the respondent 
and other health care professionals does not influence the patient’s responses. The patient will 
be provided with instructions and a quiet and comfortable place to complete the 
questionnaires. The respondent should be alone when completing the PROs. Spouses or other 
accompanying individuals should wait in a separate area during the PROs administration. 
This minimizes any influence on the respondent’s answer and ensures the PROs responses 
reflect the patient’s perspective, and not someone else’s.
When the respondent has completed the questionnaires, the study physician shall review them 
to ensure all questions have been answered. If there are any missing questions, he/she shall 
point them out to the respondent so they may be completed. However, respondents may omit 
any question they do not feel comfortable answering.
In order to protect subject confidentiality the name of the patient will not be mentioned on the 
questionnaires.
11.5.2
Data collection schedule and study flow chart
Being non-interventional and observational in nature, this study does not impose any 
diagnostic/therapeutic interventions or strict visit schedule. Patients will be treated as per the 

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routine medical practice in terms of visit frequency, types of assessments performed and with 
adherence to the local prescribing requirements for afatinib.
Upon the enrollment of each patient into the study, the investigator shall follow the below-
mentioned procedures:
1.
Review of patient’s personal medical history, in order to confirm if inclusion/exclusion 
criteria are met.
2.
Explanation of study purpose to the patient and obtainment of signed and dated written 
ICF, after having provided the required time to the patient to carefully read and 
understand the information leaflet. 
3.
Collection of the data from the medical records of the eligible patients, as required by 
the eCRF as well as completion of the eCRF.
Investigators shall record all (S)AEs that are observed by them or reported by the patients. As 
this is an observational study, patients will continue to be followed by their physicians 
according to current medical practice and the product’s SmPC requirements.
An assessment schedule in tabular format providing information on the recommended data 
collection schedule that most likely reflects the patterns of routine clinical care of most 
patients being treated with afatinib is depicted at Table 2.

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11.6
STUDY SIZE
Sample size calculation has been based on study's primary endpoint, which involves the 
determination of the proportion of study population with clinically meaningful 
improvement in the LCSS ASBI score over a 6-month treatment period. 
Due to the lack of published data on the effect of afatinib on symptom burden using the 
LCSS, the worst case scenario has been taken into account, i.e., that the proportion of 
patients experiencing symptom improvement (as defined in Section 11.1.3.1) after 6 
months of therapy will be approximately 0.50. Consequently, the assessment of 96 
patients is required to estimate the aforementioned proportion with a margin of error not 
exceeding 0.10 which represents a scientifically acceptable level of precision of the 
estimate [95% CI: 0.40-0.60; α: 0.05; Relative Standard Error (RSE): 10.21%]. This 
means that for any proportion between 0.05 and 0.95, the precision will range from 0.04 
to 0.10 at a 95% confidence limit. The sample size determination has been performed 
using the statistical software package SAS v9.4 (SAS Institute, Cary, NC).
In order to control for an estimated 25% drop out/non-evaluable rate, 128 patients are 
finally required in order to ensure the aforementioned sample size for the final statistical 
analysis.  
11.7
DATA MANAGEMENT
The study data collection will be carried out through WBDC and paper-and-pencil self-
administered PROs. 
The WBDC application will be specifically designed for the needs of the study by the 
designated Clinical Research Organisation (CRO) and will adhere to all applicable data 
protection regulations and requirements with regard to electronic records. The patients 
will be identified by subject identification number, site number, and study identification 
number.
Data (including those recorded in the paper PROs) will be entered in the WBDC system 
by the study personnel at the Investigator’s site, according to the Investigator 
Instructions Manual. Data entered in the WBDC system will be automatically saved to a 
central database and changes tracked to provide an audit trail. When data have been 
entered, reviewed and edited, the Investigator shall sign the e-CRF electronically as per 
the agreed project process and data will be locked to prevent further editing.
Query management will be performed through built-in query management functionality 
that will be incorporated into the WBDC. 
Prior to the onset of data management activities, a detailed data management plan (DMP) 
will be issued describing the procedure to be followed for processing all collected study 
data in order to ensure they are valid, complete and accurate for the interim and final 
statistical analysis. In addition, aiming at ensuring the expected quality of data, a 
thorough data cleaning session will be applied twice during the conduct of the study for 
the purposes of the interim and final analysis, respectively. When all data have been 
properly validated and the quality control procedure has been completed, a declaration of 
database lock will take place so that it can be confirmed that all important actions have 

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been properly performed. In addition, prior to database lock and prior to the initiation of 
any statistical analysis activities a comprehensive statistical analysis plan (SAP) will be 
drafted. The SAP will also include information regarding the statistical software(s) to be 
used for the analysis of the study data and any data imputation methods that may be 
applied.
11.8
DATA ANALYSIS
The study is not aimed to confirm or reject any pre-defined hypotheses; therefore 
statistical analyses will be of explorative and descriptive nature.
Continuous variables will be summarized with the use of descriptive statistical measures 
(mean value, standard deviation, median and extreme values) and categorical/distinct 
variables will be displayed as frequency tables (N, %). The normality of distribution of 
continuous variables will be examined using the Shapiro-Wilk test in order to determine 
whether or not to use parametric methods for the analysis of the sample data.
Differences between the mean values of continuous variables will be evaluated using the 
paired t-test or the non-parametric analogue (i.e., Wilcoxon signed rank test).                          
All statistical tests will be two-sided and will be performed at a 0.05 significance level. 
The exact p-values will be reported, even for non-significant results, rounded to three (3) 
decimals unless the p-value is less than 0.001 (in such case P<0.001 will be reported). 
No adjustment for multiplicity of testing will be performed.
A SAP comprising a comprehensive and detailed description of the statistical 
methodology applied for the purposes of the interim and final analysis along with 
imputation methods for missing data will be prepared prior to database lock.
Statistical analysis will be conducted using a validated statistical software package [e.g., 
Statistical Analysis System (SAS)].
11.8.1
Study populations
In accordance to the non-interventional design of the study, all statistical analyses will be 
performed in the Full Analysis Set (FAS) comprised of all eligible subjects who have 
been enrolled into the study regardless of whether or not they have finally completed 
their projected participation in the study. 
The analysis of the primary objective of the study will be performed in the Per Protocol 
Set (PPS) which will include all eligible study patients with available data pertaining to 
the study primary endpoint, i.e. 6-month symptom improvement rate as per LCSS ASBI 
score. 
Subsets of patients with available data will also be created and analysed for the purposes 
of secondary endpoint analyses.
Patients erroneously enrolled in the study (i.e., not fulfilling the eligibility criteria) will 
be excluded from all analyses of this study and any deviations from the protocol will be 
reported in detail in the clinical study report (CSR).

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11.8.2
Analysis for the primary endpoint
Pertaining to the primary endpoint the proportion of patients experiencing a minimum 
clinically important symptom improvement (as defined in Section 11.1.3.1) over a 6-
month period of treatment will be calculated along with the respective 95% confidence 
interval; in addition the relevant proportions of patients whose symptom burden has 
remained stable and deteriorated will be calculated. The 95% confidence interval will be 
derived from Wald confidence limits for a binomial proportion.
In order to examine the impact of baseline characteristics including among others, 
gender, age, BMI, educational/marital/employment status, disease stage, histological 
subtype, sites of metastases, EGFR mutation subtype, smoking status and smoking 
history, ECOG PS, type of concomitant medications and comorbidities, as well as 
adherence to therapy at 6 months on the study primary endpoint, a binary logistic 
regression model will be applied.
11.8.3
Analysis for the secondary endpoints
With regard to the secondary endpoints pertaining to the LCSS outcome measures, the 
mean change of the total LCSS, defined as the average value of all individual item 
scores, will be calculated from enrolment to all available subsequent study visits and will 
be examined for statistical significance with the use of the paired t-test or its non-
parametric analogue. Similar analysis will be performed for the ASBI subscore and each 
individual domain of LCSS. 
If applicable, pertaining to the change of the mean LCSS as well as the mean ASBI 
through the observation period, linear mixed models will be applied, in order to estimate 
the monthly predicted change in the aforementioned scores. 
Additionally, the symptom improvement rate throughout the study observation period 
will also be calculated in patient-years.
The distribution of patients by level (‘level 1: no problems’, ‘level 2: some problems’ and 
‘level 3: extreme problems’) for each dimension (mobility, self-care, usual activities, 
pain/discomfort, anxiety/ depression) as well as the distribution of patients in the 
dichotomized EQ-5D levels [‘no problems’ (level 1) and ‘problems’ (levels 2 and 3)] will 
be presented in frequency tables (N, %) for all patients with available data. Descriptive 
statistical measures will be calculated for the EQ-VAS score at each predefined study 
time-point. 
The McNemar’s test will be used in order to evaluate the change in the levels (‘with 
problems’/ ‘no problems’) of each dimension between enrolment and the post-baseline 
visits.
Descriptive statistics of the EQ-VAS will be presented for each study visit as well as for 
the observed changes in the EQ-VAS from the enrolment visit to each post-baseline 
study time-point; while the paired t-test or the Wilcoxon signed rank test will be used to 
assess the statistical significance of the change. 
The distribution of patients in the different ECOG performance status levels at every 
study time-point will be presented in frequency tables (N, %). Additionally, changes in 
the status of patients from baseline to post-baseline evaluations will be depicted in shift 
tables.

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Adherence to treatment with afatinib as well as the proportions of patients who 
discontinued or interrupted treatment, and those who underwent any dose modifications 
along with the type of dosage modifications and reasons for these, will be analysed in a 
descriptive manner.  
11.8.4
Analyses for the safety data 
All recorded AEs will be mapped by system organ class (SOC) and preferred term (PT)
according to MedDRA (most updated version at the point of coding).
The number and proportion of patients experiencing any serious or non-serious adverse 
event will be calculated by SOC and PT.
Specifically, the following data will be tabulated:  
Number and proportion of patients experiencing a serious AE (SAE) by SOC and PT.
Number and proportion of patients experiencing a non-serious AE (NSAE) by SOC 
and PT. 
Distribution of AEs by National Cancer Institute (NCI) Common Toxicity Criteria for 
Adverse Events (CTCAE) toxicity grade classification and causal relationship to study 
treatment.
Additionally, the exposure adjusted incidence rates (EAIRs) along with the respective 
95% CIs will be calculated for the following patient subpopulations: those experiencing 
at least one SAE, at least one NSAE.
Available data from other safety-related evaluations (systolic and diastolic arterial blood 
pressure, respiratory rate and pulse rate) will be summarized descriptively per visit or 
when they occurred, along with the respective change from baseline to all post-baseline 
visits.
11.8.5
Drug exposure 
The exposure (DExp) to afatinib treatment will be calculated using the number of days on 
afatinib, i.e. duration since treatment onset (dateFirst) until the date of last treatment 
administration or until the last date with available data (dateLast) according to the 
following formula.
1
)
(



First
Last
Exp
date
date
D
Descriptive statistics (n, mean, standard deviation, median, range) will be calculated for 
the duration of afatinib treatment for all patients of FAS. 
11.8.6
Additional analyses
Descriptive statistics regarding sociodemographic data such as gender, race, smoking 
history and educational background will be displayed in frequency tables (N, %).
Continuous variables concerning demographics and anthropometric characteristics such 
as age, body weight, and height as recorded at the enrolment visit will be presented with 

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mean, SD, median, minimum and maximum values. Quantitative variables will be 
presented with absolute and relative frequencies.
The number and percentage of patients with at least one medical condition as recorded at 
the enrollment visit will be calculated. Additionally, the depicting reported terms will be 
coded by MedDRA (the most updated version available at the point of coding) while 
SOC and PT will be tabulated in a frequency table (N,%).
The number and percentages of patients receiving at least one concomitant medication 
will be calculated. Concomitant medications coded with the use of ATC Drug 
Classification dictionary by WHOCC in terms of therapeutic subgroup and chemical 
substance will be presented in frequency tables (N,%). Similar analyses methods will be 
performed for all therapies related to NSCLC prior to afatinib onset.
11.8.7
Interim analysis
Taking into consideration the long-term study duration as well as the current limited 
evidence on the real-world clinical outcomes of treatment with afatinib in patients with 
NSCLC, an interim analysis is planned to be performed after the first enrolled 40 patients
(i.e., around one-third of the overall sample size) have completed the 6-month study 
observation period (i.e., have attended the 6-month study visit [V4] or have discontinued 
study participation, whichever occurs first).
The main purpose of the interim analysis is to gain preliminary information on the impact 
of afatinib in the study key outcome measures. No resultant decisions and actions will be 
taken in terms of the study progress as a consequence of the interim analysis. The interim 
analysis does not involve any stopping boundary for early stop due to efficacy or for 
sample size adjustment, thus no multiplicity adjustment will be performed.
The confidentiality of the interim analysis data will be controlled by assignment of the 
analysis to a statistical group that is independent of the Sponsor and investigators, i.e. is 
not otherwise involved in the study design or conduct. After completion of the analysis 
the results will be summarized in a synoptic interim CSR and distributed to the study 
Sponsor. The detailed interim analysis results will not be disclosed to the participating 
investigators until the overall study completion in order to account for the avoidance of 
any bias that may result from the premature disclosure and subjective interpretation of 
the preliminary findings. However, the preliminary results may be announced in the form 
of an abstract or poster/presentation in a descriptive manner, as per the Sponsor’s 
decision; in such case, the minimum required information will be disclosed aiming at 
safeguarding the scientific integrity of the final study results.  
11.9
QUALITY CONTROL
Proper quality control mechanisms and processes will be implemented in order to ensure 
data quality and integrity through the conduct of the study. All these procedures will be 
detailed in the study specific DMP and SAP. 
The query management process for the eCRF-collected data will be handled on a real-
time-basis through built-in edit and logic checks (validation rules) in the eCRF 
application. If any discrepancies (other than those predicted by the built-in validation 

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rules) arise before eCRF lock during source data verification (SDV) process (performed 
by the project monitor) or data review by the Data Manager, queries will be handled 
electronically through specific application’s query functionality, whereas for 
discrepancies that may emerge after eCRF application lock, paper Data Clarification 
Forms (pDCF) will be issued manually, using Microsoft Word. For PRO-collected data 
no queries will be issued. After all data have been properly validated, the quality control 
procedure has been completed and database lock has been declared, the extracted file 
will be transferred to sponsor. Statistical analysis performance & CSR development will 
be performed by a designated CRO.
Statistical programming performed to generate the results as well as all-related 
documents and forms will be archived electronically.
e-CRF archivals for each participating site will be prepared in CD-ROMs by the 
designated CRO, upon study completion and will be distributed to the participating sites.
The study authorized representative will provide the investigators with a folder/file in 
which the study-related documents should be archived and maintained. All study 
documents should be stored in this file by the Investigator. The monitor of the study will 
regularly check the file to ensure that all relevant documents are maintained. The 
contents of the folder/file may be subjected to audit/inspection by a designated auditor, 
regulatory authorities or Hospital Institutional Review Boards (IRBs).
The designated CRO will assure database quality by reviewing the data entered into the 
CRFs by investigational staff for completeness and accuracy, and in accordance with the 
data validation plan. The
may 
perform quality control visits at study sites to ensure implementation of the study 
protocol and all relevant regulatory and BI procedures.
11.10
LIMITATIONS OF THE RESEARCH METHODS
The main foreseen limitations for this study are attributed to its observational design and 
mainly involve patient selection bias, information bias and missing data as well as lack 
of internal validity (no control group). 
In order to control for and minimize patient selection bias, physicians will be requested 
to consecutively, thus non-selectively, enroll the first patients (based on the site-specific 
target) attending their clinic that meet the study specific eligibility criteria. In addition 
the investigators’ decision-making to administer afatinib to a patient will be based on 
current medical practice and precede the consideration of the patient’s eligibility for 
enrolment into the study. A screening log of all potentially eligible patients will be kept 
at site.
With regard to patient information/recall bias that may be introduced by the collection of 
data pertaining to patient-reported outcomes, this will be mitigated through the use of 
widely used PROs that employ no recall period as all questions refer to the symptoms 
and state of health at the day of completion. In addition, the self-administered PROs shall 
be completed by the patients themselves before the performance of any study-specific 
procedure(s) or clinical assessment(s) in order to avoid introducing any response bias.

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In regards to the patient-reported symptom and HRQoL outcome measures, a potential 
confounding factor may arise from the fact that for patients for whom the onset of 
treatment with afatinib precedes their enrolment in the study, the completion of the PROs 
will not accurately reflect their baseline symptom burden and health state; nevertheless 
since the permitted time window between these two time points has been set at a 
maximum of 7 days, this time lag is not expected to significantly impact the robustness 
of the outcomes.    
Another confounding factor to the patient-reported symptom and HRQoL outcomes is 
the potential effects of comorbidities and concomitant medications. To account for this, 
all baseline comorbid conditions as well as of concomitant medications both at baseline 
and throughout the conduct of the study (with particular emphasis among others on 
analgesics, antitussives, antidepressants, antiemetics, and antidiarrheals) will be 
collected in order to differentiate anticancer treatment effect from the effects of 
comorbidities and concomitant medication.
The possible influence of confounding factors on the outcomes of this study will be 
accounted for in the statistical analyses by use of robust multivariable analyses, if 
deemed necessary.
With regard to the external validity i.e., the ability to generalize the study results to a 
more universal population, every effort will be made for the study population to be 
representative of the overall population of patients with NSCLC treated with afatinib in 
Greece by enrolling patients from geographically diverse locations throughout Greece 
with a non-limiting set of clinical characteristics, apart from those indicated by the 
locally approved product’s SmPC, accounting for variations in medical practice 
paradigms. 
Internal validity of the outcomes will be safeguarded to the extent feasible with the 
implementation of appropriate source data verification and quality assurance measures, 
as described in the relevant Section 11.9.  
11.11
OTHER ASPECTS
11.11.1
Informed consent, data protection, study records
The study will be carried out in compliance with the protocol, the principles laid down in 
the Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline 
for GCP 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 study are described in the investigator contract. As a general rule, no study results 
should be published prior to finalisation of the CSR.

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11.11.1.1
Study approval, patient information, and informed consent
This study will be initiated only after all required legal documentation has been reviewed 
and approved by the respective Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) and competent authority (CA), where applicable, according to national 
and international regulations. The same applies for the implementation of changes 
introduced by amendments.
In particular, as per the national regulatory requirements, the protocol and the informed 
consent form (ICF) must be submitted to the IRBs (Scientific Council/Board of 
Directors) of the participating hospitals as part of the approval process. The Scientific 
Council/Board of Directors of the participating hospitals must also approve any 
amendment to the protocol or Patient ICF, prior to the implementation of the amendment 
or the use of the ICF, according to local regulations. The conduct of this non 
interventional study will adhere to the applicable national regulatory requirements 
governing the conduct of such type of clinical studies.
Prior to patient participation in the study, written informed consent must be obtained 
from each patient (or the patient’s legally accepted representative) according to ICH GCP 
and to the national regulatory and legal requirements. Each signature must be personally 
dated by each signatory and the informed consent and any additional patient-information 
form retained by the investigator as part of the study records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or 
the patient’s legally accepted representative.
The patient must be informed that his/her personal study-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.
11.11.1.2
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s study-related files and 
correspondence, and the informed consent documentation of this study.
11.11.1.3
Records
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via an 
Electronic Data Capture (EDC) system. 
11.11.1.3.1 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.

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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; also current medical records 
must be available.
All data entered in the eCRFs must be derived from source documents.
11.11.1.3.2 Direct access to source data and documents
The investigator/institution will permit study-related monitoring, audits, IRB/IEC review 
and regulatory inspection, providing direct access to all related source data / documents.
eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical 
study monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical 
Research Associate (CRA)/on site monitor and auditor may review all eCRFs, and 
written informed consents. The accuracy of the data will be verified by reviewing the 
documents described in Section 11.11.1.3.1.
11.11.1.3.3 Storage and retention of records
Patient files and other source documents must be kept for the maximum period of time 
permitted by the hospital/institution, or as specified below. The Clinical Research 
Associate (CRA)/on site monitor must be consulted if the investigator wishes to assign 
the files to someone else, remove them to another location, or if he/she is unable to retain 
them for the specified period.
The investigator must retain study records (e.g., source documents such as medical 
records, contracts, e-archivals and signed consent forms) for the amount of time 
specified by applicable laws and regulations. At a minimum, study records must be 
retained for the amount of time specified by the standing legislation, i.e., study records 
must be retained for at least 5 years after study completion. These documents should be 
retained for a longer period however if required by the applicable regulatory 
requirements or by an agreement with the study sponsor.
11.11.1.4
Statement of confidentiality
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient 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 
study need to be available for inspection on request by the participating physicians, the 
sponsor’s representatives, by the IRB/IEC and the regulatory authorities, i.e. the CA.
11.11.1.5
Completion of study
The IRB (Scientific Council/Board of Directors) of the participating hospital sites will be 
notified about the end of the study (last patient out) or early termination of the study, 

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unless otherwise mandated by the national regulations governing the conduct of such 
type of studies which may have been altered by the time of study completion. 

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12.
PROTECTION OF HUMAN SUBJECTS
By signing this protocol, the investigator agrees to treat all patient data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, 
rules and regulations.
The confidentiality of patient data will be maintained at all times and no documents 
containing the patient’s name or other identifying information will be collected by the 
Sponsor. It may be necessary for the sponsor’s representatives, the IRBs and regulatory 
authority representatives to have direct access to the patient’s medical records. If study 
documents need to be photocopied during the process of verifying eCRF data, the patient 
will be identified by a unique code only; full names/initials and other identifying 
information will be masked.
By signing this protocol, the investigator also affirms to the sponsor that information 
provided to the investigator by the sponsor will be maintained in confidence and will be 
divulged only as necessary to the IRBs and institution employees directly involved in the 
study. IRB members and employees also understand the confidentiality requirements for 
any information divulged to them. The data generated by this study will be considered 
confidential by the investigator, except to the extent that it is included in a publication as 
agreed in the publication policy of this protocol.
By signing the ICF, the patient accepts being informed of the following: 

What kind of personal information (data) will be collected from participants in this 
study;

Who will have access to that information and why;

Who will use or disclose that information;

What are the rights of a research participants pertaining to the potential revoke of 
their authorization for use of their personal data.
In case of patient authorization revoking, the investigator maintains the right to use the 
information collected prior to the revoke.

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13.
MANAGEMENT 
AND 
REPORTING 
OF 
ADVERSE 
EVENTS/ADVERSE REACTIONS
13.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment. An adverse event can therefore 
be any unfavourable and unintended sign (e.g. an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
Adverse reaction (ADR)
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility. Adverse 
reactions may arise from use of the product within or outside the terms of the marketing 
authorisation or from occupational exposure. Conditions of use outside the marketing 
authorisation include off-label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event is defined as any AE which
-
results in death, 
-
is life-threatening, 
-
requires in-patient hospitalisation, or
-
prolongation of existing hospitalisation, 
-
results in persistent or significant disability or incapacity, or 
-
is a congenital anomaly/birth defect.
Life-threatening in this context refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might 
have caused death if more severe.
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not 
be immediately life threatening or result in death or hospitalisation but might jeopardise 
the patient or might require intervention to prevent one of the other outcomes listed 
above. Examples of such events are intensive treatment in an emergency room or at home 
for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation or development of dependency or abuse. Any suspected transmission via a 
medicinal product of an infectious agent is also considered a serious adverse reaction.
Every new occurrence of cancer is to be considered as SAE regardless of the duration 
between discontinuation of the study medication and the occurrence of the cancer.

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Protocol-specified adverse events of special interest (AESIs)
There are no Protocol-specified Adverse Events of Special Interest for this study.
13.2
ADVERSE 
EVENT 
AND 
SERIOUS 
ADVERSE 
EVENT 
COLLECTION AND REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
Collection of AEs
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorisation. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug. For this reason the following AE collection and reporting requirements 
have been defined.
The following must be collected by the investigator in the eCRF from signing the 
informed consent onwards until the end of the study: 
-
all ADRs (serious and non-serious), 
-
all AEs with fatal outcome,  
-
all AEs which are relevant for a serious ADR or an AE with fatal outcome.
All ADRs, including those persisting after study completion must be followed up until 
they are resolved, have been sufficiently characterized, or no further information can be 
obtained.
The investigator carefully assesses whether an AE constitutes an ADR using the 
information below. 
Causal relationship of adverse event
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal 
relationship between a medicinal product and an occurrence is suspected. 
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. 
Arguments that may suggest a reasonable causal relationship could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced.

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•
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population
not exposed to drugs (e.g. Stevens-Johnson syndrome).
Arguments that may suggest that there is no reasonable possibility of a causal
relationship could be:
•
No plausible time to onset of the event relative to the time of drug exposure is 
evident (e.g. pre-treatment cases, diagnosis of cancer or chronic disease within 
days/weeks of drug administration; an allergic reaction weeks after 
discontinuation of the drug concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
•
Of note, this criterion may not be applicable to events whose time course is 
prolonged despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation 
(e.g. situations where other drugs or underlying diseases appear to provide a more 
likely explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the study drug treatment continues or 
remains unchanged.
Intensity of adverse event
The intensity of adverse events should be classified and recorded according to the NCI 
CTCAE version 4.0 [June 2010], in the eCRF.
The NCI CTCAE V4.0 can be viewed on-line at the following NCI weblink:
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40.
If a specific event is not included in the NCI CTCAE toxicity scale, the following scale 
should be used to grade that specific event: 
Table 3:
Grading Scale for Toxicities Not Included in the NCI CTCAE
Grade 
Definition 
1
Mild; Awareness of sign(s) or symptom(s) which is/are easily tolerated
2
Moderate; Enough discomfort to cause interference with usual activity
3
Severe; Incapacitating or causing inability to work or to perform usual activities
Pregnancy:
In rare cases, pregnancy might occur in a study. Once a female subject has been enrolled 
into the study, after having taken the study drug afatinib, the investigator must report any 
drug exposure during pregnancy to the Sponsor by means of Part A of the Pregnancy 

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Monitoring Form. The outcome of the pregnancy associated with the drug exposure 
during pregnancy must be followed up and reported by means of Part B of the Pregnancy 
Monitoring Form. 
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be 
completed, otherwise the NIS AE form is to be completed and forwarded in addition to 
the Pregnancy Monitoring Form within the respective timelines. 
Expedited Reporting of AEs and Drug Exposure During Pregnancy
The following must be reported by the investigator on the NIS AE form from signing the 
informed consent onwards until the end of the study: 
-
Αll SADRs (serious ADRs) including all AEs which are relevant for a serious 
ADR immediately (within 24 hours)
-
Αll AEs with fatal outcome including all AEs which are relevant for an AE with 
fatal outcome immediately (within 24 hours)
-
All non-serious ADRs within 7 calendar days
-
All Drug Exposure During Pregnancy within 7 calendar days 
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions the Investigator could inform the Sponsor upfront via 
telephone. This does not replace the requirement to complete and fax the NIS AE form.
The NIS AE form is to be forwarded to the defined unique entry point identified for 
 Details provided in the Investigator Site File.
Information required
For each reportable adverse event, the investigator should provide the information 
requested on the appropriate eCRF pages and the NIS AE form.
Reporting of related Adverse Events associated with any other BI drug
The investigator is encouraged to report all adverse events related to any BI drug other 
than the study drug afatinib according to the local regulatory requirements for 
spontaneous AE reporting at the investigator’s discretion by using the locally established 
routes and AE report forms. The term AE includes drug exposure during pregnancy, and, 
regardless of whether an AE occurred or not, any abuse, off-label use, misuse, 
medication error, occupational exposure, lack of effect, and unexpected benefit.
13.3
TIME WINDOWS
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 the study medicinal product (i.e., afatinib) this is the Investigational 
Brochure (IB). The current version of this reference document is to be provided in the 
ISF.

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13.4
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the Marketing 
Authorisation Holder (MAH)
according to local and international regulatory 
requirements. 

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14.
PLANS FOR DISSEMINATING AND COMMUNICATING
STUDY RESULTS
Upon completion of the study, a final CSR of the study results will be prepared by the 
Sponsor in accordance with the schedule. 
The results of the study may also be published in a relevant medical journal and may be 
announced at scientific congresses. Publications will comply with the International 
Committee of Medical Journal Editors (ICMJE) guidelines.  
The publication strategy and the authors’ list will be agreed between the 
and the participating investigators. 
In addition, the study and its result will be posted on the web-based platform of the Non-
Interventional Studies Register [Dilon, weblink: www.dilon.sfee.gr] as per the local 
requirements. This webpage pertains to the electronic register and is posted on the 
website of the Hellenic Association of Pharmaceutical Companies (SFEE).

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15.
REFERENCES
15.1
PUBLISHED REFERENCES
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trachea and bronchus. Weblink: eco.iarc.fr/eucan. Accessed, December 8, 
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[2]
EUCAN Factsheets 2012, Country Factsheets: Greece. Weblink: 
eco.iarc.fr/eucan. Accessed, December 8, 2014. (R15-3732)
[3]
Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gemcitabine 
for first-line treatment of Asian patients with advanced non-small-cell 
lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, 
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[4]
D’Archangelo, Hirsch FR. Clinical and comparative utility of afatinib in 
non-small cell lung cancer. Biologics: Targ Ther. 2014; 8: 183-192. (P14-
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[5]
Scagliotti GV, Kortsik C, Dark GG, et al. Pemetrexed combined with 
oxaliplatin or carboplatin as first-line treatment in advanced non-small cell 
lung cancer: a multicenter, randomized, phase II trial. Clin Cancer Res. 
2005; 11(2 Pt 1): 690-696. (R15-3744)
[6]
Iyer S, Roughley A, Rider A, Taylor-Stokes G. The symptom burden of 
non-small cell lung cancer in the USA: a real-world cross-sectional study. 
Support Care Cancer. 2014; 22 (1): 181-187. (R15-3743)
[7]
Bridges JFP, Mohamed AF, Finnern HW. Patients’ preferences for 
treatment outcomes for advanced non-small cell lung cancer: A conjoint 
analysis. Lung Cancer. 2012; 77 (1): 224-231. (R12-3785)
[8]
Silvestri G, Pritchard R, Welch HG. Preferences for chemotherapy in 
patients with advanced non-small cell lung cancer: descriptive study based 
on scripted interviews. BMJ. 1998; 317 (7161): 771-775. (R08-4150)
[9]
Hirsh V. Is the Evaluation of Quality of Life in NSCLC Trials Important? 
Are the Results to be Trusted? Front Oncol. 2014; 4:173. eCollection 
2014. (R15-3742)
[10]
Anant M, Guleria R, Pathak AK, et al. Quality of life measures in lung 
cancer. Indian J Cancer. 2005; 42 (3): 125-132. (R15-3741)
[11]
Lemonnier I, Guillemin F, Arveux P, et al. Quality of life after the initial 
treatments of non-small cell lung cancer: a persistent predictor for 
patients' survival. Health Qual Life Outcomes. 2014; 12: 73. (R15-3740)

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[12]
Movsas B, Moughan J, Sarna L, et al. Quality of life supersedes the classic 
prognosticators for long-term survival in locally advanced non-small-cell 
lung cancer: an analysis of RTOG 9801. J Clin Oncol. 2009; 27 (34): 
5816-5822. (R15-3739)
[13]
Jacot W, Colinet B, Bertrand D, et al. OncoLR health network. Quality of 
life and comorbidity score as prognostic determinants in non-small-cell 
lung cancer patients. Ann Oncol. 2008; 19 (8): 1458-1464. (R08-5076)
[14]
Qi Y, Schild SE, Mandrekar SJ, et al. Pretreatment quality of life is an 
independent prognostic factor for overall survival in patients with 
advanced stage non-small cell lung cancer. J Thorac Oncol. 2009; 4 (9): 
1075-1082. (R15-3738)
[15]
Sloan JA, Zhao X, Novotny PJ, et al. Relationship between deficits in 
overall quality of life and non-small-cell lung cancer survival. J Clin 
Oncol. 2012; 30 (13): 1498-1504. (R15-3737)
[16]
Damm K, Roeske N, Jacob C. Health related quality of life questionnaires 
in lung cancer trials: a systematic literature review. Health Econ Rev. 
2013; 3 (1): 15. (R15-3736)
[17]
Rabin R, de Charro F: EQ-5D: a measure of health status from the 
EuroQol Group. Ann Med 2001; 33 (5): 337-343. (R09-0051)
[18]
Bergman B, Aaronson NK, Ahmedzai S, et al. The EORTC QLQ-LC13: a 
modular supplement to the EORTC Core Quality of Life Questionnaire 
(QLQ-C30) for use in lung cancer clinical trials. EORTC Study Group on 
Quality of Life. Eur J Cancer. 1994; 30A (5): 635-642. (R07-2060)
[19]
Cella DF, Bonomi AE, Lloyd SR, et al. Reliability and validity of the 
Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life 
instrument. Lung Cancer. 1995; 12 (3):199-220. (R07-4313)
[20]
Hollen PJ, Gralla RJ, Kris MG, Potanovich LM. Quality of life assessment 
in individuals with lung cancer: testing the Lung Cancer Symptom Scale 
(LCSS). Eur J Cancer. 1993; 29A Suppl 1: S51-S58. (R07-4307)
[21]
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria 
of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982; 5 
(6): 649-655. (R01-0787)
[22]
Tam TC, Ho JC, Wong MK, Wong WM, et al. Treatment outcomes in 
elderly with advanced-stage non-small cell lung cancer. Lung. 2013; 191 
(6): 645-654. (R15-3881)

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[23]
Sweeney CJ, Zhu J, Sandler AB, et al. Outcome of patients with a 
performance status of 2 in Eastern Cooperative Oncology Group Study 
E1594: a Phase II trial in patients with metastatic non-small cell lung 
carcinoma. Cancer. 2001; 92 (10): 2639-2647. (R15-3735)
[24]
Christine L. Patient Adherence to Oral Cancer Therapies: A Nursing 
Resource Guide. OncoLink. Last Modified: May 23, 2014. Weblink: 
www.oncolink.org/resources/article.cfm?c=424&id=7058. 
Accessed 
November 20, 2014. (R15-3733)
[25]
Nguyen KS, Neal JW, Wakelee H. Review of the current targeted 
therapies for non-small-cell lung cancer. World J Clin Oncol. 2014; 5 (4): 
576-587. (P14-15210)
[26]
Pal SK, Figlin RA, Reckamp K. Targeted therapies for non-small cell lung 
cancer: an evolving landscape. Mol Cancer Ther. 2010; 9 (7): 1931-1944. 
(P15-07192)
[27]
Sacco PC, Maione P, Rossi A. The PI3k inhibitors: new hopes in the battle 
against advanced NSCLC. Front Biosci (Landmark Ed). 2014; 19: 259-
271. (P15-07197)
[28]
Hirsh V, Cadranel J, Cong XJ, et al. Symptom and quality of life benefit 
of afatinib in advanced non-small-cell lung cancer patients previously 
treated with erlotinib or gefitinib: results of a randomized phase IIb/III 
trial (LUX-Lung 1). J Thorac Oncol. 2013; 8 (2): 229–237. (P13-01011)
[29]
Sequist LV, Yang JC-H, Yamamoto N, et al: Phase III study of afatinib or 
cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma 
with EGFR mutations. J Clin Oncol 2013; 31 (27): 3327-3334. (P13-
07382)
[30]
Yang JC, Hirsh V, Schuler M, et al. Symptom control and quality of life in 
LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in 
patients with advanced lung adenocarcinoma with EGFR mutations. J Clin 
Oncol. 2013; 31 (27): 3342-3350. (P13-07383)
[31]
Yang JC, Wu YL, Schuler M, et al. Afatinib versus cisplatin-based 
chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-
Lung 3 and LUX-Lung 6): analysis of overall survival data from two 
randomised, phase 3 trials. Lancet Oncol. 2015; 16 (2):141-151. (P15-
00344)
[32]
Osoba D, RodriguesG, MylesJ, et al. Interpreting the significance of 
changes in health-related quality of life scores. J Clin Oncol. 1998; 16 (1): 
139–144. (R99-1223)

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[33]
Osoba D, Bezjak A, Brundage M, et al. Analysis and interpretation of 
health-related quality-of-life data from clinical trials: basic approach of 
The National Cancer Institute of Canada Clinical Trials Group. Eur J 
Cancer. 2005; 41 (2): 280-287. (R15-3728)
[34]
Hollen P, Gralla R. Evaluating clinical versus statistical significance with 
the LCSS quality of life instrument and the Karnofsky Performance Status 
(KPS). Lung Cancer 2000; 29 (1): 34-34. (R15-3880)
[35]
Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-
related quality of life: the remarkable universality of half a standard 
deviation. Med Care. 2003; 41 (5): 582-592. (R14-4031)
[36]
Hollen PJ, Gralla RJ, Kris MG, Cox C, Belani CP, Grunberg SM, 
Crawford J and Neidhart JA. Measurement of quality of life in patients 
with lung cancer in multicenter trials of new therapies: Psychometric 
assessment of the Lung Cancer Symptom Scale. Cancer. 1994; 73 (8): 
2087-2098. (R07-4352)
[37]
Hollen PJ, Gralla RJ, Kris MG. Lung Cancer Symptom Scale (LCSS): 
Administration, scoring, and procedures manual. Second Edition, LCSS 
Associates, 1995. (provided by first author after purchase of License for 
use of the LCSS). (R15-3879)
[38]
Yfantopoulos J. The Greek Version of EuroQol (EQ-5D) Instrument. 
Archives Hellenic Med. 2001; 18: 180-191. (R15-3730)
[39]
Rabin R, Oemar M and Oppe M. EQ-5D-3L User Guide: Basic 
information on how to use the EQ-5D-3L Instrument. Version 4.0; 2011: 
pp. 
1-24. 
Weblink: 
www.euroqol.org/about-eq-5d/publications/user-
guide.html. (R15-3734)
[40]
Ruddy K, Mayer E and Partridge A. Patient adherence and persistence 
with oral anticancer treatment. CA Cancer J Clin. 2009; 59 (1): 56-66. 
(R15-3729)

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15.2
UNPUBLISHED REFERENCES
Not applicable

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Documents listed in the following table of Annex 1 will be maintained separately from the 
study protocol. They will be clearly identifiable and provided on request.
Table 4:
List of Stand-Alone Documents
Number
Document 
Reference Number
Date
Title
1
c03664764
24 June 2015
2015-06-24-letter-
list-of-
participating-
investigators
(list and contact 
details of 
participating 
investigators)

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ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS (REVISION 2)
Note: Page number(s) refer(s) to the first page number of the relevant Section.  
Section 1: Milestones
Yes
No
N/A
Page 
Number(s)
1.1 Does the protocol specify timelines for 
1.1.1 Start of data collection
1.1.2 End of data collection
1.1.3 Study progress report(s) 
1.1.4 Interim progress report(s)
1.1.5 Registration in the EU PAS register
1.1.6 Final report of study results.
28
28
-
28
-
28
Comments:
1.1.3 Not required as per the national requirements for non-interventional studies
1.1.5 Not required since this study is not considered a PASS 
Section 2: Research question
Yes
No
N/A
Page 
Number(s)
2.1
Does the formulation of the research question and objectives 
clearly explain: 
2.1.1 Why the study is conducted? (e.g. to address an important public 
health concern, a risk identified in the risk management plan, an emerging 
safety issue)
2.1.2 The objective(s) of the study?
31
33
2.1.3 The target population? (i.e. population or subgroup to whom the 
study results are intended to be generalised)
2.1.4 Which formal hypothesis(-es) is (are) to be tested? 
2.1.5 If applicable, that there is no a priori hypothesis?
38
-
-
Comments:
2.1.4 & 2.1.5 This study is not hypothesis-driven and will primarily make use of descriptive statistical 
methods; any analysis to be performed will be exploratory in nature.
Section 3: Study design
Yes
No
N/A
Page 
Number(s)
3.1
Is the study design described? (e.g. cohort, case-control, randomised 
controlled trial, new or alternative design) 
34
3.2
Does the protocol specify the primary and secondary (if 
applicable) endpoint(s) to be investigated?
36
3.3
Does the protocol describe the measure(s) of effect? (e.g. relative 
risk, odds ratio, deaths per 1000 person-years, absolute risk, excess risk, 
incidence rate ratio, hazard ratio, number needed to harm (NNH) per year)
36 & 52
Comments:
N/A
Section 4: Source and study populations
Yes
No
N/A
Page 
Number(s)

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Section 4: Source and study populations
Yes
No
N/A
Page 
Number(s)
4.1
Is the source population described?
38
4.2
Is the planned study population defined in terms of:
4.2.1 Study time period?
4.2.2 Age and sex?
4.2.3 Country of origin?
4.2.4 Disease/indication? 
4.2.5 Comorbidity?
4.2.6 Seasonality?
37
38
34
38
38
-
4.3
Does the protocol define how the study population will be 
sampled from the source population? (e.g. event or inclusion/exclusion 
criteria) 
38
Comments:
4.2.6 Seasonality variation and pattern fall outside the context of this study and do not directly apply in the 
study population and disease under observation. 
Section 5: Exposure definition and measurement
Yes
No
N/A
Page 
Number(s)
5.1
Does the protocol describe how exposure is defined and 
measured? (e.g. operational details for defining and categorising exposure)
44 & 54
5.2
Does 
the 
protocol 
discuss 
the 
validity 
of 
exposure 
measurement? (e.g. precision, accuracy, prospective ascertainment, 
exposure information recorded before the outcome occurred, use of validation 
sub-study)
5.3
Is exposure classified according to time windows? (e.g. current 
user, former user, non-use)
5.4
Is exposure classified based on biological mechanism of action 
and 
taking 
into 
account 
the 
pharmacokinetics 
and 
pharmacodynamics of the drug?
5.5
Does the protocol specify whether a dose-dependent or 
duration-dependent response is measured?
Comments:
5.2, 5.3, 5.4 & 5.5 The study medication will be administered as per the routine clinical practice and the 
locally approved product’s label. 
Section 6: Endpoint definition and measurement
Yes
No
N/A
Page 
Number(s)
6.1
Does the protocol describe how the endpoints are defined and 
measured? 
36
6.2
Does 
the 
protocol 
discuss 
the 
validity 
of 
endpoint 
measurement? (e.g. precision, accuracy, sensitivity, specificity, positive 
predictive value, prospective or retrospective ascertainment, use of validation 
sub-study)
44 & 53 & 53
Comments:
N/A

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Section 7: Confounders and effect modifiers
Yes
No
N/A
Page 
Number(s)
7.1
Does the protocol address known confounders? (e.g. collection of 
data on known confounders, methods of controlling for known confounders)
44 & 53
7.2
Does the protocol address known effect modifiers? (e.g. collection 
of data on known effect modifiers, anticipated direction of effect)
44 & 53
Comments:
N/A
Section 8: Data sources
Yes
No
N/A
Page 
Number(s)
8.1
Does the protocol describe the data source(s) used in the study 
for the ascertainment of:
8.1.1 Exposure? (e.g. pharmacy dispensing, general practice prescribing, 
claims data, self-report, face-to-face interview, etc.)
8.1.2 Endpoints? (e.g. clinical records, laboratory markers or values, claims 
data, self-report, patient interview including scales and questionnaires, vital 
statistics, etc.)
8.1.3 Covariates? 
44
44
44
8.2
Does the protocol describe the information available from the 
data source(s) on:
8.2.1 Exposure? (e.g. date of dispensing, drug quantity, dose, number of 
days of supply prescription, daily dosage, prescriber)
8.2.2 Endpoints? (e.g. date of occurrence, multiple event, severity measures 
related to event)
8.2.3 Covariates? (e.g. age, sex, clinical and drug use history, comorbidity, 
co-medications, life style, etc.)
44
44
44
8.3
Is a coding system described for:
8.3.1 Diseases? (e.g. International Classification of Diseases (ICD)-10)
8.3.2 Endpoints? (e.g. Medical Dictionary for Regulatory Activities 
(MedDRA) for adverse events)
8.3.3 Exposure? (e.g. WHO Drug Dictionary, Anatomical Therapeutic 
Chemical (ATC)Classification System)
44
-
44
8.4
Is the linkage method between data sources described? (e.g. based 
on a unique identifier or other)
46
Comments:
8.3.2 No coding is applicable in the context of the study-specific endpoints. 
Section 9: Study size and power
Yes
No
N/A
Page 
Number(s)
9.1 Is sample size and/or statistical power calculated? 
51
Comments:
N/A
Section 10: Analysis plan
Yes
No
N/A
Page 
Number(s)
10.1
Does the plan include measurement of excess risks?
-
10.2
Is the choice of statistical techniques described? 
52

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Section 10: Analysis plan
Yes
No
N/A
Page 
Number(s)
10.3
Are descriptive analyses included?
52
10.4
Are stratified analyses included?
-
10.5
Does the plan describe methods for adjusting for 
confounding?
53
10.6
Does 
the 
plan 
describe 
methods 
addressing 
effect 
modification?
53
Comments:
10.1 No excess risks are foreseen due to the non-interventional observational study design that aims at 
depicting the daily routine clinical practice. 
10.4 No stratification is planned to be implemented per the study design.   
Section 11: Data management and quality control
Yes
No
N/A
Page 
Number(s)
11.1
Is information provided on the management of missing data?
51 & 52
11.2
Does the protocol provide information on data storage? (e.g. 
software and IT environment, database maintenance and anti-fraud 
protection, archiving)
51 & 58
11.3
Are methods of quality assurance described?
58
11.4 
Does the protocol describe possible quality issues related to 
the data source(s)?
58
11.5
Is there a system in place for independent review of study 
results? 
-
Comments:
11.5 
The study design does not mandate independent review of the results; however the 
handling/management and analysis of the data will be performed by an independent CRO assigned by the 
Sponsor
Section 12: Limitations
Yes
No
N/A
Page 
Number(s)
12.1
Does the protocol discuss:
12.1.1 Selection biases?
12.1.2 Information biases?
(e.g. anticipated direction and magnitude of such biases, validation sub-study, 
use of validation and external data, analytical methods)
56
56
12.2
Does the protocol discuss study feasibility? (e.g. sample size, 
anticipated exposure, duration of follow-up in a cohort study, patient 
recruitment)
37
12.3 Does the protocol address other limitations? 
56
Comments:
N/A

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Section 13: Ethical issues
Yes
No
N/A
Page 
Number(s)
13.1
Have requirements of Ethics Committee/Institutional Review 
Board approval been described?
58
13.2
Has any outcome of an ethical review procedure been 
addressed?
13.3
Have data protection requirements been described?
61
Comments:
N/A
Section 14: Amendments and deviations
Yes
No
N/A
Page 
Number(s)
14.1
Does the protocol include a section to document future 
amendments and deviations? 
18
& 58
Comments:
N/A
Section 15: Plans for communication of study results
Yes
No
N/A
Page 
Number(s)
15.1
Are plans described for communicating study results (e.g. to 
regulatory authorities)? 
67
15.2
Are plans described for disseminating study results externally, 
including publication?
67
Comments:
N/A
Name of the main author of the protocol: ___________________________
Date: 
/
/
Signature: ___________________________

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ANNEX 3. ADDITIONAL INFORMATION
ECOG PERFORMANCE STATUS
Table 5:
ECOG Performance Status Grading
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 self-care 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:
R01-0787         Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982; 5: 649-655.

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EQ-5D-3L (Sample) 

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EQ-5D-3L (SAMPLE) Continued (Page 2 of 2)

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LCSS PATIENT SCALE (Sample) 

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LCSS (SAMPLE) Continued (Page 2 of 2)

 
 
 
 
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clinical-trial-protocol
A multicentre, cohort study to assess the impact on SYMptom burden and patient
health-related quality of Life of afatinib treatment in advanced non-small cell lung
cancer in a real world setting in Greece. The ‘SYM-Less’ study
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Affairs
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Approval-Medical 
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Approval-Medical 
31 Aug 2018 15:34 CEST
Approval-Therapeutic Area 
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Approval-Biostatistics
10 Sep 2018 17:41 CEST
Approval-
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Therapeutic Area
12 Sep 2018 00:21 CEST
Approval
of Global
Epidemiology
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