A Non-interventional Biomarker Study in Patients With Non-Small Cell Lung Cancer (NSCLC) of Adenocarcinoma Tumour Histology Eligible for Treatment With Vargatef® According to the Approved Label.
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Boehringer Ingelheim

ABCD
TITLE PAGE
Non-interventional Study Protocol
Document Number:
c03352377-02
BI Study Number:
1199.223
BI Investigational
Product(s):
Vargatef® (nintedanib)
Title:
A non-interventional biomarker study in patients with Non-
Small Cell Lung Cancer (NSCLC) of adenocarcinoma tumour 
histology eligible for treatment with Vargatef® according to the 
approved label.
Protocol version 
identifier:
02
Date of last version of 
protocol:
09 May 2019
PASS:
No
EU PAS register 
number:
ENCEPP/SDPP/11885
Active substance:
Nintedanib
Antineoplastic agents, protein kinase inhibitors
ATC code: L01XE31
Medicinal product:
Vargatef®,100 mg and 150 mg soft capsules
Product reference:
EU/1/14/954/001-004
Procedure number:
EMA/H/C/002569
Marketing authorisation 
holder(s):
Boehringer Ingelheim International GmbH
Joint PASS:
No
Research question and 
objectives:
To explore whether genetic/genomic markers (alone or 
combined with clinical covariates) could be used to predict 
overall survival (OS) in NSCLC patients eligible for treatment 
with Vargatef® according to the approved label
Countries of study:
Multi-center study conducted in 13 countries: Austria, Belgium, 
Denmark, Germany, Greece, Hungary, Italy, Lithuania, 

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Luxembourg, Netherlands, Spain, Sweden and UK.
Author:
Direct phone: 
Marketing authorisation 
holder(s):
Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany
Date:
09 May  2019
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 7
4.
ABSTRACT........................................................................................................... 8
5.
AMENDMENTS AND UPDATES..................................................................... 10
6.
MILESTONES..................................................................................................... 11
7.
RATIONALE AND BACKGROUND................................................................ 12
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 14
9.
RESEARCH METHODS .................................................................................... 15
9.1
STUDY DESIGN............................................................................................ 15
9.2
SETTING........................................................................................................ 16
9.2.1
Selection of study population.................................................................. 17
9.2.2
Details of study procedures..................................................................... 18
9.3
VARIABLES .................................................................................................. 18
9.3.1
Exposure.................................................................................................. 19
9.3.2
Effectiveness outcome............................................................................. 19
9.3.3
Covariates (biomarkers) .......................................................................... 20
9.3.4
Safety....................................................................................................... 21
9.3.5
Other........................................................................................................ 21
9.4
DATA SOURCES........................................................................................... 21
9.5
STUDY SIZE.................................................................................................. 22
9.6
DATA MANAGEMENT................................................................................ 23
9.7
DATA ANALYSIS......................................................................................... 23
9.7.1
Analysis of efficacy................................................................................. 24
9.7.2
Statistical models for analyzing associations of biomarker with OS...... 24
9.7.2.1
Univariate screening approaches .................................................... 25
9.7.2.2
Multivariate approaches.................................................................. 25
9.7.3
Analyses of biomarkers........................................................................... 26
9.7.4
Analyses of safety ................................................................................... 26
9.7.5
Handling of missing data......................................................................... 27
9.8
QUALITY CONTROL................................................................................... 27
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 27

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9.10
OTHER ASPECTS ......................................................................................... 28
9.10.1
Data quality assurance............................................................................. 28
9.10.2
Records.................................................................................................... 28
9.10.2.1
Source documents........................................................................... 28
9.10.2.2
Direct access to source data and documents................................... 28
9.10.3
Statement of confidentiality .................................................................... 28
9.10.4
Patient completion................................................................................... 29
9.10.5
Completion of study................................................................................ 29
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 30
10.1
INFORMED CONSENT, DATA PROTECTION, STUDY RECORDS....... 30
10.1.1
Study approval, patient information and informed consent .................... 30
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 31
11.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 31
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 32
11.3
TIME WINDOWS .......................................................................................... 34
11.4
DOCUMENTATION OF ADVERSE EVENTS AND PATIENT NARRATIVES  
……..…………………………………………………………………………34
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 35
13.
REFERENCES .................................................................................................... 36
13.1
PUBLISHED REFERENCES......................................................................... 36
13.2
UNPUBLISHED REFERENCES................................................................... 36
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 37
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 38
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 43
ANNEX 3.1 ECOG PERFORMANCE STATUS...................................................... 43

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2.
LIST OF ABBREVIATIONS
Abl1
ABL proto-oncogene 1, non-receptor tyrosine kinase
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALK
Anaplastic Lymphoma Kinase
BI
Boehringer Ingelheim
BRAF
B-Raf proto-oncogene, serine/threonine kinase
CA
Competent Authority
CDR
Clinical Data Repository
CI
Confidence Interval
CRA
Clinical Research Associate
CRO
CTL
CTM
Contract Research Organization
Clinical Trial Leader
Clinical Trial Manager
CTNNB1
Catenin (cadherin-associated protein), beta 1, 88kDa
CTR
Clinical Trial Report
DDR1&2
Discoidin Domain Receptor tyrosine kinase 1 and 2
DNA
Deoxyribonucleic Acid
eCRF
Electronic Case Report Form
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group performance score
EDTA
Etylen-Diamin-Tetra-Acetat
EGFR
Epidermal Growth Factor Receptor
EMA
European Medicines Agency
EU
European Union
EU PAS
European Union Post-Authorization Studies
FDA
US Food and Drug Administration
FPE
Fixed Paraffin Embedded
FGFR
Fibroblast Growth Factor Receptor
Flt3
Fms-related tyrosine kinase 3
GCP
Good Clinical Practice
GEP
Good Epidemiological Practice
GPP
Guidelines for Good Pharmacoepidemiology Practice
HER2
erb-b2 receptor tyrosine kinase 2 (ERBB2)
HR
Hazard Ratio
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board 
ISF
Investigator Site File
Kit
v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog
KRAS
Kirsten rat sarcoma viral oncogene homolog
Lck
LCK proto-oncogene, Src family tyrosine kinase
LDH
Lactade Dehydrogenase
MedDRA
Medical Dictionary for Drug Regulatory Activities
Melk
Maternal embryonic leucine zipper kinase
ml
milliliter

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NIS
Non-Interventional Study
NRAS
Neuroblastoma RAS viral (v-ras) oncogene homolog
NSCLC
Non-Small Cell Lung Cancer
OPU
Operative Unit
OS
Overall Survival
PDGFR
PD-L1
Platelet Derived Growth Factor Receptor
Programmed death-ligand 1
PIK3CA
phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit 
alpha
RDC
Remote Data Capture
RECIST
Response Evaluation Criteria In Solid Tumours
Ret
Ret proto-oncogene
RNA
Ribonucleic acid
ROS
Proto-oncogene 1 , receptor tyrosine kinase
SAE
Serious Adverse Event
SCLC
Small-Cell Lung Cancer
SADR
Serious Adverse Drug Reaction
SEAP
Statistical and Epidemiological Analysis Plan
SOP
Standard Operating Procedure
SPC
Summary of Product Characteristics
Src
SRC proto-oncogene, non-receptor tyrosine kinase
SUSAR
Suspected Unexpected Serious Adverse Reactions
TMF
Trial Master File
TMM
Team Member Medicine
TrkA (NTRK1)
Neurotrophic Tyrosine Kinase, receptor, type 1
TrkC (NTRK3)
Neurotrophic Tyrosine Kinase, receptor, type 3
VEGF
Vascular Endothelial Growth Factor
VEGFR
Vascular Endothelial Growth Factor Receptor

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3.
RESPONSIBLE PARTIES
Boehringer Ingelheim (BI) has appointed a Clinical Trial Leader (CTL), responsible for 
coordinating all required activities, in order to

manage the study in accordance with applicable regulations and internal standard 
operating procedures (SOPs),

direct the study team in the preparation, conduct, and reporting of the study,

order the materials as needed for the study,

ensure appropriate training and information of  Clinical Trial Managers (CTMs), 
Clinical Research Associate (CRAs), and Physicians of participating countries.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
The organization of the study in the participating countries will be done by the respective 
local BI-operative unit (OPU) or by a Contract Research Organization (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the study. In each local BI OPU participating in this study, a CTM will be appointed 
responsible for coordinating the activities required in order to manage the study in 
accordance with applicable regulations and internal SOPs in the countries covered by the 
respective BI OPU. On-site monitoring will be performed by BI or a CRO appointed by BI.
Assessments of pharmacogenomics and biomarkers is planned to be performed centrally. All 
samples will be sent by the participating sites to a vendor and forwarded subsequently to the
central laboratory for analysis.
An Investigator Site File (ISF) containing all relevant study related documentation will be
maintained according to local regulations and BI SOPs at each study site. A copy of the ISF 
documents will also be kept as an electronic Trial Master File (TMF) at BI according to BI 
SOPs. Documents related to participating physicians and other important participants,
especially their curricula vitae, will be filed in the TMF.
The coordinating physicians who will sign the non-interventional study report of this study 
have been appointed by BI. The coordinating physician has experience in this type of studies.
Coordinating physician: 
Co- Coordinating physician:

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Vargatef®
Name of active ingredient:
Nintedanib,
Antineoplastic agents,  
protein kinase inhibitors,
ATC code: L01XE31
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:  
07 October 2015
1199.223
02/01
09 May 2019
Title of study:
A non-interventional biomarker study in patients with NSCLC of 
adenocarcinoma tumour histology eligible for treatment with 
Vargatef® according to the approved label.
Rationale and 
background:
At present there are no validated predictive tumour- or serum-derived 
biomarkers available guiding the usage of anti-angiogenic therapies in 
NSCLC. 
The objective of this non-interventional study (NIS) is to explore
predictive genetic/genomic markers (alone or combined with clinical 
covariates) in NSCLC patients eligible for treatment with Vargatef®. 
The analyses in this study are exploratory in nature and considered to 
be hypothesis generating. The results from these investigations may 
help to expand our understanding of the disease and the response to 
Vargatef®.
Research question 
and objectives:
To explore whether genetic/genomic markers (alone or combined with 
clinical covariates) could be used to predict OS in NSCLC patients 
treated with Vargatef® according to the approved label.
Study design:
Non-interventional, multi-country, multi-site study based on newly 
collected data in patients that are assigned to receive Vargatef® as 
part of the routine treatment according to the approved label for the 
first time (new users design). Patients will be followed up until death, 
lost to follow-up, withdrawal of consent, or until required number of 
OS events has occurred, whichever occurs first.
Population:
Patients that are assigned to treatment with Vargatef® as part of the 
routine treatment according to the approved label are eligible for 
participation in the study.

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Vargatef®
Name of active ingredient:
Nintedanib,
Antineoplastic agents,  
protein kinase inhibitors,
ATC code: L01XE31
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:  
07 October 2015
1199.223
02/01
09 May 2019
It is intended that about 100 sites with oncologists/pulmonologists at 
hospitals mainly based in Europe will participate. An average of 0.2 
patients/months/site is expected. If patient recruitment takes longer 
than expected, the number of participating sites and the number of 
included patients per site may be increased.
Variables:
Primary outcome: OS in relation to exploratory biomarker assessment, 
including gene-expressions and genomic alterations.
Data sources:
NIS based on new data collection (NISnd).
Study size:
At least 300 evaluable patients. In order to account for possible non-
evaluable patients up to 375 can be enrolled.
Data analysis:
Univariate and multivariate prediction models will be used to identify 
gene expressions and tumour genomic alterations to predict OS in 
patients with NSCLC treated with Vargatef®.
Milestones:
First included patient 14 March-2016.
Final report of study results expected in August-2020

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5.
AMENDMENTS AND UPDATES
Global Amendment 1
Number
Section of 
study protocol
Amendment or 
update
reason
1
Title page
EU PAS 
register number
Not assigned before finalization of the 
protocol
2
Title page
Countries of 
study
Updated with the participating 
countries
3
P.2
Author
Name and address of the author 
updated
4
Section 2
List of 
abbreviations 
Updated with missing (PD-L1) and 
updated (TCM→CTL and 
CML→CTM)  abbreviations 
throughout the protocol
5
Section 4
Milestones
Updated with actual date for first 
included patient and revised planned  
expected date of the final study report
6
Section 6
Milestones
Updated with actual and planned 
dates
7
Section 9.3
Variables 
collected at 
Baseline visit
Corrections of percentage of PD-L1 
positive myeloid cells to PD-L1 
positive immune cells
8
Section 9.3
Variables 
collected at 
Follow-up visits
Added to collect: 
Best response after Vargatef® and 
docetaxel treatment (according to 
RECIST 1.1(R09-262) if possible).

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6.
MILESTONES
Milestone
Planned Date
Registration in the 
European Union (EU) Post-
Authorization Studies
(PAS) register
22-Jan-2016
Start of data collection
14 Mar 2016
End of data collection
30-Aug-2019
Final report of study results:
30-Aug-2020

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7.
RATIONALE AND BACKGROUND
Lung cancer is the most common cancer worldwide. In 2008, 1.6 million people were newly 
diagnosed with lung cancer worldwide, and 1.4 million deaths were caused by lung cancer 
i.e., 18% of the overall cancer mortality, being so the leading cause of cancer deaths in men 
and the second leading cause of cancer deaths in women (R12-1150). Histologically, a 
distinction is drawn between NSCLC and small-cell lung cancer (SCLC), based on the 
differences in terms of biological behaviour, prognosis and treatment options. About 80% -
85% of lung cancers involve NSCLCs, which are divided into three basic histological 
subgroups: adenocarcinoma, squamous cell carcinoma and large cell carcinoma (R08-5110). 
The majority of patients with lung cancer are diagnosed after the disease has progressed to an 
advanced stage. The prognosis for the majority of patients with advanced stage disease has 
not changed significantly in the past decade. With an overall 5-year survival rate of 9 to 13%, 
the treatment of NSCLC remains a major clinical challenge (R11-0052). Although 
considerable progress has been made in understanding the underlying biologic and genetic 
basis of cancer which has resulted in the development of more effective and targeted 
treatment strategies.
The aim of treatment of NSCLC is the reduction of tumour -related symptoms and the 
prolongation of survival time.
Vargatef® is an oral small molecule triple receptor tyrosine kinase inhibitor that potently 
blocks vascular endothelial growth factor-receptor (VEGFR) 1-3, fibroblast growth 
factor/receptor (FGFR) 1 and 3, as well as platelet derived growth factor- receptor (PDGFR), 
beside Ret proto-oncogene (ret), Src and Fms-related tyrosine kinase 3 (FLT3)  in low 
nanomolar concentrations.
Vargatef® was approved in the EU on 12 November 2014 by the European Medicines 
Agency (EMA) for the following indication: Vargatef® is indicated in combination with 
docetaxel for the treatment of adult patients with locally advanced, metastatic or locally 
recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy 
(c01632700-18).
The approval of Vargatef® was based on the survival benefit observed in the LUME-Lung 1 
study. LUME-Lung 1 was a double-blind, randomised, phase III study to evaluate the 
efficacy and safety of Vargatef® in combination with docetaxel in patients with locally 
advanced/metastatic or recurrent NSCLC following failure of first-line chemotherapy versus 
placebo plus docetaxel. The median OS of NSCLC patients with adenocarcinoma was 
prolonged by combination therapy of Vargatef®+ docetaxel versus docetaxel monotherapy 
from 10.3 to 12.6 months (Hazard Ratio (HR) 0.83; p = 0.0359). In addition, it was shown in 
a prespecified analysis that patients with progression during or shortly after first-line therapy 
(within 9 months after the start of first line chemotherapy) benefited with a median OS 
prolongation from 7.9 to 10.9 months (HR 0.75; p = 0.0073). A further exploratory 
evaluation was performed for patients who progressed directly on first-line therapy. In these 
patients, OS was also prolonged from 6.3 to 9.8 months (HR 0.62; p = 0.0246).
The most common adverse events (AEs) to be observed in the LUME-Lung 1 study were 
gastrointestinal adverse effects as well as reversible increases in liver enzymes, which were 

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usually well controlled by supportive measures or dose reduction. In terms of the class-
specific adverse effects known for antiangiogenic therapies (hypertension, haemorrhage or 
thrombosis of grade 3 severity), no differences were found between the two treatment arms 
(P14-00479).
At present there are no approved predictive tumour- or serum-derived biomarkers guiding 
usage of anti-angiogenic therapies in patients with adenocarcinoma of NSCLC. 
Consequently, EMA requested BI to search for potential predictive biomarkers in NSCLC 
patients eligible for treatment with Vargatef®. The objective of this NIS is to examine 
whether genetic/genomic markers (alone or combined with clinical covariates) could be used 
to predict OS in NSCLC patients eligible for treatment with Vargatef®. The investigations in 
this study are exploratory in nature and considered to be hypothesis generating. The results 
from these investigations may help to expand our understanding of the disease and the 
response to Vargatef®.

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8.
RESEARCH QUESTION AND OBJECTIVES
The primary objective of the study is to generate hypotheses whether gene expression 
patterns (alone or combined with clinical covariates) or genetic markers could be used to 
predict OS in patients treated with Vargatef® according to the approved label.
Further objectives of the study are:

to investigate potential association between the covariate “time since start of first line
chemotherapy until start of Vargatef® therapy” and gene-expression patterns.

to identify potential biomarkers, tumour genomic alterations and/or gene expression 
patterns to characterize the survival outcome potential of patients with late 
progression (≥9 months) versus early progression(< 9 months) from start of first line 
chemotherapy until start of Vargatef® therapy.

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9.
RESEARCH METHODS
The intention of this NIS is to collect biomarker data in adult patients with NSCLC of 
adenocarcinoma histology, who failed first line chemotherapy and will be treated for their 
disease with Vargatef®, 200 mg twice daily (except the day of docetaxel infusion) in 
combination with docetaxel at 75 mg/m² every 21 days as indicated in the approved labels of 
Vargatef® and docetaxel.
9.1
STUDY DESIGN
This is a non-interventional, multi-country, multi-center, study based on newly collected data, 
in patients initiating Vargatef® for the first time (new users design) and followed up until 
death, lost to follow-up, withdrawal of consent or until required number of OS events has 
been reached, whichever occurs first.
In order to reflect real world usage of Vargatef® and outcomes, the choice of a non-
interventional design is more appropriate than the experimental design. Moreover new data 
collection is also more appropriate to ensure adequate collection of gene expression patterns 
or genetic markers in combination with clinical characteristics, which may not be available or 
with insufficient accuracy in patient’s medical records.
Per design, all included patients will be exposed to Vargatef® and docetaxel (according to 
Summary of Product Characteristics (SPC)).
As for any NIS, the assignment of the patient to Vargatef® or any other treatment falls within 
current practice and prior to the decision to talk to the patient about the study, so that the 
decision to prescribe Vargatef® is clearly separated from the decision to include the patient 
in the study. The decision of treatment, including the intended duration of treatment, is at the 
discretion of the physician providing care for the patient. Consequently, the medicines under 
observation are not provided by the marketing authorization holder.
Patients who qualify will be treated according to the approved label of Vargatef®: Vargatef®
(200 mg administered twice daily except on the day of docetaxel infusion) in combination 
with docetaxel 75 mg/m² every 3 weeks for the treatment of adult patients with locally 
advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology after 
first-line chemotherapy.
The primary outcome will be OS and a sample size of at least 300 evaluable patients is 
considered sufficient to fulfill the objective of this hypothesis-generating exploratory study.
In order to account for possible non-evaluable patients up to 375 can be enrolled.
The analysis of OS will be conducted when 250 patients have had died. This is expected to 
occur after approximately 49 months from first patient in, assuming an accrual rate of 20
patients/month.
The end of the study will occur when the last patient has completed his/her follow-up visit 
and/or the required number of OS events has occurred, whichever occurs first. No further 
data will be collected afterwards (see Section 9.7.1). 

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9.2
SETTING
The NIS will be conducted in about 100 oncology/pulmonology sites mainly in Europe which 
are experienced in lung cancer treatment. An average of 0.2 patient/month/site is expected. If 
patient recruitment takes longer than expected, the number of participating sites and the 
number of included patients per site may be increased.
Patient participation in this NIS is voluntary and it is not a prerequisite to be treated (see 
Section 9.1). Patients are treated according to the standard of care independent of their
consent to participate in this NIS. 
For tissue-derived investigations, samples of tumour tissue, obtained at diagnosis and/or at re-
biopsy before the first line treatment initiation (either tumour blocks or slides, minimum of 
10 slides and up to 20 slides if possible at 5μm thickness), will be collected after informed 
consent is given. Patient without tumour tissue are not eligible for participation in this NIS.
If tumour tissues are available from more than one time point, samples from the latest 
obtained biopsy before first line chemotherapy treatment should be provided whenever 
possible, assuming tumour quantity is equivalent.
If there are post-chemotherapy, re-biopsy samples at relapse, these should be provided, if 
available.
The site (primary tumour or metastatic site) and the date when the original tumour tissue was 
collected will be recorded in the electronic Case Report Form (eCRF).
During patient`s blood withdrawal, included in the regular clinical laboratory assessment, 
additional blood amount of 2 milliliters (ml) will be collected at baseline or at any time after 
Vargatef® initiation for blood derived investigations. No additional puncturing will be 
required and samples will only be used after signed informed consent. If blood sample is not 
available, a buccal swab may be requested.
Patient bio specimens will be sent for storage and analysis to BI or a central laboratory 
qualified and approved by BI.
Collected samples might be kept for up to 15 years according to local guidelines and 
regulations (see Section 9.3.3 for details). Storage location and identification of the samples 
will be adequately documented.

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9.2.1
Selection of study population
Inclusion criteria:
All consecutive patients can be included if all the following criteria are present:

Age ≥ 18 years.

Women and men with locally advanced, metastatic or locally recurrent NSCLC with 
histology of adenocarcinoma.

Signed and dated written informed consent.

Vargatef ® is initiated and administered in accordance with the SPC.

Available fixed and paraffin embedded (FPE) tumour tissue routinely obtained at 
diagnosis and/or at re-biopsy before the initiation of the first line treatment (either 
block or slides, minimum of 10 slides and up to 20 slides if possible at 5μm 
thickness).
Exclusion criteria:
Patient won't be included if any of the following criteria is present:

Any contraindication to Vargatef® or docetaxel as specified in their respective labels.

Vargatef® initiated more than 7 days prior to inclusion in this NIS.

Patients participating simultaneously in a clinical trial.
No additional medical procedures are required other than those which the patients would 
have received even if they were not included in the NIS. The treatment, as well as the
diagnosis and monitoring procedures, follow the standard medical treatment practice.
There is therefore no risk to participating patients over and above the usual treatment risk 
with therapy with Vargatef® in combination with docetaxel.
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the ISF at the study site irrespective of whether they have participated in the 
NIS or not.
BI reserves the right to discontinue the study overall or at a particular study site at any time 
for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular study site.
2. Emergence of any efficacy/safety information that could significantly affect 
continuation of the study, or any administrative reason.
3. Violation of Good Clinical Practice (GCP) (as applicable), the Study Protocol, or the 
contract by a study site or physician, disturbing the appropriate conduct of the study.
The physician/ the study site will be reimbursed for reasonable expenses incurred in case of 
study termination (except in case of the third reason).

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9.2.2
Details of study procedures
The study procedures will consist of:

a baseline visit (if the patient is eligible for the study), visit from docetaxel 
administration up to 7 days after Vargatef® treatment initiation.

and follow-up visits – every 6 months (± 1 month) until death or the end of the study,
whichever occurs first.
9.3
VARIABLES
The following variables will be collected during the study according to different time points:
A. Baseline visit - The baseline visit is the visit from docetaxel administration up to 7 
days after Vargatef® treatment initiation.
The following will be obtained and/or performed:

Informed consent.

Demographics (sex, birth date).

Medical history (oncological, relevant non-oncological, smoking status, 
comorbidities, Epidermal Growth Factor Receptor (EGFR) mutation and Anaplastic 
Lymphoma Kinase (ALK) translocation status) and other mutations, if available.

Eastern Cooperative Oncology Group performance score (ECOG).

Start and end date of first line chemotherapy and drugs used.

Date of progression in first line chemotherapy.

Best response to first line chemotherapy (according to RECIST 1.1(R09-0262) if 
possible).

Start and end date of other prior anti-cancer treatment (excluding chemotherapy) and 
drugs used.

Date of progression under prior other anti-cancer treatment.

Best response to prior other anti-cancer treatment (according to RECIST 1.1(R09-
0262) if possible).

Start date of docetaxel and Vargatef® treatment.

Lactade Dehydrogenase (LDH) level measured within the last 7 days, if available.

Percentage of Programmed death-ligand 1 (PD-L1) positive tumour cells, percentage 
of PD-L1 positive immune cells and type of diagnostic anti PD-L1 antibodies, if 
available.

Ensure that tumour sample (paraffin block or tissue slides) is available for collection 
at any time during the study, including data on the site (primary tumour or metastatic 
site) and the date when the original tumour tissue was collected. 

During patient`s blood withdrawal, included in the regular clinical laboratory 
assessment, additional blood amount of 2 ml will be collected at baseline or at any 
time after Vargatef® initiation for  blood derived investigations. No additional 
puncturing will be required and samples will only be used after signed informed 
consent. If blood sample is not available, a buccal swab may be requested.

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B. Follow-up visits – every 6 months (± 1 month) until death or the end of the study
whichever occurs first.

If the blood sample is not collected at the baseline visit, during patient’s blood 
withdrawal, included in the regular clinical laboratory assessment, additional blood 
amount of 2 ml will be collected at any time after Vargatef® initiation for blood
derived investigations. No additional puncturing will be required and samples will 
only be used after signed informed consent. If blood sample is not available, a buccal 
swab may be requested.

Date of progressive disease (according to RECIST 1.1(R09-262) if possible).

Subsequent anti-cancer therapy (start/stop date and dosage) after stop of Vargatef®
and docetaxel.

Dates and reason of Vargatef® and/or docetaxel discontinuation.

Best response after Vargatef® and docetaxel treatment (according to RECIST 
1.1(R09-262) if possible).

Date of death.

All Adverse Drug Reactions (ADRs) (serious and non-serious).

All AEs with fatal outcome.
9.3.1
Exposure
Patients will be exposed to Vargatef®, 200 mg twice daily, except the day of docetaxel 
infusion in combination with docetaxel at 75 mg/m² every 21 days as indicated in the 
approved labels of Vargatef® and docetaxel.
9.3.2
Effectiveness outcome
1. Overall Survival (primary outcome)
OS is defined as the time from start of entering the study to time of death (irrespective of 
reason). The OS will be defined as follows:

For patients with known date of death (regardless of the cause of death):
OS [days] = date of death – date of treatment start + 1.

For patients known to be alive by the end of study or follow-up visit:
OS (censored) [days] = date of last contact when the patient is known to be alive –
date of treatment start + 1.
2. Time since start of first line therapy until start of Vargatef® therapy
Time since start of first line therapy until start of Vargatef® therapy is divided into 2 
subgroups as follows:

“Late progression group”: time from start of first line therapy until start of Vargatef®
≥9 months (T≥9)

“Early progression group”: time from start of first line therapy until start of Vargatef®
<9 months (T<9)

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9.3.3
Covariates (biomarkers)
In this NIS explorative biomarkers will be investigated. These analyses are hypothesis 
generating and will be used to expand our understanding of the disease and study drug.
Expression profiling and genomic characterization of tumour tissue
FPE tumour tissue (either block or slides, minimum of 10 slides and up to 20 slides if 
possible at 5μm thickness), obtained at diagnosis and/or at re-biopsy before the first line 
treatment initiation will be required for global analysis of gene expression (e.g. but not 
limited to angiogenesis-related pathway genes, drug target genes and NSCLC driver genes). 
In addition, tumour samples will be analysed if tissue quantity and quality permits for 
mutations in a panel of cancer and Vargatef® target genes, e.g. VEGFR 1-3, FGFR1-3, 
PDGFR&, Ret, Kit, BRAF, NRAS, HER2, KRAS, EGFR, ALK, PIK3CA, ROS and for 
expression of e.g. PD-L1 and CD133. Moreover, if tumour tissue quantity and quality is 
sufficient additional markers related to the disease or drug response and resistance 
mechanisms will be assessed.
Genomic evaluation of blood samples
One blood sample should be collected at baseline or at any time after Vargatef® treatment 
initiation as a part of the regular/routine clinical laboratory assessment if possible for 
genomic analyses. The blood sample (approximately 2 ml in an EDTA tube) is a reference 
(normal tissue) to distinguish tumour-acquired somatic mutations and will be analyzed for the 
same set of genes as the tumour tissue (see above). In addition, variants in angiogenesis-
related and/or drug target genes (e.g. VEGF-A, VEGFR1) will be analyzed if sample amount 
and quality permits. If blood sample is not available, a buccal swab may be requested.
Analytical determinations from tumour tissue and blood samples
From tumour tissue and blood or buccal swab samples nucleic acids (Deoxyribonucleic acid
and Ribonucleic acid) will be extracted and analyzed according to standard molecular genetic 
methods and technologies. Assessment of protein markers e.g. PD-L1 and CD133 if tumour 
tissue quantity and quality is sufficient will be performed according to qualified histological 
methods and technologies.
In case patients do not consent to optional biobanking (see below) all remaining material, 
including blood, tissue, isolated deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) 
from these blood and tumour samples will be destroyed no later than three months after final 
report archived (i.e. study end).
Detailed instructions for sampling, handling and shipment of samples will be provided in the 
lab manual.
The biomarker analyses will be performed by BI or a qualified and BI approved central 
laboratory.
Biobanking (optional)
If quantity of blood samples and tumour tissue allows after initial prespecified analysis (see 
above) and separate optional consent is agreed upon by the patient, remaining material (e.g. 
isolated RNA and DNA) will be stored at BI or a qualified and approved CRO for up to 

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fifteen (15) years after the end of the study according to local guidelines and regulations. 
Storage location and identification of the samples will be adequately documented. These 
samples will be used for future research to evaluate additional biomarkers that may elucidate 
further understanding of the disease or the study drug.
9.3.4
Safety
Safety will be collected with a focus on the following variables:

all (ADR) (serious and non-serious),

all AEs with fatal outcome.
How to collect and report AEs including the definitions are described in Section 11.
9.3.5
Other
Baseline characteristics
The following variables based on physician’s report will be considered as important baseline 
characteristics and potential risk factors for the events of interest. 
Demographics:

Age

Sex

ECOG

Smoking history

Oncological history 

Date of first diagnosis

Start and end date of first line chemotherapy and the drugs used 

Date of progression in first line chemotherapy

Best response to first line chemotherapy 

Start and end date of other prior anti-cancer treatment (excluding chemotherapy) and 
the drugs used 

Date of progression under other prior anti-cancer treatment

Best response to prior other anti-cancer treatment

Start date of docetaxel and Vargatef® treatment

Disease stage (locally advanced versus metastatic) at start of Vargatef® treatment

Presence of adrenal metastasis / liver metastasis

Number of metastatic organs

LDH level measured within the last 7 days, if available.

Percentage of PD-L1 positive tumour cells, percentage of PD-L1 positive myeloid 
cells and type of diagnostic anti PD-L1 antibodies, if available.
9.4
DATA SOURCES
NIS with new data collection.

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9.5
STUDY SIZE
Assuming that there is only one dichotomized genetic/genomic marker that divides the 
population into a biomarker positive (b+) or biomarker negative (b-) subgroup, the study is 
sized as such that the probability of detecting a true survival difference between these two 
biomarker groups is sufficiently large, while the probability of erroneously observing a 
survival difference is small.
Table 9.5: 1 summarizes the associated probabilities for observing HRs (i.e., the survival 
differences between the subgroups defined by the biomarker) below prespecified thresholds 
based on the assumption that a true survival difference is characterized by a HR of 0.85 and 
that no survival difference is characterized by a HR of 1 between the two groups for different 
numbers of OS events. We further assume that the distribution of biomarker subgroup b+ 
versus b- is 70% and 30%, respectively.
Table 9.5: 1
Probabilities for observing HRs for survival differences between the biomarker 
subgroups below prespecified thresholds 
True HR* 0.85
True HR* 1.00
Probability of observing a HR below 
prespecified threshold
Probability of observing a HR below 
prespecified threshold
OS events
0.9$
0.95$
1.0$
0.85$
0.9$
0.95$
200
0.64
0.76
0.85
0.15
0.25
0.37
250
0.66
0.79
0.88
0.12
0.22
0.36
300
0.68
0.81
0.90
0.10
0.20
0.34
*HR for biomarker positive versus biomarker negative group $prespecified thresholds.
The calculations are based on the approximate normal distribution of the estimated log HR. 
With 250 OS events, if the true survival differences between the biomarker subgroups is 
characterized by a HR of 0.85, the probability of observing a HR≤0.9 is 66% and the 
probability of observing a HR ≤0.95 is 79%, while the risk of erroneously observing a HR>1 
is only 12%. However, if there is no survival difference between the two biomarker 
subgroups, the risk of erroneously observing a HR≤0.85 or ≤0.9 is only 12% and 22%,
respectively.
Assuming a recruitment rate of 20 patients per month (15 months accrual duration), a 10% 
drop-out rate, and a median OS of 11 versus 13 months (HR=0.85) for the biomarker 
subgroups, the observation of 250 OS events in a study with 300 patients is estimated to 
occur after approximately 49 months (see Clinical Trial Report (CTR) 1199.13,U13-1504-01)
These sample size calculations are based on the assumption of only one dichotomized 
genetic/genomic marker. Indeed, several genetic/genomic markers will be evaluated in this 
study, thus multiplicity issues will need to be considered. 
Still, the sample size of at least 300 evaluable patients is in line with biomarker studies from 
literature. In the paper published by the Director's Challenge Consortium for the Molecular 
Classification of Lung Adenocarcinoma (R14-1926), gene expression-based survival 
prediction was investigated based on 442 lung adenocarcinoma patients with particularly 
investigating subgroups of patients according to the staging of their disease. Even this large 

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study was not powered to make inferences with statistical confidence, but nevertheless 
provided interesting trends. Therefore, without accounting for a subgroup as staging of their 
disease in our study, a sample size of at least 300 evaluable patients is considered sufficient 
to fulfill the objective of this hypotheses-generating exploratory study. In order to account for 
possible non-evaluable patients up to 375 can be enrolled.
9.6
DATA MANAGEMENT
Patients’ data will be gathered by Remote Data Capture (RDC) system.
The data management procedures to ensure the quality of the data are described in detail in 
the Statistical and Epidemiological Analysis Plan (SEAP) available in TMF.
9.7
DATA ANALYSIS
The primary objective of the statistical epidemiological analysis is to generate hypotheses 
whether gene expression patterns (alone or combined with clinical covariates) or genetic 
markers could be used to predict OS.
Further objectives of the study are:

to investigate potential associations between the covariate “time since start of first line
therapy until start of Vargatef® therapy” and gene-expression patterns;

to identify potential biomarkers, tumour genomic alterations of gene and/or gene 
expression patterns to characterize the survival outcome of patients with late 
progression (≥9months) versus early progression (<9months) from start of first line 
therapy until start of Vargatef® therapy.
Predefined Subgroups:
Time since start of first line therapy until start of Vargatef® therapy is divided into 2 
subgroups as follows:

“Late progression group”: time from start of first line therapy until start of Vargatef®
therapy ≥9 months (T≥9)

“Early progression group”: time from start of first line therapy until start of Vargatef®
therapy <9 months (T<9)
Additional subgroups based on the available biomarker variables and clinical covariates will
be defined if deemed necessary.
Analyses on predefined or additional subgroups will be only performed if the number of 
subjects per group is sufficient.
All subjects entered with evaluable biomarker data value will be included in the statistical 
analyses.
Descriptive Statistics
The following descriptive statistics will be calculated for all continuous biomarkers, for all 
subjects and by subgroup (T≥9 vs T<9) at available time points : N, arithmetic mean, 
standard deviation, minimum, median, maximum, percentiles, arithmetic coefficient of 
variation.
For all categorical biomarkers frequency tables will be calculated. 

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Furthermore, correlations among biomarkers and/or clinical covariates will be evaluated. 
9.7.1
Analysis of efficacy
The median and range of OS and other descriptive statistics will be calculated (Kaplan-Meier 
estimates).
Table 9.7.1: 1 describes how patients will be classified for the analysis of death. Patients will 
be censored at the date of last contact if the physician is no longer able to contact a patient or 
caregiver, and vital status cannot otherwise be determined.
Table 9.7.1: 1 Outcome determination for OS
Situation
Outcome (event or censored) Date of death or censoring
Patients died and the date
of death is known
event
Date of death
Patients died and date of
death is unknown
censored
Date of last contact when the
patient is known to be alive
Patient alive
censored
Date of last contact
Unknown
censored
Date of last contact when the
patient is known to be alive
Patients who are enrolled, but never received the combination therapy of docetaxel and 
Vargatef® therapy will be censored on the day of enrollment.
Additional clinical factors that might be relevant and included as covariates and/or used as 
subgroups in the models below will be pre-specified in the SEAP.
9.7.2
Statistical models for analyzing associations of biomarker with OS
Biomarkers will be investigated by univariate and multivariate prediction models and 
regression analysis.
For all univariate screening approaches, multiplicity correction of p-values will be performed.
Model performances will be quantified and uncertainty will be evaluated by resampling 
methods.
Categorical biomarkers will only be investigated provided there are sufficient patient
numbers within the subgroups defined by the categorical biomarkers. For all selected 
categorical biomarkers the estimate of the HR/odds ratio and its 95% confidence interval (CI)
will be presented. For continuous biomarkers the HR/odds ratio for a change per unit will be 
presented.

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9.7.2.1
Univariate screening approaches
Model to identify potential prognostic markers
The association between a biomarker and the efficacy endpoint OS will be explored by Cox’s 
proportional hazard model.
For all biomarkers the hazard function hi of the ith patient is modeled as
hi (t) = h0 (t) ∙ exp(βB ∙Bi )
(Model 1)
where
t
Time point
h0
Baseline hazard function
βB
Effect of biomarker
Other known prognostic factors, e.g. “time since start of first line until start of Vargatef®
therapy“, might be added to the model above, if applicable.
The Cox proportional-hazards models will be used to derive the estimates and 95 % CIs for 
the HR.
Logistic Regression Model
The logistic regression model will be used to characterize the pre-defined subgroup by 
biomarkers measured at diagnosis. The probability of being in the subgroup T< 9 will be 
investigated for each biomarker separately.
For all biomarkers measured at diagnosis the probability of being in one or the other 
subgroup will be calculated using a logistic regression model, with 
Pr(Yi = yi | Bi ) = 
pi, 
if yi = 1, i.e. the i-th patient is in the subgroup (T<9)
1- pi, 
if yi = 0, i.e. the i-th patient is in the subgroup (T>=9) 
logit(pi) = ln(pi / (1-pi) ) = ß0 + ß1Bi                                (Model 2)
where
ß0
Intercept
ß1
Effect of Biomarker
The Logistic regression models will be used to derive the estimates and 95 % CIs for the odds 
ratio.
9.7.2.2
Multivariate approaches
To identify prognostic biomarker signatures based on gene-expression and genomic 
alterations, multivariate Cox regression modelling and/or other regression models in 
combination with variable selection or alternative multivariate approaches will be used.

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9.7.3
Analyses of biomarkers
Investigation of gene-expressions and gene-expression-signatures to predict OS
Gene-expressions will be investigated as prognostic biomarkers (see Section 9.7.2) in 
different scenarios:
Univariate approaches:

gene-expression can predict OS in all patients (Model 1)

gene-expression and basic clinical covariates can predict OS in all patients (Model 1)

gene-expression can characterize predefined subgroups (T≥9 vs T<9) (Model 2)
Multivariate approaches:

gene-expression-signatures can predict OS in all patients (see Section 9.7.2.2)

gene-expression-signatures and basic clinical covariates can predict OS in all patients 
(see Section 9.7.2.2)
Correlations between “time since start of first line until start of Vargatef® therapy” and gene-
expression patterns will be assessed using correlation coefficients.
Investigation of tumour genomic alterations to predict OS (if quality and amount of 
data permits)
To investigate the potential of tumour genomic alterations as prognostic biomarkers, each 
selected biomarker (dependent on the frequency threshold of appearance, i.e. mutation must 
be present in a reasonable amount of patients) will be analysed separately (see Section 
9.7.2.1).
To investigate the potential of tumour genomic alterations as prognostic biomarker 
signatures, selected biomarkers (dependent on the frequency threshold of appearance, i.e. 
mutation must be present in a reasonable amount of patients) will be analysed (see Section 
9.7.2.2).
Additional exploratory analysis for biomarkers will be specified in the SEAP.
9.7.4
Analyses of safety
The safety analysis will include all patients registered in the study and receiving the 
Vargatef® treatment. In general, safety analyses will be descriptive in nature, will be based 
on BI standards, and will focus on ADRs related to the Vargatef® treatment.
AEs will be coded using the current version of the Medical Dictionary for Drug Regulatory 
Activities (MedDRA). All AEs occurring between first intake of Vargatef® prescribed at 
baseline visit and till the patient leaves the study will be collected (see Section 9.10.4). An 
AE is considered to be an ADR if either the physician who has reported the AE or the 
sponsor assesses that there is a reasonable possibility for causal relationship to Vargatef®.

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The frequency of AEs/ADRs will be tabulated by system organ class and preferred term for 
overall and for subgroups based on the important baseline characteristics, if deemed 
necessary (see Section 9.3.4). 
No imputation is planned for missing AE data except for missing onset dates which will be 
handled according to BI standard.
9.7.5
Handling of missing data
Missing biomarker data will not be imputed. Missing data for OS will be handled according 
to Table 9.7.1: 1.
9.8
QUALITY CONTROL
All entries in the eCRF and the existing codings will be stored in a database. The structure of 
the database is based on the division into sections and entry fields defined in the eCRF. To 
improve and ensure data quality, data checks will be performed automatically in the eCRF 
directly on electronic entry at the study site.
Plausible value ranges for numerical data entries and logical data and list entries will be filed
in the eCRF. The tests for consistency and completeness based on this will be performed 
during entry in the eCRF. The validity of the recorded data will therefore be ensured by the 
validations incorporated in the documentation system, which highlight incorrect or 
implausible entries to the data entry clerk/doctor.
If corrections are necessary after the data are saved, these will be documented in an audit 
trail.
For the further quality assurance of the documented patient observations, a sample-based 
source data comparison will be performed on about 30% of included patients. An additional 
inspection/quality assurance check of this NIS can be performed in case of any deviation.
9.9
LIMITATIONS OF THE RESEARCH METHODS
As for any NIS, the study may be subject to biases. The main anticipated one is related to 
selection bias. Indeed, the study objectives may bias the selection of patients especially 
because of the required minimum number (10) of tumour tissue slides to be included. This 
minimum number is a trade-off between what would be considered as the lowest possible 
number of slides to ensure the goals of the study will be reached and the number of patients 
that may not be included into the study just because of insufficient number of archived slides. 
However, consultations with experts in the field have shown that this figure is often what is 
collected in routine practice. So the impact should be limited in the selection of patients. As 
the extent of this potential selection bias in a NIS with new data collection may be difficult to 
quantify, methodological efforts have been taken to reduce it. As an example, physician will 
be asked to include all consecutive patients that fit with inclusion criteria. As a consequence, 
a small amount of information will be collected for all patients considered for the study on a 
screening log and entered in the study database in order to describe the extent of such 
potential selection bias. This information will be very minimal and non-identifiable since it 
will be collected outside the patient’s consent; so limited to patient’s age range, gender and 
reason for non-inclusion (consent not provided, not enough archived tumour tissue slides or 
other reason). Comparing this information with the one of included patients will allow us to 
quantify any potential selection bias.

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9.10
OTHER ASPECTS
9.10.1
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) or by regulatory authorities. The quality assurance auditor will have access to all 
medical records, the physician’s study-related files and correspondence, and the informed 
consent documentation of this NIS.
9.10.2
Records
eCRFs for individual patients will be provided by the sponsor (BI), via remote data capture. 
9.10.2.1
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 physician’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. 
Transfer of the results from the biomarker and pharmacogenomics analysis to the clinical 
data warehouse will be done by Clinical Data Repository (CDR).
9.10.2.2
Direct access to source data and documents
The physician / 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. Food and Drug Administration ( FDA)). The 
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
9.10.2.1.
9.10.3
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.

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9.10.4
Patient completion
The collection of the data per patients will continue until death or lost to follow-up, 
withdrawal of consent or until the required number of OS events has been reached.
At the earliest of the above criteria, the Patient Completion information should be completed
in the eCRF.
9.10.5
Completion of study
The end of the study will occur when the last patient has completed his/her follow-up visit
and/or the required number of OS events has occurred, whichever occurs first (see Section 
9.7.1). No further data will be collected afterwards.
The EC/ Competent Authority (CA) in each participating EU member state needs to be 
notified about the end of the study (last patient/patient out) or early termination of the study. 

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10.
PROTECTION OF HUMAN SUBJECTS
10.1
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 International Conference on Harmonisation 
(ICH) Harmonized Tripartite Guideline for GCP (to the extent applicable to the NIS setting 
and required by local regulations), Good Epidemiological Practice (GEP), Guidelines for 
Good Pharmacoepidemiology Practice (GPP), and relevant BI SOPs. Standard medical care 
(prophylactic, diagnostic and therapeutic procedures) remains in the responsibility of the 
treating physician of the patient.
The physician 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 physician and of the sponsor with regard to publication of the results of this 
study are described in the physician contract. As a general rule, no study results should be 
published prior to finalization of the Study Report.
10.1.1
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 IRBs/IECs and CA according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the study, written informed consent must be obtained from 
each patient (or the patient’s legally accepted representative) according to the regulatory and 
legal requirements of the participating country. Each signature must be personally dated by 
each signatory and the informed consent retained by the physician 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 BI in 
accordance with the local data protection law. The level of disclosure must also be explained 
to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CTM/CRA) or Clinical Quality Assurance auditors appointed by BI, by appropriate 
IRB / IEC members, and by inspectors from regulatory authorities.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
11.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable 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
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an AE is at least a reasonable possibility. Adverse reactions may arise from use 
of the product within or outside the terms of the marketing authorization or from occupational 
exposure. Conditions of use outside the marketing authorization 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 hospitalization, 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 judgement 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.
AE of Special Interest (AESI)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this 

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study, e.g. the potential for AEs based on knowledge from other compounds in the same 
class. 
No AESIs have been defined for this study.
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING
The physician 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 authorization. Sufficient data from controlled 
interventional studies 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.
- all ADRs (serious and non-serious)
- all AEs 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 physician carefully assesses whether an AE constitutes an ADR using the information 
below.
Causal relationship of AE
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an AE. An adverse reaction, in 
contrast to an AE, is characterized 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.

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).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).

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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; 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 AE
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
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 study medication, Vargatef® , the physician must report any 
drug exposure during pregnancy to the sponsor by means of Part A of the Pregnancy 
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 as well within the respective 
timelines. 
Expedited Reporting of AEs and Drug Exposure During Pregnancy
The following must be reported by the physician on the NIS AE form from signing the 
informed consent onwards until the end of the study: 

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Table 11.2: 1 Report types and timelines
Type of Report
Timeline
All Serious Adverse Drug Reactions
(SADRs) associated with the nintedanib
immediately within 24 hours
All AEs with fatal outcome in patients 
exposed to nintedanib
immediately within 24 hours
All non-serious ADRs associated with the 
nintedanib
7 calendar days
All pregnancy monitoring forms
7 calendar days
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions the physician could inform the sponsor upfront via telephone. 
This does not replace the requirement to complete and fax the NIS AE form.
Information required
For each reportable AE, the physician should provide the information requested on the 
appropriate (e) CRF pages and the NIS AE form.
Reporting of related AEs associated with any other BI drug
The physician is encouraged to report all AEs related to any BI drug other than the Vargatef®
according to the local regulatory requirements for spontaneous AE reporting at the 
physician’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.
11.3
TIME WINDOWS
Adverse event reporting to regulatory agencies will be done by the MAH according to local 
and international regulatory requirements.
11.4
DOCUMENTATION OF ADVERSE EVENTS AND PATIENT 
NARRATIVES
Expedited reporting of Serious Adverse Events (SAE), e.g. suspected unexpected serious 
adverse reactions (SUSARs) to health authorities and IRBs/IECs, will be done according to 
local regulatory requirements. Further details regarding this reporting procedure are provided 
in the ISF.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
BI intends to use data from this study to prepare peer-reviewed publications and other 
scientific communications such as abstracts, posters, and podiums presentations.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
P14-00479
Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, 
Pawel J von, Gottfried M, Bondarenko I, Liao M, Gann CN, Barrueco J, 
Gaschler-Markefski B, Novello S, LUME-Lung 1 Study Group
Docetaxel plus nintedanib versus docetaxel plus placebo in patients with 
previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, 
double-blind, randomised controlled trial.
Lancet Oncol 15 (2), 143 - 155 (2014)
R08-5110
Herbst RS, Heymach JV, Lippman SM
Lung cancer.N Engl J Med 359 (13), 1367 - 1380 (2008)
R09-0262
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford 
R,Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, 
Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1).Eur J Cancer 45, 228 -
247 (2009)
R11-0052
Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, 
Postmus PE, Rusch V, Sobin L, International Association for the Study of 
Lung Cancer International Staging Committee and Participating Institutions
The IASLC Lung Cancer Staging Project: Proposals for the Revision of the 
TNM Stage Groupings in the Forthcoming (Seventh) Edition of the TNM 
Classification of Malignant Tumours.
J Thorac Oncol 2 (8), 706 - 714 (2007)
R12-1150
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D
Global cancer statistics.CA 61 (2), 69 - 90 (2011)
R14-1926
Shedden K, et al
Gene expression-based survival prediction in lung adenocarcinoma: a multi-
site, blinded validation study: Director's Challenge Consortium for the 
Molecular Classification of Lung Adenocarcinoma.
Nature Med 14 (8), 822 - 827 (2008)
13.2
UNPUBLISHED REFERENCES
c01632700-18 Investigator`s Brochure: Nintedanib (BIBF 1120), Indication: Oncology
1199.P1/1199.P2/ 1199.P4/1199.P5/ 1199.P6/1199.P7/1199.P8//1199.P11, 
Version 14, 19-Jan-2015

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
None.

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS

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

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03352377
2.0
1199-223--protocol
A non-interventional biomarker study in patients with Non-Small Cell Lung Cancer
(NSCLC) of adenocarcinoma tumour histology eligible for treatment with Vargatef
according to the approved label
Approval-Clinical Trial Leader
10 May 2019 09:38 CEST
Approval-
 Safety Evaluation
Therapeutic Area
10 May 2019 10:37 CEST
Author-Trial Statistician
10 May 2019 11:08 CEST
Approval-Translational Medicine
Expert
10 May 2019 11:23 CEST
Approval-Team Member Medicine
10 May 2019 13:16 CEST
Approval-Therapeutic Area 
10 May 2019 17:09 CEST
Approval-
 of Global
Epidemiology
13 May 2019 16:55 CEST
Verification-Paper Signature
Completion
15 May 2019 08:29 CEST

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(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03352377
2.0