Real-world Data on Gi(l)Otrif® Dose Adjustment in First-line Treatment, TKI-naïve, Advanced Non-small Cell Lung Cancer Patients With EGFR Activating Mutations
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Boehringer Ingelheim

ABCD
TITLE PAGE
Protocol for non-interventional studies based on existing data
TITLE PAGE
Document Number:
c09038525-01
BI Study Number:
1200.270
BI Investigational
Product:
Gi(l)otrif®(afatinib)
Title:
RealGiDo: Real-world data on Gi(l)otrif® dose adjustment in 
first-line treatment, TKI-naïve, advanced non-small cell lung 
cancer patients with EGFR activating mutations
Brief lay title:
Real World Data on Gi(l)otrif® dose adjustment
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
01 March 2016
PASS:
No
EU PAS register 
number:
EU PAS register number not yet assigned as the study is not yet
registered in the EU PAS Register. The study will be registered
shortly before the start of data collection.
Active substance:
afatinib
Antineoplastic agents, tyrosine kinase inhibitors
ATC code: L01XE13
Medicinal product:
Gi(l)otrif® 50mg, 40mg, 30mg, 20mg tablet
Product reference:
20mg: EU/1/13/879/001, EU/1/13/879/002, EU/1/13/879/003
30mg: EU/1/13/879/004, EU/1/13/879/005, EU/1/13/879/006
40mg: EU/1/13/879/007, EU/1/13/879/008, EU/1/13/879/009
50mg: EU/1/13/879/010, EU/1/13/879/011, EU/1/13/879/012
Procedure number:
EMEA/H/C/002280
Joint PASS:
No
Research question and 
objectives:
Primary objective:
To assess the effects of Gi(l)otrif® dose modification on the 
frequency and severity of adverse drug reactions, time on 
treatment and time to progression with Gi(l)otrif® in real-world 
setting and compare with data from Lux-Lung 3 trial in a 
descriptive manner.
Secondary objective:
To obtain information on frequency and reasons for a modified 
starting dose of Gi(l)otrif® in real-world setting

Boehringer Ingelheim
Page 2 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Countries of study:
Austria, Canada, France, Germany, Italy, Japan, Korea, Mexico, 
Poland, Singapore, Spain, Taiwan, US
Author:
Phone: 
Fax: 
E-mail: 
Marketing authorisation 
holder:
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
Date:
01 March 2016
Page 1 of 38
Proprietary confidential information
© 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

Boehringer Ingelheim
Page 3 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
1.
TABLE OF CONTENTS
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........................................................................................................ 15
9.2.1
Selection of study population.................................................................. 15
9.2.2
Details of study procedures..................................................................... 16
9.3
VARIABLES .................................................................................................. 17
9.3.1
Exposures ................................................................................................ 17
9.3.2
Outcomes................................................................................................. 18
9.3.2.1
Primary outcomes................................................................................18
9.3.2.2
Secondary outcomes............................................................................18
9.3.2.3
Further outcomes ................................................................................18
9.3.3
Covariates................................................................................................ 18
9.4
DATA SOURCES........................................................................................... 18
9.5
STUDY SIZE.................................................................................................. 18
9.6
DATA MANAGEMENT................................................................................ 19
9.7
DATA ANALYSIS......................................................................................... 19
9.7.1
Main analysis........................................................................................... 19
....................................................................................... 20
9.8
QUALITY CONTROL................................................................................... 20
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 20
9.10
OTHER ASPECTS ......................................................................................... 21
9.10.1
Data quality assurance............................................................................. 21
9.10.2
Records.................................................................................................... 21
9.10.3
Statement of confidentiality .................................................................... 22

Boehringer Ingelheim
Page 4 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.10.4
Patient completion................................................................................... 22
9.10.5
Completion of study................................................................................ 22
9.10.6
Protocol Violations.................................................................................. 22
9.10.7
Compensation available to the patient in the event of study related injury22
9.11
SUBJECTS...................................................................................................... 22
9.11.1
Cases........................................................................................................ 23
9.11.2
Controls................................................................................................... 23
9.12
BIAS................................................................................................................ 23
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 24
10.1
INFORMED CONSENT, DATA PROTECTION, STUDY RECORDS....... 24
10.1.1 Study approval, patient information, and informed consent........................ 24
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
DRUG REACTIONS .......................................................................................... 26
11.1
Definitions of adverse events.......................................................................... 26
11.2
Adverse event and serious adverse event collection and reporting................. 27
11.3
Reporting to health Authorities....................................................................... 29
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS............................................................................................................ 30
13.
REFERENCES .................................................................................................... 31
13.1
PUBLISHED REFERENCES......................................................................... 31
13.2
UNPUBLISHED REFERENCES................................................................... 31
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 32
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS ................................. 33
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 38
ANNEX 3.1 ECOG PERFORMANCE STATUS...................................................... 38

Boehringer Ingelheim
Page 5 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
ASCO
American Society of Clinical Oncology
AUC
Area under the Curve
BI
Boehringer Ingelheim
CA
Competent Authority
CI
Confidence Interval
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRO
Clinical Research Organization
eCRF
Electronic Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
Del19
EGFR Exon 19 Deletion
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EGFR
Epidermal Growth Factor Receptor
EGFRm+
Epidermal Growth Factor Receptor Mutation Positive
ErbB
Erythroblastic Leukemia Viral Oncogene Homolog
EU
European Union
FDA
Food Drug Administration
GCP
Good Clinical Practice
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practice
HER2
Human Epidermal Growth Factor Receptor 2
HR
Hazard Ratio
ICH GCP
International Conference on Harmonisation guideline for Good 
Clinical Practice
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator Site File
L858R
L858R mutation at EGFR exon 21
LUX-Lung 3
BI Trial No.1200.32
MAH
Marketing Authorization Holder
NIS
Non-Interventional Study
NISed
Non-Interventional Study based on existing data
NSCLC
Non-Small Cell Lung Cancer
OPU
Operative Unit
OS
Overall Survival
PFS
Progression Free Survival
PK
Pharmacokinetics

Boehringer Ingelheim
Page 6 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
PRO
Patients Reported Outcome
RDC
Remote Data Capture
RWD
Real World Data
SADR
Serious Adverse Drug Reaction
SAE
Serious Adverse Event
SD
Standard Deviation
SDV
Source Data Verification
SEAP
Statistical and Epidemiological Analysis Plan
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
TCM
Trial Clinical Monitor
TKI
Tyrosine Kinase Inhibitor
TMF
Trial Master File

Boehringer Ingelheim
Page 7 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
3.
RESPONSIBLE PARTIES
Boehringer Ingelheim (BI) has appointed a Trial Clinical Monitor (TCM), 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,

Ensure appropriate training and information of Local Clinical Monitors (CMLs), 
Clinical Research Associate (CRAs), and investigators 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 CML 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.
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 investigators and other important participants,
especially their curricula vitae, will be filed in the TMF.
The coordinating investigator who will sign the report of this non-interventional study has
been appointed by BI. The coordinating investigator has experience in lung cancer studies.
Co-ordinating investigator:
Phone:

Boehringer Ingelheim
Page 8 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Gi(l)otrif®
Name of active ingredient:
afatinib
Antineoplastic agents, 
tyrosine kinase inhibitors
ATC code: L01XE13
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
01 March 2016
1200.270
1.0
Title of study:
RealGiDo: Real-world data on Gi(l)otrif® dose adjustment in first-line 
treatment, TKI-naïve, advanced non-small cell lung cancer patients 
with EGFR activating mutations
Rationale and 
background:
Post-hoc analyses from LUX-Lung 3 suggest that tolerability-guided 
dose adjustment of afatinib is an effective measure to reduce 
treatment-related AEs without affecting therapeutic efficacy.
The objective of this non-interventional study (NIS):
Real-World Data will help to understand if dose modifications are 
done similar as in LUX-Lung 3 trial and if the outcome on safety and 
effectiveness are as in trial settings. Furthermore, data on modified 
starting doses, the underlying reasons and effects on safety and 
outcome will be collected.
Research question 
and objectives:
Primary objective:
To assess the effects of Gi(l)otrif® dose modification on the frequency 
and severity of adverse drug reactions, time on treatment and time to 
progression with Gi(l)otrif® in real-world setting and compare with 
data from LUX-Lung 3 trial in a descriptive manner.
Secondary objective:
To obtain information on frequency and reasons for a modified starting 
dose of Gi(l)otrif® in real-world setting.
Study design:
Non-interventional, multi-country, multi-site study based on existing 
data from medical records of patients treated with Gi(l)otrif® as part of 
the routine treatment according to the approved label.
Population:
Sites in countries with launch dates prior to 1st Jan 2015 and known to 
prescribe Gi(l)otrif® on a regular basis will be chosen.
In/-Exclusion criteria:

Boehringer Ingelheim
Page 9 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
1.
EGFR mutated (common mutations), TKI-naïve advanced NSCLC 
treated with Gi(l)otrif® as the first-line treatment for NSCLC 
within the approved label will be included
2.
Patients treated within clinical trials are excluded
3.
Patients still on treatment with Gi(l)otrif® will be excluded unless 
treatment period is ≥ 6 months
Variables:
Primary outcomes:
Safety outcomes:
Percentage of subjects with adverse drug reactions by severity class
Effectiveness outcomes:
Time on treatment with Gi(l)otrif®
Time to progression with Gi(l)otrif®
Data sources:
NIS based on existing data from medical records of patients.
Study size:
At least 200 patients. ≥200 patients are planned based on feasibility 
aspects and assumptions.
Data analysis:
Safety data will be analysed in a descriptive manner. Incidence and 
severity of adverse drug reactions will be summarized and displayed. 
For patients who have dose modifications, frequency and severity of 
the most common AEs pre- and post-dose modification will be 
summarized and displayed.
For effectiveness analysis, both time on treatment and time to 
progression will be estimated using Kaplan-Meier method, and the 
median along with two-sided 95% CI will be displayed (use the 
Greenwood’s formula for estimation of standard errors). Log-rank test 
will be applied to compare between patients with and without dose 
modifications.
Milestones:
Start of data collection in May 2016
End of data collection in December 2016
Final report of study results expected in March 2017

Boehringer Ingelheim
Page 10 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
5.
AMENDMENTS AND UPDATES
Not applicable.

Boehringer Ingelheim
Page 11 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.
MILESTONES
Milestone
Planned Date
Registration in the
European Union (EU) Post-
Authorization Studies
(PAS) register
EU PAS register number not yet assigned as the study
is not yet registered in the EU PAS Register. The study
will be registered shortly before the start of data
collection.
Start of data collection
31 May 2016
End of data collection
31 Dec 2016
Final report of study results:
31 Mar 2017

Boehringer Ingelheim
Page 12 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.
RATIONALE AND BACKGROUND
The first marketing approval of afatinib was granted on 12 Jul 2013 in the USA (trade name 
Gilotrif®) for the indication of 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.
It was approved in the European Union on 25 Sep 2013 (trade name Giotrif®) as monotherapy
indicated for the treatment of EGFR TKI-naïve adult patients with locally advanced or
metastatic NSCLC with activating EGFR mutation(s).
The approval of Giotrif® was based on the results observed in the pivotal trial LUX-Lung 3
study. The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with 
afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling 
from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor 
receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against 
EGFR mutations. A total of 1,269 patients were screened, and 345 were randomly assigned to 
treatment (afatinib or chemotherapy). Median progression-free survival (PFS) was 11.1 
months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 
to 0.78; P.001). Median PFS among those with exon 19 deletions and L858R EGFR 
mutations (n308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 
95% CI, 0.34 to 0.65; P.001). The most common treatment related adverse events were 
diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for 
chemotherapy. Patients reported outcomes (PROs) favored afatinib, with better control of 
cough, dyspnea, and pain (P13-07382).
Afatinib 40 mg/day (oral) is approved for the treatment of patients with advanced EGFRm+ 
NSCLC. Dose adjustments are recommended based on pre-defined tolerability criteria. A 
post-hoc analyses of the effects of afatinib dose reduction on adverse events (AEs), 
pharmacokinetics (PK) and PFS in the phase III LUX-Lung 3 trial showed that dose 
reductions occurred in 53% (122/229) of patients; the majority (86%) within the first 6 
months of treatment. In patients who dose reduced, decreases in the incidences of drug-
related all grade (grade ≥3) AEs were 99.2% (20.5%) to 46.7% (4.1%) for diarrhea, 88.5% 
(26.2%) to 38.5% (3.3%) for rash/acne, 77.0% (12.3%) to 27.9% (0%) for stomatitis, and 
44.3% (16.4%) to 36.9% (4.9%) for nail effects. Dose reductions tended to be more common 
in female patients, older patients, patients of Eastern Asian ethnicity, and patients with lower 
body weight. Dose reduction was more likely in patients with higher plasma concentrations 
of afatinib. On Day 43, patients who dose reduced to 30 mg ≥4 days previously (n=38) had 
geometric mean plasma afatinib concentrations of 24.4 ng/mL, vs 23.7 ng/mL in patients who 
remained on the 40 mg dose (n=126). Median PFS was 11.3 months in patients who dose 
reduced during the first 6 months of treatment, vs 11.0 months in patients who did not 
(HR=1.25 [95% CI, 0.91–1.72]). [ASCO 2015, Yang et al, # 8073] (P15-05676).
Post-hoc analyses from LUX-Lung 3 suggest that tolerability-guided dose adjustment of 
afatinib is an effective measure to reduce treatment-related AEs without affecting therapeutic 
efficacy:

Boehringer Ingelheim
Page 13 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

The frequency and severity of treatment-related AEs was lower following dose 
reduction

Tolerability-guided dose modification reduced the inter-patient variability of afatinib 
exposure, while maintaining efficacious plasma levels

Efficacy outcomes were similar in patients who dose reduced due to AEs versus those 
who did not
This real-world data (RWD) study will help to understand if dose modifications are done 
similar as in LUX-Lung 3 trial and if the outcome on safety and effectiveness are as in trial 
settings.

Boehringer Ingelheim
Page 14 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
8.
RESEARCH QUESTION AND OBJECTIVES
Research objective:
Data from real-world will help to understand if dose modifications are done similar as in 
LUX-Lung 3 trial and if the outcome on safety and effectiveness are as in trial settings. 
Furthermore, data on modified starting doses, the underlying reasons and effects on safety 
and outcome are needed.
Primary objective:
To assess the effects of Gi(l)otrif® dose modification on the frequency and severity of 
adverse drug reactions (ADRs), time on treatment and time to progression with Gi(l)otrif® in 
real-world setting and compare with data from LUX-Lung 3 trial in a descriptive manner.
Secondary objective:
To obtain information on frequency and reasons for a modified starting dose of Gi(l)otrif® in 
real-world setting.

Boehringer Ingelheim
Page 15 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a non-interventional, multi-country, multi-site study based on existing data from 
medical records of patients treated with Gi(l)otrif® as part of the routine treatment according 
to the approved label.
Key study outcomes are:

Effects of Gi(l)otrif® dose reduction on frequency of ADRs, and time on treatment, 
time to progression

Proportion of patients starting with modified Gi(l)otrif® dose and the underlying 
reason(s) 
Data on diagnosis, gender, date of birth, ethnicity, body weight and height, Eastern 
Cooperative Oncology Group performance score (ECOG) (R14-0080), EGFR mutational 
subgroup (Del19/L858R), starting dose of Gi(l)otrif®, start date of Gi(l)otrif®  treatment, dose 
modifications with date, ADRs, concomitant medications (limited to medication for 
management of diarrhea, skin effects, mucositis/stomatitis as dichotomous variables (e.g. 
received anti-diarrhea medication yes/no), reason for dose modification of Gi(l)otrif®, 
treatment duration of Gi(l)otrif®, time to progression and type of progression (clinical, 
radiographic or both clinical/radiographic progression) will be collected from patients 
medical records by investigators.
9.2
SETTING
The NIS will be conducted in about 25-30 sites globally which are experienced in lung cancer 
treatment. An average of 8-10 patients per site (with a maximum of up to 15 patients per site)
is expected. 
Patient participation in this NIS is voluntary. Patients were treated and are treated according 
to the standard of care independent of patient’s consent to participate in this NIS.
9.2.1
Selection of study population
Site selection:
Sites in countries with launch dates prior to 1st Jan 2015 and known to prescribe Gi(l)otrif®
on a regular basis will be chosen. Asian and Non-Asian countries will be included.
Inclusion criteria:
All consecutive patients will be included if all the following criteria are present:

Age ≥18 years

Boehringer Ingelheim
Page 16 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Patients with EGFR mutation (common mutations), TKI-naïve advanced NSCLC, 
treated with Gi(l)otrif® as the first-line treatment for NSCLC within the approved 
label

Signed and dated written informed consent per regulations. (Exemption of a written 
informed consent for retrospective observational studies in some countries per local 
regulations and legal requirements.)
Exclusion criteria:
Patient won't be included if any of the following criteria is present:

Any contraindication to Gi(l)otrif® as specified in label.

Patients with uncommon mutations are excluded as uncommon mutations are not 
within label in all participating countries (e.g. USA).

Patients still on treatment with Gi(l)otrif® will be excluded unless treatment period is 
≥6 months.

Patients treated with Gi(l)otrif® within an interventional trial.
A log of all patients included into the study will be maintained in the ISF at the
investigational site.
Patients treated with Gi(l)otrif® in interventional trials are excluded to ensure the non-
interventional setting of this study. The threshold of ≥ 6 months treatment with Gi(l)otrif® for 
patients being still on treatment was chosen to avoid early censoring and enable collection of 
mature data on ADRs and treatment duration. However, patients who stopped Gi(l)otrif® < 6 
months will be included to avoid bias. All patients fulfilling inclusion and exclusion criteria 
from a site will be entered to avoid bias. The maximum of 15 patients per site was chosen to 
avoid bias by high proportion of patients coming from one site.
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. Violation of Good Clinical Practice (GCP) (as applicable), the Study Protocol, or the 
contract by a study site or investigator, disturbing the appropriate conduct of the 
study.
9.2.2
Details of study procedures
The study procedures will consist of:

Start of data collection:
Data of eligible and included patients will be collected after the site initiation visit
(site initiation visit will be done in a virtual meeting). Data source is from existing 
data from patients’ medical records.

End of data collection:

Boehringer Ingelheim
Page 17 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
After all data of eligible and included patients are collected, source data verification 
(SDV) will be completed and site close out visit will be performed. Sites will be 
visited once after data collection for SDV and closing visit.
9.3
VARIABLES
Data will be documented from the date of first dose of Gi(l)otrif® treatment until the date of 
last dose of Gi(l)otrif® treatment or end of data collection whichever occurs first.
During the data collection period, the following data will be collected from medical records
in an eCRF by investigators during the study:

Informed consent

Diagnosis

Demographics (gender, date of birth, ethnicity)

Body weight and height at start of Gi(l)otrif® treatment

ECOG performance score at start of Gi(l)otrif® treatment

EGFR mutational subgroup (Del19/L858R)

Starting dose of Gi(l)otrif®

Start date of Gi(l)otrif®treatment

End date of Gi(l)otrif®treatment

Gi(l)otrif® dose modification(s) and date(s)

ADRs

Concomitant medications (limited to medication for management of diarrhea, skin 
effects, mucositis/stomatitis as dichotomous variables (e.g. received anti-diarrhea 
medication yes/no))

Reason for dose modification(s)

Date of progression

Type of progression: 
a.
clinical
b. radiographic
c.
both clinical/radiographic progression
9.3.1
Exposures
Patients were/are treated with Gi(l)otrif® 50mg, 40mg, 30mg, 20mg tablet once daily as 
indicated in the approved labels of Gi(l)otrif®.
The recommended starting dose of Gi(l)otrif® is 40mg once daily. A modified starting dose of 
Gi(l)otrif® per objective would be considered as any other dose different than 40mg once 
daily.
The Summaries of Product Characteristics on Gi(l)otrif® is contained in the NIS ISF in the 
“Summary of Product Characteristics” section.

Boehringer Ingelheim
Page 18 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.3.2
Outcomes
9.3.2.1
Primary outcomes
Safety outcomes:

Percentage of subjects with adverse drug reactions (ADRs) by severity class
Effectiveness outcomes:

Time on treatment with Gi(l)otrif®

Time to progression with Gi(l)otrif®
9.3.2.2
Secondary outcomes

Percentage of subjects with a modified starting dose of Gi(l)otrif®

Reasons of modifying starting dose
9.3.2.3
Further outcomes
n.a
9.3.3
Covariates
n.a
9.4
DATA SOURCES
NIS based on existing data from patients’ medical records. Data will be collected in the 
eCRF. SDV will be performed on about 30% of included patients.
9.5
STUDY SIZE
The post-hoc analysis of LUX-Lung 3 providing the rationale for this study was based on 229 
patients with 53% patients experiencing dose reduction. With a sample size of 200 we would 
be in the same range as in the LUX-Lung 3 analysis which provided robust data. It will be 
sufficient to analyse the effects of dose modification on patients’ safety and effectiveness and
to compare it with data from LUX-Lung 3 trial descriptively.
Based on feedback from physicians we expect 25-30% patients starting with a lower dose.
There will be around 50 patients starting with a modified dose, and around half of them with 
further de-/-escalation. This is a sufficient sample size to get some impression on the reasons 
of a modified starting dose in real-world setting.

Boehringer Ingelheim
Page 19 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.6
DATA MANAGEMENT
Patients’ data will be gathered in Remote Data Capture (RDC) system.
The data management procedures to ensure the quality of the data will be described in detail 
in the Statistical and Epidemiological Analysis Plan (SEAP) available in TMF.
9.7
DATA ANALYSIS
9.7.1
Main analysis
All collected data will be analysed separately for patients starting with 40mg and ≤ 30mg. 
Although due to anticipated low sample size in patients starting with ≤30mg, it will be 
mainly for exploratory purpose. Baseline demographics will be analysed with descriptive 
statistics (N, median, mean, 25%, 75% percentile, SD) and compared descriptively between 
patients who have dose modifications within the first 6 months of Gi(l)otrif® treatment and 
those who do not. All the demographics, safety and efficacy data from this study in real-
world setting will be compared with data from LUX-Lung 3 trial in descriptive manner.
Analysis of Safety:
Safety analysis will include all patients treated with Gi(l)otrif® and be descriptive in nature. 
Incidence and severity of ADRs according to Common Terminology Criteria for Adverse 
Events (CTCAE) criteria (version 4.0) (R15-5988) when available will be summarized and 
displayed in number/percentage. For patients who had Gi(l)otrif® dose modifications within 
the first 6 months of Gi(l)otrif® treatment, frequency and severity of the common ADRs pre-
and post-dose modification will be analysed (≥ 40mg vs < 40mg; and ≥ 30mg vs < 30mg).
Missing or incomplete ADR dates will be imputed according to BI internal SOPs.
Analysis of Effectiveness:
Effectiveness analysis will include all patients treated with Gi(l)otrif®. Time on treatment is 
from the date of first dose of Gi(l)otrif® treatment to the date of last dose of Gi(l)otrif®
treatment. Time to progression is from the date of first dose of Gi(l)otrif® treatment to the 
earliest date of documented progression (clinical, radiographic or both clinical/radiographic 
progression) or death. Time on treatment and time to progression will be estimated using 
Kaplan-Meier method, and the median along with two-sided 95% CI will be displayed (use 
the Greenwood’s formula for estimation of standard errors). Log-rank test will be applied to 
compare between patients with and without dose modifications. Time on treatment and time 
to progression will be compared between patients who dose reduced to < 40 mg within the 
first 6 months of Gi(l)otrif® treatment and those who remained on Gi(l)otrif® 40 mg once 
daily. This is in analogy to the analysis made on LUX-Lung 3 where a cut-off of 6 months 
was used as most dose reductions occur during this time.
In the analyses of the two time-to-event endpoints, missing or incomplete data are managed 
by standard survival analysis techniques. For patients still on treatment, time on treatment 
will be censored at the date of data collection. For patients still on treatment and without 
progression, time to progression will be censored at the date of data collection. For patients 
stopped treatment and without progression/death or progression/death date missing, time to 

Boehringer Ingelheim
Page 20 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
progression will be censored on the last contact date.
9.8
QUALITY CONTROL
All entries in the eCRF 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-size based 
source data verification 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
The generalization and consequently the external validity of the study results, may be limited 
by the participation in the study of only sites that prescribe Gi(l)otrif® on a regular basis to 
ensure sufficient patient recruitment. Patients treated by investigators with less experience 
might experience more side effects during their treatment with Gi(l)otrif®.
Methodological efforts have been taken to minimize selection bias: these efforts include the 
recommendation to include consecutive patients meeting each of the inclusion criteria and 
none of the exclusion criteria. In addition, this possible selection bias may be limited by the 
retrospective aspect of the data collection, data that have been already collected at the time of 
the study. Linked to this aspect is then the limitation due to data availability. Indeed, no 
additional data will be collected for the study purpose. So if the data is not available in the 
patient files, then this will be considered as missing data.
In addition, to reduce error in data collection, a standard study eCRF will be used, ensuring a 
measure of consistency among the collectors.
Another limitation is coming from the diverse handling of data collection from deceased 
patients which is allowed without informed consent in some countries but not in all. 
However, no country-based analyses will be done. Given the median overall survival (31.6 
months in LUX-Lung 3) and that time from launch of Gi(l)otrif to data collection in the 
participating countries is shorter than the median overall survival (OS) the majority of the 
patients are expected to be alive.

Boehringer Ingelheim
Page 21 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
External validity is provided by the global approach of this study and the broad inclusion 
criteria but limited to patients treated within the label and at the selected, experienced sites. 
Internal validity will be given by source data verification.
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 investigator’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 RDC system.
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 investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent
with the source documents or the discrepancies must be explained.
The investigator may need to request previous medical records or transfer records, current 
medical records must be available.
9.10.2.2      Direct access to source data and documents
The investigator / institution will permit study-related monitoring, audits, Institutional 
Review Board (IRB) / Independent Ethics Committee (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.
9.10.2.3      Storage of records
Study Site: The site must retain the source documents and essential documents for a period 
defined by regulations and the site’s contract with the sponsor.
Sponsor: The sponsor must retain the essential documents according to the sponsor’s SOP.

Boehringer Ingelheim
Page 22 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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.
Data generated as a result of the study need to be available for inspection on request by the 
participating investigators, the sponsor’s representatives, by the IRB / IEC and the regulatory 
authorities.
9.10.4
Patient completion
The collection of the data of patients will continue until end of data collection or withdrawal 
of consent which occurs first.
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 end of data collection of the last patient’s data. No 
further data will be collected afterwards.
When the study is completed, the investigator should inform the head of the study site of the 
completion in writing, and the head of study site should prompt inform IRB and sponsor of 
the completion in writing (For Japan).
The EC/Competent Authority (CA) in each participating country, as required, needs to be
notified about the end of the study or early termination of the study.
9.10.6
Protocol Violations
There are no protocol waivers. All protocol violations must be reported to the sponsor
immediately.
9.10.7
Compensation available to the patient in the event of study related injury
In the event of health injury associated with marketed product in routine medical practice, the
sponsor is not responsible for compensation.
9.11
SUBJECTS
Please refer to Section 9.2.1 (Selection of study population).

Boehringer Ingelheim
Page 23 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.11.1
Cases
n.a
9.11.2
Controls
n.a
9.12
BIAS
Methodological efforts have been taken to minimize selection bias: these efforts include the 
recommendation to include consecutive patients meeting each of the inclusion criteria and 
none of the exclusion criteria. In addition, this possible selection bias may be limited by the 
retrospective aspect of the data collection, data that have been already collected at the time of 
the study.

Boehringer Ingelheim
Page 24 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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 investigator 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 and Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997).
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in the investigator contract. As a general rule, no trial results should be 
published prior to finalisation of the 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 IRB / IEC and competent authority (CA) according to national 
and international regulations. The same applies for the implementation of changes introduced 
by amendments.
In some countries, retrospective observational studies can be exempt from a written informed 
consent per local regulations and legal requirements, IRB / IEC often grants a waiver of 
consent for retrospective chart review studies. In order to avoid bias by exclusion of subjects 
that cannot be given informed consent for any reason like death, missing contact information 
etc., exempt from a written informed consent should be asked for such situations.
In case such a waiver is not given, prior to patient participation in the study, written informed 
consent must be obtained from each patient (or the patient’s legally accepted representative) 
according to ICH GCP and to the regulatory and legal requirements of the participating 
country.
Each signature must be personally dated by each signatory and the informed consent and any 
additional patient-information form retained by the investigator as part of the trial records. A 
signed copy of the informed consent and any additional patient information must be given to 
each patient or the patient’s legally accepted representative.

Boehringer Ingelheim
Page 25 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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.

Boehringer Ingelheim
Page 26 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE DRUG REACTIONS
11.1
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 AE 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
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 authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) 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 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 hospitalization but might jeopardize 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 hospitalization or
development of dependency or abuse. Any suspected transmission via a medicinal product of
an infectious agent is also considered a serious adverse reaction.
For Japan, an AE which possibly leads to disability will be reported as an SAE.
Adverse Event of Special Interest (AESI)

Boehringer Ingelheim
Page 27 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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 
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 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 authorization. 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

for Japan:  an AE which possibly leads to disability will be reported as an SAE
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 AEs
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 (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

Boehringer Ingelheim
Page 28 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

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).
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 AEs
The intensity of adverse events should be classified and recorded according to the CTCAE 
criteria (version 4.0) (R15-5988) in the eCRF.
Pregnancy
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the 
study, after having taken Gi(l)otrif® the investigator must report any drug exposure during
pregnancy, which occurred in a female subject or in a partner to a male subject 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.
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B).
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 investigator on the NIS AE form from signing the
informed consent onwards until the end of the study:
Type of Report
Timeline

Boehringer Ingelheim
Page 29 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
All Serious Adverse Drug Reactions
(SADRs) associated with Gi(l)otrif®
immediately within 24 hours
All AEs with fatal outcome in patients
exposed to Gi(l)otrif®
immediately within 24 hours
For Japan:  AE which possibly leads to 
disability in patients exposed to Gi(l)otrif®
immediately within 24 hours
All non-serious ADRs associated with 
Gi(l)otrif®
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 investigator should provide the information requested on the
appropriate eCRF pages and the NIS AE form.
Reporting of related AEs associated with any other BI drug
The investigator is encouraged to report all AEs related to any BI drug other than Gi(l)otrif®
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.
11.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to local 
and international regulatory requirements. 
Expedited reporting of serious adverse events (SAE), e.g. suspected unexpected serious 
adverse reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to 
local regulatory requirements. Further details regarding this reporting procedure are provided 
in the ISF.

Boehringer Ingelheim
Page 30 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
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 Study Report.
BI intends to use data from this study to prepare peer-reviewed publications and other
scientific communications such as abstracts, posters, and podiums presentations.

Boehringer Ingelheim
Page 31 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
13.
REFERENCES
13.1
PUBLISHED REFERENCES
P13-07382
Sequist LV, Yang JCH, Yamamoto N, O'Byrne K, Hirsh V, Mok T, 
Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, 
Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, 
Schuler M
Phase III study of afatinib or cisplatin plus pemetrexed in patients with 
metastatic lung adenocarcinoma with EGFR mutations.
J Clin Oncol 31 (27), 3327 - 3334 (2013)
P15-05676
Yang JCH, Ahn MJ, Dickgreber NJ, Halmos B, Hirsh V, Hochmair MJ, 
Levy BP, Marinis F de, Mok T, O'Byrne K, Okamoto I, Schuler MH, 
Sebastian M, Shah RNH, Tan EH, Yamamoto N, Marten A, Massey D, 
Wind S, Carbone DP; 
Influence of dose adjustment on afatinib safety and efficacy in patients 
with advanced EGFR mutation-positive (EGFRm+) non-small cell lung 
cancer (NSCLC).
51st Annual Meeting of the American Society of Clinical Oncology 
(ASCO), Chicago, 29 May - 2 Jun 2015
J Clin Oncol 33 (15) (Suppl), Abstr 8073 (2015)
R14-0080
Eastern Cooperative Oncology Group (ECOG)
ECOG performance status (revised: July 27, 2006).
http://ecog.dfci.harvard.edu/general/perf_stat.html (access date: 7 January 
2014); Eastern Cooperative Oncology Group (ECOG) (2006)
R15-5988
Common terminology criteria for adverse events (CTCAE): version4.0 
(NIH publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 
2010), revised June 2010, reprinted June 2010, 5x7, 196 pages).
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf (access date: 30 November 2015) (2010)
 
 

Boehringer Ingelheim
Page 32 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
The stand-alone documents for this non-interventional study are:

Informed Consent Form

Statistical and Epidemiological Analysis Plan (SEAP)
The above documents will be archived in the Trial Master File in their original English 
master version.

Boehringer Ingelheim
Page 33 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS

Boehringer Ingelheim
Page 34 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 35 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 36 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 37 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 38 of 38
Protocol for non-interventional studies based on existing data
BI Study Number 1200.270
c09038525-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours
4
Completely disabled, cannot carry on any self-care, totally confined to bed 
or chair
5
Dead

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number:  
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09038525
1.0
clinical-trial-protocol
1200.270 clinical trial protocol
Approval-Trial Clinical Monitor
01 Mar 2016 15:53 CET
Approval-
Safety Evaluation
Therapeutic Area
01 Mar 2016 16:00 CET
Approval-Therapeutic Area
01 Mar 2016 16:06 CET
Approval-Team Member Medicine
02 Mar 2016 09:30 CET
Approval-On behalf of 
 or 
or 
02 Mar 2016 16:15 CET
Approval-Other
02 Mar 2016 19:09 CET
Verification-Paper Signature
Completion
03 Mar 2016 15:26 CET

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09038525
1.0