Conditions: Carcinoma, Non-Small-Cell Lung ErbB Receptors
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 25
Healthy volunteers: no

Brief summary:
Continuous treatment until progression or occurence of intolerable Adverse Event (AE) or end of trial. The end of trial is one year after the last patient has entered the study.

Detailed description:

Arms:
arm 1: afatinib starting at 30 mg daily dose

Interventions: intervention 1: Afatinib
Intervention descriptions: intervention 1: afatinib starting at 30 mg daily dose

Protocol document:
Prot_000.pdf: 
Clinical Trial Protocol
Doc. No.: c02364424-03
BI Trial No.:
1200.209
BI Investigational
Product:
Giotrif®/ Gilotrif® (Afatinib)
Title:
A Single Arm Phase IV Study of Afatinib in Elderly Patients with recurrent or 
Stage IV Non-Small Cell Lung Cancer (NSCLC) Whose Tumors Have Common
Epidermal Growth Factor Receptor (EGFR) mutations (Exon 19 Deletions or 
Exon 21 L858R Substitution Mutations)
Clinical Phase:
IV
Trial Clinical 
Monitor:
Tel:       
Mobile: 
                                                                                         
Fax:      
Co-ordinating 
Investigator:
                                                                                         
Tel:    
                                                                                                  
Fax:    
                     
                                       
Status:
Final Protocol (Revised Protocol (based on global amendment 2))
   Version and Date:
Version: 3.0            
Date: 15 February 2018
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TITLE PAGE


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product: Giotrif®/ Gilotrif®
(Afatinib)
Name of active ingredient: Giotrif®/ Gilotrif® 
(Afatinib)
Protocol date:
Trial number:
Revision date:
15FEB2018
20 MAR 2015
1200.209
Title of trial:
A Single Arm Phase IV Study of Afatinib in Elderly Patients with recurrent or Stage 
IV Non-Small Cell Lung Cancer (NSCLC) Whose Tumors Have Common  
Epidermal Growth Factor Receptor (EGFR) mutations (Exon 19 Deletions or Exon 
21 L858R Substitution Mutations).
Co-ordinating 
Investigator:
                                                                                              
Tel:     
                                                                                                       
Fax:    
                      
Trial sites:
Multi-center trial in the US
Clinical phase:
IV
Objective:
The objective of this study is to describe the occurrence of AEs leading to dose 
reduction following afatinib treatment in NSCLC patients with common EGFR 
mutations (Deletion 19 and/or L858R) who are 70 years of age or older. 
Methodology:
Open-label, non-randomized, Phase IV, single arm study
No. of patients: 
total entered:
Approximately 25
each treatment:
Approximately 25
Diagnosis :
Recurrent or Stage IV Non-Small Cell Lung Cancer (includes cytologically proven 
pleural effusion or pericardial effusion) harbouring EGFR del 19 or L858R mutation.
Main criteria
for inclusion:

Pathologically confirmed diagnosis of recurrent or stage IV NSCLC (includes 
cytologically proven pleural effusion or pericardial effusion) not amenable for 
curative intent local radiotherapy. Staging is based on AJCC Staging for 
NSCLC 7th Edition

Documented EGFR mutations (deletion 19 and/or L858R substitution)

Age ≥ 70  years

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

No prior systemic therapy for metastatic or recurrent NSCLC


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product: Giotrif®/ Gilotrif®
(Afatinib)
Name of active ingredient: Giotrif®/ Gilotrif® 
(Afatinib)
Protocol date:
Trial number:
Revision date:
15FEB2018
20 MAR 2015
1200.209
Test product:
Giotrif®/ Gilotrif® (Afatinib)
dose:
Starting dose 30 mg per day
mode of admin.:
Orally, once daily
Comparator products:
Not Applicable
dose:
Not Applicable
mode of admin.:
Not Applicable
Duration of treatment:
Continuous treatment until progression or occurrence of intolerable AE or end of trial
Criteria for efficacy:
Endpoints: 
Primary and secondary endpoints are safety endpoints
 
Criteria for safety:
Primary endpoint: 
Occurrence of AEs leading to dose reduction of afatinib
Secondary endpoints: 
Occurrence of CTCAE grade 3 or higher diarrhoea, rash/acne+, stomatitis+ and 
paronychia+ (+ represents grouped term)
Adverse events; time to first dose reduction of afatinib caused by AEs.
Other endpoints (safety):
Adverse events will be evaluated according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Statistical methods:
Descriptive statistics


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FLOW CHART
Study Period
Scree
ning
(a)
Treatment Courses (b)
EOT
(c)
FU (d)
VS (r)
SCR
Course 1
Course 2
Course 
3 
onwards
Visits (V)
1
2
3
1
2
1
EOT
FU
VS
Days
-28 to -
1
1
8
15
1
15
1
≤7 
days 
of last 
Tx
28 +7 
days 
after last 
Tx
Q3mths
Maximum Visit window 
(in days)
0
0
±2
±2
-3, 
+2
±2
-3, +2
90±14 
days
Informed consent (e)
X
X
Demographics
X
Medical history/ 
Documentation of EGFR 
mutation
X
Inclusion/Exclusion
X
Height
X
Weight
X
X
12 Lead Digital ECG 
(f)
X
Physical exam (g)
X
X
X
X
X
Vital signs (h)
X
X
X
X
X
X
X
X
ECOG Performance 
Status
X
X
X
X
X
X
X
Safety lab: CBC, serum 
chemistries (i,j)
X
X
X
X
X
X
X
Safety lab: INR, aPTT (j)
X
X
Safety lab: urinalysis
(j,k)
X
X
 
Dispense medication 
X
X
X
Interactive Response 
Technologies call/ 
notification (m)
X
X
X
X
X
Administration of 
afatinib
Continuous
Compliance  check
X
X
X
X
X
X
Adverse event (n)
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X (o)
 
Termination of trial 
medication 
X
Conclusion of
study participation
X
Vital Status (r)
X


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a 
Screening: the screening visit should be performed within 28 days of the first dose of  afatinib. Safety lab at the 
screening assessment can serve as the Day 1 pre-treatment assessment of Course 1 if performed within 72 hours 
before the first treatment and does not need to be repeated  
b
Treatment courses: all courses are 4 weeks in duration (28 days). During the treatment period, clinical assessments 
and safety laboratory tests must be performed prior to study drug administration on the visit day. All subsequent 
visit dates should be calculated based on Course 1 Visit 1 date. One or more visits can be skipped in case of 
treatment interruption. Patients may continue on treatment until the criteria for stopping medication are met (see 
Section 3.3.4). 
c
EOT: if the decision to permanently discontinue afatinib treatment is taken during a scheduled visit, the End Of 
Treatment (EOT) visit should be performed instead of the scheduled visit ( or within 7 calendar days after last drug 
administration)
d
FU: all patients should have a follow-up (FU) visit 28+7 days after the permanent discontinuation of afatinib
e
Written informed consent must be obtained before any protocol specific screening assessment is performed
f
A 12-lead resting digital electrocardiogram (ECG) will be performed at Screening and reviewed by the 
investigator. Refer to Section 5.2.4 for details
g
Physical exam: includes a thorough cardiopulmonary, abdominal and regional lymph node exam and an 
assessment of the mental and neurological status. No need to repeat the physical exam on C1V1D1 if within three 
calendar days of the screening physical exam and the patient is deemed stable by the investigator
h
Vital signs: includes respiratory rate, pulse, temperature and blood pressure
i
Safety lab: CBC: include white blood cell count, neutrophil and bands, differential, hemoglobin, hematocrit and 
platelet count. Serum chemistries: include sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, 
AST, ALT, GGT, total bilirubin, alkaline phosphatase, calcium, magnesium. See Section 5.2.3
j
Additional laboratory assessments should be performed if clinically indicated 
k
Urine analysis: include pH, protein, glucose, ketones, blood, leucocytes, nitrite, bilirubin, urobilinogen, and 
specific gravity.  In case of pathological finding, further evaluation should be performed and results documented in 
the source document  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
m
Interactive Response Technologies (IRT): patient’s screening, all drug dispensation visits and EOT will be 
collected in the IRT system 
n
Adverse event: from 28 days after last trial drug administration new AEs will only be collected, documented and 
reported if they are considered related to trial drug 
o
Concomitant therapy: during FU concomitant therapy only needs to be recorded if  indicated for the treatment of 
an AE
           
 
 
 
 


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.
r
For patients that consent to be followed, vital status will be collected every 3 months until the end of the trial. 


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................7
ABBREVIATIONS.......................................................................................... 11
1.
INTRODUCTION.................................................................................... 13
1.1
MEDICAL BACKGROUND............................................................................13
1.2
DRUG PROFILE...............................................................................................14
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 17
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................17
2.2
TRIAL OBJECTIVES.......................................................................................18
2.3
BENEFIT - RISK ASSESSMENT ...................................................................18
3.      DESCRIPTION OF DESIGN AND TRIAL POPULATION ............ 20
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................20
3.1.1
Administrative structure of the trial...................................................20
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................21
3.3
SELECTION OF TRIAL POPULATION ......................................................21
3.3.1
Main diagnosis for study entry............................................................21
3.3.2
Inclusion criteria...................................................................................21
3.3.3
Exclusion criteria ..................................................................................22
3.3.4
Removal of patients from therapy or assessments.............................23
3.3.4.1
Removal of individual patients................................................23
3.3.4.2
Discontinuation of the trial by the sponsor..............................24
4.
TREATMENTS........................................................................................ 25
4.1
TREATMENTS TO BE ADMINISTERED....................................................25
4.1.1
Identity of BI investigational product and comparator product......25
4.1.2
Method of assigning patients to treatment groups ............................25
4.1.3
Selection of doses in the trial................................................................25
4.1.4
Drug assignment and administration of doses for each patient .......25
4.1.5
Blinding and procedures for unblinding ............................................26
4.1.5.1
Blinding....................................................................................26
4.1.5.2
Procedures for emergency unblinding .....................................26
4.1.6
Packaging, labelling, and re-supply ....................................................26
4.1.7
Storage conditions.................................................................................27
4.1.8
Drug accountability ..............................................................................27


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................28
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................28
4.2.1.1
Rescue medication ...................................................................28
4.2.1.2
Emergency procedures.............................................................28
4.2.1.3
Additional treatments...............................................................28
4.2.2
Restrictions............................................................................................29
4.2.2.1
Restrictions regarding concomitant treatment .........................29
4.2.2.2
Restrictions on diet and life style.............................................29
4.2.2.3
Men capable of fathering a child and pregnancy prevention...29
4.3
TREATMENT COMPLIANCE.......................................................................30
4.4
MANAGEMENT OF DOSE REDUCTION AND EXPECTED ADVERSE 
EVENTS..............................................................................................................30
4.4.1
Management of dose reduction for afatinib .......................................30
4.4.2
Management of expected adverse events............................................31
4.4.2.1 Management of diarrhoea and hydration status following 
treatment with afatinib.............................................................31
4.4.2.2 Management recommendations for dermatological AEs 
following treatment with afatinib.............................................32
4.4.2.3
Management of mucositis/stomatitis .......................................35
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 36
5.2
SAFETY..............................................................................................................37
5.2.1
Endpoints of safety................................................................................37
5.2.2
Assessment of adverse events...............................................................37
5.2.2.1
Definitions of adverse events...................................................37
5.2.2.2
Adverse event and serious adverse event reporting.................39
5.2.3
Assessment of safety laboratory parameters......................................41
5.2.4
Electrocardiogram................................................................................42
5.2.5
Assessment of other safety parameters...............................................42
5.2.5.1 Physical examination, vital signs, height and weight.................42
5.2.5.2 Vital Signs..................................................................................42
    
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................44


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6.
INVESTIGATIONAL PLAN.................................................................. 45
6.1
VISIT SCHEDULE............................................................................................45
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................45
6.2.1
Screening period....................................................................................45
6.2.2
Treatment periods.................................................................................45
6.2.3
End of treatment visit...........................................................................45
6.2.4
Follow-up visit.......................................................................................46
6.2.5 
Vital Status ...........................................................................................46
6.3
END OF TRIAL.................................................................................................46
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 47
7.1
STATISTICAL DESIGN – MODEL ...............................................................47
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................47
7.3
PLANNED ANALYSES....................................................................................47
7.3.1
Primary analyses...................................................................................47
7.3.2
Secondary and other analyses..............................................................47
7.3.2.1 Secondary analyses ....................................................................47
7.3.3
Safety analyses.......................................................................................48
7.3.3.1
Primary analysis.......................................................................48
7.3.3.2
Secondary analyses ..................................................................49
7.3.3.3
Other analyses..........................................................................49
7.3.3.4
Primary laboratory tests ...........................................................50
7.3.4
Interim analyses ....................................................................................50
7.4
HANDLING OF MISSING DATA ..................................................................50
7.5
RANDOMISATION ..........................................................................................50
7.6
DETERMINATION OF SAMPLE SIZE ........................................................50
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 52
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................52
8.2
DATA QUALITY ASSURANCE .....................................................................52
8.3
RECORDS..........................................................................................................53
8.3.1
Source documents .................................................................................53
8.3.2
Direct access to source data and documents.......................................53
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................53
8.4.1
Listedness...............................................................................................53
8.4.2
Expedited reporting to health authorities and IECs/IRBs................53
8.5
STATEMENT OF CONFIDENTIALITY.......................................................54
9.
REFERENCES......................................................................................... 55


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9.1
PUBLISHED REFERENCES...........................................................................55
9.2
UNPUBLISHED REFERENCES.....................................................................58
11. DESCRIPTION OF GLOBAL AMENDMENTS................................. 83


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ABBREVIATIONS
AE
Adverse Event
AUC
Area under the Curve
CI
Confidence Interval
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
DILI
Drug Induced Liver Injury
eCRF
Electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EGFR
Epidermal Growth Factor Receptors
EOT
EudraCT
End of Treatment
European Clinical Trials Database
GCP
Good Clinical Practice
HR
Hazard Ratio
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IRB
ILD
Institutional Review Board
Interstitial Lung Disease
ISF
Investigator Site File
i.v.
intravenous
MedDRA
Medical Dictionary for Drug Regulatory Activities
MTD
NSCLC
NYHA
Maximum Tolerated Dose
Non-Small Cell Lung Cancer
New York Heart Association
OPU
Operative Unit
QoL
RDC
REP
Quality of Life
Remote Data Capture
Residual Effect Period
SAE
SCR
SMQ
Serious Adverse Event
Screening
Standardised MedDRA Query


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SOC
SRS
TCM
System Organ Class
Stereotactic Radio Surgery
Trial Clinical Monitor
TKI
TMF
TSAP
TX
ULN
Tyrosine Kinase Inhibitors
Trial Master File
Trial Statistical Analysis Plan
Treatment
Upper Limit of Normal
VS
Vital Status


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer-related deaths in many 
countries, including the US. The prognosis for advanced stage disease has improved modestly 
in the past 20 years. With an overall 5-year survival rate of only 15% the treatment of this 
disease clearly remains a major clinical challenge (R05-0867).
While systemic chemotherapy has demonstrated modest activity in advanced NSCLC, novel 
targeted therapies based on specific molecular and biological characteristics of lung cancer 
have emerged as a new treatment paradigm. Among the molecules most extensively studied 
are the Epidermal Growth Factor Receptors (EGFR) or the Subclass I of the superfamily of 
transmembrane tyrosine kinase receptors (R06-1301, R06-1302).
Aberrant activation of EGFR frequently observed in a variety of malignant tumors can be 
induced by different molecular mechanisms including receptor overexpression, mutation, 
ligand-dependent receptor dimerization, and ligand-independent activation. Overexpression 
of EGFR has been detected in 40% to 80% of NSCLC patients (R06-1301, R06-1393, R06-
1394). However, recent clinical experiences with specific EGFR-Tyrosine Kinase Inhibitors 
(TKI) have demonstrated tumor regression in only 10% to 15% of unselected NSCLC 
patients (R05-0867, R06-1301, R06-1306). The treatment with EGFR TKIs is associated with
higher Response Rate (RR) in patients with tumors which harbor EGFR mutations.  In a 
recent meta-analysis based on 13 randomized trials, the response rate was 70% vs. 33.2% in 
first-line trials. In three second-line trials, response rates were 47.4% vs. 28.5%, with a 
benefit similar to first-line trials (Relative Risk, 1.79; p = .04) (R12-4000).  Somatic 
mutations between exons 18 through 21 of the EGFR gene was found to occur in 
approximately 10% of NSCLC patients from the US, Europe or Australia compared to up to 
30% in patients from Japan and Taiwan (R06-1262, R06-1306, R06-1393). The most 
common EGFR mutations are a short, in-frame deletion in exon 19 (E19del [LREA deletion] 
found in approximately 46% of patients) and a point mutation (CTG to CGG) that results in a 
substitution of leucine by arginine at codon 858 of exon 21 ([L858R] found in 37.5% of 
patients) (R14-2119).
Two large multinational randomized Phase III studies of afatinib in the first line treatment of 
mutation positive stage IV NSCLC patients have been performed: the LUX-Lung 3 (1200.32) 
and LUX-Lung 6 (1200.34) studies. 
LUX-Lung 3 compared first line afatinib to up to six cycles of cisplatin /pemetrexed (N=345 
with 2:1 randomization). Adult patients with performance status (PS) 0-1 were included in 
the trial without age limitation. Seventy-two percent (72%) of all trial patients were Asian 
with the remainder classified as non-Asian. In this trial patients treated with afatinib 
demonstrated significant and clinically meaningful improvements in progression free survival 
(PFS, median PFS afatinib vs. cisplatin/pemetrexed 11.1 vs. 6.9 months, hazard ratio 0.58; 
95% CI, 0.43 to 0.78; P=.001) and Objective Response Rate (ORR, afatinib vs cisplatin 
/pemetrexed 56% vs. 23%; P= .001).  This was accompanied by significant delays in time to 
deterioration of the cancer-related symptoms of cough (afatinib /cisplatin pemetrexed, Hazard 


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Ratio, HR, 0.60; 95% CI, 0.41 to 0.87; P = .007) and dyspnea (HR, 0.68; 95% CI, 0.50 to 
0.93; P =.01). A pre-planned analysis of PFS in patients (n=308) with exon del 19 or L858R 
mutation was 13.6 months for afatinib and 6.9 months for chemotherapy (HR 0.47; 95% CI: 
0.34 to 0.65; P=0.001). Higher response rates were observed in afatinib groups compared 
with chemotherapy 69% and 44%, respectively (P13-07382 ).
LUX-Lung 6 compared first line afatinib to up to six cycles of cisplatin/gemcitabine (N=364 
with 2:1 randomization afatinib: cisplatin/gemcitabine). All patients were Asian. As in LUX-
Lung 3, patients with performance status 0-1 were included in the trial without age limitation. 
Patients treated with afatinib demonstrated significant improvements in progression free 
survival (median PFS afatinib vs. cisplatin/gemcitabine 11.0 months vs. 5.6 months, hazard 
ratio 0.28; 95% CI 0.20 to 0.39; P<0.0001) and ORR (afatinib vs. cisplatin/gemcitabine 
66.9% vs. 23.0 %, P <0 .0001).  This was accompanied by significant delays in time to 
deterioration of the cancer-related symptoms of cough (afatinib vs. cisplatin/gemcitabine HR
0.45, 95% CI, 0.30 to 0.68; P = .0001) and dyspnea (HR 0.54; 95% CI, 0.40 to 0.73; P< 
0.0001) [P14-00758]
In a separate single arm study (LUX-Lung 2) [P12-03681] in lung adenocarcinoma patients 
(stage IIIb with pleural effusion or stage IV) with EGFR mutations, 129 patients were treated 
in first-line or second-line with afatinib, 99 with a starting dose of 50 mg and 30 with a 
starting dose of 40 mg. 79 (61%) of 129 patients had an objective response (two complete 
responses, 77 partial responses). 70 (66%) of the 106 patients with the two most common 
activating EGFR mutations (deletion 19 or L858R) had an objective response, as did nine 
(39%) of 23 patients with less common mutations.
For patients previously treated with a reversible EGFR TKI and clinically enriched for EGFR 
mutations, treatment with afatinib plus best supportive care resulted in a significant 
improvement in median PFS over patients treated with a placebo plus best supportive care 
(LUX-Lung 1/1200.23) [U10-3048-01].This improvement in PFS was accompanied by 
significant and meaningful improvements in cough, dyspnoea, and pain, compared to the 
placebo group. Treatment with afatinib was also found to significantly delay the time to 
deterioration for Global Health Status/Quality of Life (QoL). 
A subsequent and larger study (LUX-Lung 5/1200.42) enrolling a similar population of 
patients resulted in a very similar median PFS as in LUX-Lung 1. In these studies, the PFS 
benefit of afatinib was consistent across all pre-planned subgroups with at least 50 patients, 
including gender, age, race, baseline Eastern Cooperative Oncology Group (ECOG) 
performance status, type of prior EGFR TKI, baseline tumor size, and lines of prior 
chemotherapy. In both of these studies (LUX-Lung 1 and 5) treatment with afatinib had the 
greatest PFS benefit for those patients who belonged to a subgroup highly clinically enriched 
for EGFR mutations or who were positive for EGFR mutations by testing of tumor tissue.  
1.2
DRUG PROFILE
Afatinib (BIBW2992) is a small molecule, selective and irreversible erbB family blocker. In 
preclinical models it effectively inhibits EGFR, HER2 and HER4 phosphorylation resulting 


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in tumour growth inhibition and regression of established subcutaneous tumours derived from 
four human cell-lines known to co-express ErbB receptors. 
For the latest information on the drug profile of afatinib, please refer to the current afatinib 
Investigator Brochure (IB) (c01802941-09).  All references in this protocol concerning 
afatinib refer to the free base compound afatinib which is used as the oral formulation.
Afatinib is moderately fast absorbed after oral administration. Maximum plasma 
concentrations of afatinib were achieved mainly at 2 to 5 hours after oral drug administration. 
Afatinib maximum plasma concentrations and area under the curve increased slightly over-
proportional with increasing doses in the therapeutic range of 20-50mg. Moderate to high 
inter- and intra-individual differences in plasma concentration were seen. Afatinib is highly 
distributed out of the blood and has a moderate to high clearance. The overall gMean terminal 
half-life at steady state was 37.2 hours in cancer patients. Steady state was reached no later 
than 8 days after the first administration. The major route of elimination of afatinib was via 
faeces. After food intake, a decreased systemic exposure was observed compared to 
administration under fasted conditions. Therefore, afatinib should be taken without food (i.e. 
food should not be consumed for at least 2 hours before and at least 1 hour after taking 
afatinib). The PK characteristics in Caucasian cancer patients were comparable to those 
observed in Japanese cancer patients. 
Afatinib is bound covalently to proteins to a variable extent and covalent protein adducts 
were the major circulating metabolites in the plasma. Afatinib did not show relevant 
inhibition or induction of cytochrome P450 isoenzymes, and it appears unlikely that drug-
drug interactions based on this mechanism will occur. 
Afatinib is a substrate of the P-gp transporter. Concomitant administration of the potent P-gp
inhibitor ritonavir did not relevantly change the exposure to 40 mg afatinib when taken
simultaneously with or 6 h after afatinib but increased the bioavailability of afatinib (single
dose of 20 mg) by 48% and 39% for AUC0-∞ and Cmax when given 1 h before afatinib,
respectively. Pretreatment with the potent P-gp inducer rifampicin decreased the plasma
exposure of 40 mg afatinib by 34 % afatinib (AUC0-∞) and 22 % (Cmax), respectively.
Caution should be exercised when combining afatinib with potent P-gp modulators.
In pre-clinical studies afatinib is not an irritant to intact skin but an ocular irritant.
!"#$%$&'()'$*% *+ )+)'$%$, '* -(./%)%' (),,$'& )' "*&.& *+ 0 #/12/ 3)--(*4$#)'.56 789 '$#.& 
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Two phase I open label dose-escalation studies determined the Maximum Tolerated Dose 
(MTD) with continuous dosing of afatinib in patients with advanced solid tumours at 40mg 
and 50mg daily, respectively (U07-3128-02, U08-1023-02). Adverse events (AE) observed 
with afatinib are consistent with those reported for other EGFR and dual EGFR/HER2 
inhibitors. The most frequent investigator defined drug-related AEs were associated with 
gastrointestinal disorders (including diarrhoea, and stomatitis), skin and subcutaneous tissue 
disorders (rash, dry skin, pruritus, acneiform rash, acne), nail effects, epistaxis, fatigue, and 
decreased appetite. Early and proactive management of diarrhoea, mucositis/stomatitis and 
skin rash together with treatment interruptions and dose reductions is recommended in line 
with recent guidelines in the management of common toxicities of EGFR and EGFR/HER2 
TKIs and monoclonal antibodies (R07-4077, P07-11507, R07-4078).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
The US registration of the EGFR TKIs afatinib and erlotinib has changed the clinical 
management of patients with advanced NSCLC (R06-1394, R06-1307, R07-1049, R07-
1134). A significant clinical benefit may be achieved by a treatment that controls NSCLC 
progression with acceptable levels of side effects through a defined and specific targeted 
molecular mechanism.
Elderly patients (variously defined in the literature as ≥ 65 years of age or >70 years of age)
tend to be underrepresented in clinical trials (R14-1781, R14-1839, R14-1840). For this trial 
we will define elderly patients as those patients who are 70 years of age or older. 
Half of all NSCLC patients are 70 years of age or older at the time of initial diagnosis (R14-
1781).
There are several retrospective subset analyses from large clinical trials of the safety and 
efficacy of EGFR TKIs in elderly patients (age > 70). These trials were conducted regardless 
of mutational status and allowed multiple prior lines of therapy (R09-2250, R14-1350). One 
such study in Canadian patients demonstrated significant improvement in progression free 
survival in both elderly and younger populations compared to placebo (R09-2250). Elderly 
patients however, had significantly more overall and severe toxicity (grade 3/4 35% vs. 
18.5%; p< .001).  The elderly were also more likely to have > grade 3 rash, fatigue, 
stomatitis, or dehydration.  
A subset analysis of a Japanese population based observational study in  patients ≥75 years of 
age treated with the same EGFR TKI as in the Canadian study was performed. Patients 
received treatment without regard to mutational status and had multiple prior lines of therapy.
In this study there was a statistical difference between the disease control rate in the elderly
and non- elderly (58.2 % vs. 42.5 % P= 0.0228). There was no statistical difference in the 
time to treatment failure or in overall survival between the two groups. There was also no 
significant difference in the occurrence of grade > 3 toxicities between the groups. [R15-
0770]  
Afatinib is approved in the United States for the first line treatment of patients with Exon 19 
Deletions or Exon 21(L858R) substitution mutations based on the results of the LUX-Lung 3 
clinical trial. In that first line trial, encompassing 345 patients with varying EGFR mutations, 
the mean age was 60.3 years; 230 patients were randomized to Afatinib, from which 48 
patients were 70 years of age.  Of these patients, 41 had exon 19 deletions or L858R 
mutations.
This trial is proposed to obtain additional information about the tolerability of treatment with 
first line afatinib in the US elderly population by evaluating the proportion of patients with 
AEs leading to dose reduction of afatinib.  It is felt that the use of the 30 mg dose of 
afatinib in this vulnerable patient population (patients with ECOG PS of 2 or 3) reflects 
actual clinical practice. 


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2.2
TRIAL OBJECTIVES
The objective of this study is to describe the occurrence of AEs leading to dose reduction 
following afatinib treatment in NSCLC patients with common EGFR mutations (Deletion 19
and/or L858R) who are 70 years of age or older. 
See Section 5 for a detailed description of the study endpoints.
2.3
BENEFIT - RISK ASSESSMENT
Despite recent advances, NSCLC still has a dismal prognosis with an overall 5 year survival 
rate of 15%.   Afatinib is approved in the United States for the first line treatment of patients 
with Exon 19 Deletions or Exon 21(L858R) substitution mutations. In the LUX-Lung 3 trial, 
afatinib showed a statistically significant and clinically meaningful improvement in PFS, 
response rate and lung cancer symptoms compared to chemotherapy in NSCLC patients with 
common EGFR mutation (P13-07382). Across all afatinib clinical trials, diarrhoea, including 
severe diarrhoea, has been reported during treatment. Diarrhoea may result in dehydration 
with or without renal impairment, which in rare cases has resulted in fatal outcomes. Diarrhea 
usually occurred within the first 2 weeks of treatment. Grade 3 diarrhea is reported in about 
15% of patients and most frequently occurred within the first 6 weeks of treatment. 
The dermatological AEs in afatinib trials are captured as group terms including rash, acne, 
paronychia, pruritus, dry skin, eczema, and folliculitis. Across all trials rash/acne occurred at 
a high frequency and half of the cases begin within 4 weeks of exposure to afatinib. Grade 3 
rash was observed in about 17-18% of patients and those at higher risk for Grade 3 rash/acne 
appear to be the patients of low body weight/body surface area and patients with low baseline 
renal function. 
Interstitial lung disease (ILD) is a rare and serious (potentially fatal) AE reported with other
EGFR TKIs. The frequency of ILD-like AEs in all afatinib treated patients was low 
(approximately 1%) and similar to that observed with other EGFR TKIs. In this study, 
patients with known pre-existing ILD will be excluded. Afatinib treatment will be interrupted 
if patients experience acute onset and/or unexplained worsening of pulmonary symptoms 
(including dyspnea, cough, and fever). If interstitial lung disease is diagnosed, study drug 
must be permanently discontinued and appropriate treatment should be instituted as 
necessary.
Although rare, a potential for drug-induced liver injury (DILI) due to afatinib is under 
constant surveillance by sponsors and regulators. Therefore, this study requires timely 
detection, evaluation, and follow-up of laboratory alterations of selected liver laboratory 
parameters to ensure patient safety.
Keratitis was identified using the MedDRA SMQ (Medical Dictionary for Drug Regulatory 
Activities Standardised MedDRA Queries) (narrow) for corneal disorders and Boehringer 
Ingelheim’s internal database was searched. In all afatinib-treated patients as of 15 January 


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2013, 32 patients (0.7%) were identified using the SMQ search with the most common 
preferred term being keratitis (19 patients [0.4%]).
In regard to treatment of older patients, in the LUX-Lung 3 study, the predominant adverse 
events noted in patients aged 70 and over (N= 48) receiving afatinib treatment were diarrhoea
95.8% (10.4% > grade 3), rash/acne 85.4% (12.5% > grade 3), stomatitis 66.7% (6.3% > 
grade 3) and nail effects 56.3% (16.7% > grade 3). These adverse events were treated 
symptomatically, and with treatment interruption and dose reductions. For patients aged 70 
and over, therapy was discontinued because of treatment related AEs in 14.6% of the patients 
receiving afatinib. Of the most common AEs associated with afatinib, only diarrhoea (4.2%) 
and paronychia (2.1%) were cause for treatment discontinuation. There were no cases of 
interstitial lung disease-like events potentially related to afatinib in patients 70 years of age or 
older. Two deaths in this age group were considered to be related to afatinib treatment (one 
respiratory decompensation and one sepsis). In the first line Lux Lung 6 trial encompassing
364 patients with varying EGFR mutations, one hundred percent of patients were Asian. The 
mean age was 56 years, 25 (6.9 %) afatinib patients were 70 years of age or older and had 
exon 19 deletions or L858R mutations. The tolerability of afatinib in this study was 
consistent with what was reported in the LUX-Lung 3 trial. .
In this study, the guideline for management of expected side effects of afatinib will be 
followed (refer to Section 4.4). Regular and frequent monitoring of the safety as well as the 
clinical benefit throughout the trial will be implemented, including scheduled clinical visits 
when the emergence of afatinib related AEs are expected.  Hence, early management and 
education will take place to mitigate worsening of symptoms. In addition, periodic tumor 
assessment will be performed by the investigator; patients lacking clinical benefit will be 
removed from afatinib treatment. 
In summary, there is a medical need for improving treatment of elderly patients with EGFR 
driver mutations. 


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3.      DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is an open label, non-randomized, single arm Phase IV study in patients 70 years of age 
or older with stage IV or recurrent Non-Small Cell Lung Cancer whose tumors harbor 
common EGFR mutations. A total of approximately 25 patients will be entered into the trial.
After completion of the screening assessments, eligible patients will be treated with a starting 
dose of 30 mg afatinib daily as monotherapy. The dose may be reduced dependent on the AE 
profile of the individual patient and concomitant medication. See Section 4.4 on afatinib dose 
modification.
The patient participation in the trial is considered to be concluded when the follow-up visit is 
complete. For patients that agree to be followed, vital status will be collected every 3 months 
until the end of the trial.  The end of the trial is defined approximately one year after the last 
patient has entered the study.
The diagram below depicts the stages of a patient’s participation in this protocol:
Figure 3.1:1 Study design
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim.
The investigators participating in the trial must have experience in diagnosing and treating 
patients with non-small cell lung cancer. The coordinating investigator is an investigator 
participating in the trial who is experienced in treatment and investigations of lung cancer. 
The coordinating investigator has been designated by Boehringer Ingelheim and will sign the 
clinical trial report. There will be no steering committee or data monitoring committee for 
this trial.
SCREENING
Up to 28 days
AFATINIB 
TREATMENT
Divided into 28 
days Courses 
END OF 
TREATMENT 
(EOT) 
0-7 days afater 
permanent 
discontinuation 
of afatinib
FOLLOW 
UP (FU)
28-35 days 
after last 
afatinib 
intake
VITAL 
STATUS
Collected 
q3mths


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On-site monitoring will be performed by BI or a Contract Research Organization (CRO) 
appointed by BI.
All trial relevant documentation will be stored in the Trial Master File (TMF) at BI. In 
addition each site will have an Investigator Site File (ISF) containing all trial documents 
relevant for the site.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
This trial is a single arm, open-label uncontrolled study.  Treatment will be administered in 
courses of 28 days.  The starting dose of afatinib will be 30 mg daily.  Dose reductions will 
be permitted as described in Section 4.4.1.
3.3
SELECTION OF TRIAL POPULATION
Elderly patients determined to have the common EGFR mutations Del 19 and L858R as part 
of standard of care testing will be eligible to be screened for participation in this trial. It is 
foreseen that approximately 25 patients will be treated at approximately 15 to 20 study sites 
in the US. The rate of enrolment will vary by study site, but is expected to be approximately 1
to 2 patients per site. Additional sites may be added if necessary. Given changes in the 
treatment landscape and ability to recruit patients within the study population, study 
discontinuation prior to meeting expected enrollment goals may be considered as described in 
Section 3.3.4.2.
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with study drug or not.
3.3.1
Main diagnosis for study entry
The study will be performed in elderly patients with Stage IV or recurrent non-small cell lung 
cancer harbouring Deletion 19 and/or L858R EGFR mutation.
3.3.2
Inclusion criteria
1. Pathologically or cytologically confirmed Stage IV Cancer NSCLC (includes 
cytologically proven pleural effusion or pericardial effusion) or recurrent 
disease not amenable for curative intent local radiotherapy.  Staging is based on 
AJCC Staging for NSCLC 7th edition (R12-4710)
2. Evidence of common EGFR mutation (Del 19 and/or L858R)
3. Age ≥ 70 years
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (R01-
0787) (See Appendix 10.1)


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5. Adequate organ function, defined as all of the following:
-
Absolute neutrophil count (ANC) > 1500 / mm3
-
Platelet count >75,000 / mm3.
-
Baseline creatinine of < or = 1.5 g/dl or, if > 1.5, estimated creatinine 
clearance > 45ml / min. (Cockcroft-gault formula -refer to Appendix 10.3
-
Total Bilirubin < 1.5 times upper limit of institutional normal (ULN)
-
Aspartate amino transferase (AST) and alanine amino transferase (ALT) 
< three times ULN (if related to liver metastases < five times ULN)
6. Recovery from any previous therapy related toxicity to ≤Grade 1 at study entry 
(except for stable sensory neuropathy ≤Grade 2 and alopecia)
7. Life expectancy of at least three months
8. Written informed consent that is consistent with ICH-GCP guidelines
3.3.3
Exclusion criteria
1. Prior participation in an afatinib clinical study, even if not assigned to afatinib 
treatment
2. Prior systemic therapy for metastatic or recurrent NSCLC including prior 
treatment with EGFR targeting small molecules or antibodies. . Note: 
radiotherapy alone and adjuvant/neoadjuvant treatment is not counted as a line 
of therapy. 
3. Concurrent investigational therapy or investigational therapy within 4 weeks of 
start of afatinib therapy   
4. Radiotherapy within 4 weeks prior to start of study treatment, except as follows:
i.) Palliative radiation to target organs other than chest may be allowed up to 2 
weeks prior to study treatment, or
ii.) Single dose palliative treatment (e.g SRS or SBRT) for symptomatic 
metastasis outside above allowance to be discussed with sponsor prior to 
enrolling.
5. Major surgery within 4 weeks before starting study treatment or scheduled for 
surgery during the projected course of the study
6. Men, capable of fathering a child, who are unwilling to use adequate 
contraception prior to study entry, for the duration of study participation, and for 
at least 28 days after treatment has ended. Refer to Section 4.2.2.3 for details
7. Presence of an active infection or with a fever > 38.5 C within 3 days of the 
first scheduled day of dosing
8. Known hypersensitivity to afatinib or the excipients of afatinib


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9. Known pre-existing interstitial lung disease
10. Meningeal Carcinomatosis - Pathologically documented meningeal 
carcinomatosis (i.e. cytology (+) lumbar puncture ; radiology reports alone 
raising this as a possibility, in the absence of true symptomatology, would not 
constitute an exclusion)
11. Presence of brain or subdural metastases, unless local therapy has been 
completed and use of corticosteroids has been discontinued or the dose has been 
stable for at least 4 weeks before starting study treatment. Any symptoms 
attributed to brain metastases must be stable for at least 4 weeks before starting 
study treatment Pts post SRS can be enrolled earlier as long as their symptoms 
are stable or improved and they are off steroids)
12. Previous or concomitant malignancies at other sites, except effectively treated 
non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in 
situ or effectively treated malignancy that has been in remission for more than 2 
years and is considered to be cured
13. History or presence of clinically relevant cardiovascular abnormalities such as 
uncontrolled hypertension, congestive heart failure NYHA classification of 3 or 
4 unstable angina or poorly controlled arrhythmia as determined by the 
investigator. Myocardial infarction within 6 months prior to start of afatinib 
treatment
14. Any history or presence of poorly controlled gastrointestinal disorders that could 
affect the absorption of the study drug (e.g. Crohn’s disease, ulcerative colitis, 
chronic diarrhoea, malabsorption) 
15. Known or suspected active hepatitis B infection (defined as presence of HepB 
sAg and/ or Hep B DNA), active hepatitis C infection (defined as presence of 
Hep C RNA) and/or known HIV carrier
16. Any history of or concomitant condition that, in the opinion of the Investigator, 
would compromise the patient’s ability to comply with the study or interfere 
with the evaluation of the safety and efficacy of the test drug 
17. Treatment with any of the prohibited concomitant medications (refer to Section 
4.2.2.1) that cannot be stopped for the duration of trial participation
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
The investigator or patient may stop study treatment at any time for safety or personal 
reasons.  
A patient has to be withdrawn from study treatment in case any of the following applies:


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
The patient withdraws consent from study treatment

Has radiologic (or clinical) documentation of progressive disease (Section 5.1.2). 
(except for patients who develop symptomatic brain metastasis requiring single dose 
palliative treatment (e.g SRS) .These patients may remain on study after receiving this 
radiation treatment if stable post RT and there is no evidence of progression aside 
from the brain lesions.) 

Is diagnosed with interstitial lung disease (ILD)

The patient is no longer able to receive study treatments (e.g. adverse events, 
concomitant diagnoses, surgery, concomitant medications or administrative reasons)

Has a significant deviation from the protocol or eligibility criteria. The decision to 
continue or withdraw treatment will be made by the sponsor in agreement with the 
investigator
Patients who withdraw from the trial after commencing treatment will not be replaced.  
Procedures that need to be completed are found in Section 6.2.3 and 6.2.4.
After the end of the trial, the sponsor will assist patients still on treatment with access to 
afatinib through marketed product.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:

Failure to meet expected enrolment goals overall or at a particular trial site,

Emergence of any efficacy/safety information that could significantly affect 
continuation of the trial.

Violation of GCP (Good Clinical Practice), the protocol, or the contract by a trial site 
or investigator, disturbing the appropriate conduct of the trial.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
Eligible patients will receive continuous afatinib treatment until progression or intolerable
adverse events or other reasons necessitating withdrawal (see Section 3.3.4.1). The 
manufacturer for afatinib is listed in Section 4.1.1. 
4.1.1
Identity of BI investigational product and comparator product
Substance (INN)
Afatinib 
(Brand name):
Giotrif®/ GilotrifTM
Pharmaceutical form:
Film-coated tablet
Source:
Boehringer-Ingelheim Pharma GmbH & Co. KG
Unit strength:
20 and 30 mg film-coated tablets (the dose of afatinib in the 
film-coated tablets is related to the free base equivalent to 
afatinib)
Route of administration:
Oral
Posology
Once daily
4.1.2
Method of assigning patients to treatment groups
This is a single-arm non randomized study. Patients who have given their written informed 
consent will be enrolled sequentially on a first come first enrolled basis and will be registered 
in the trial. Patients who meet all eligibility criteria will be entered into the study and the start 
of treatment will be documented by the investigator. The trial will continue to enroll patients 
until the goal of approximately 25 patients entered into the study is reached. 
4.1.3
Selection of doses in the trial
Per approved label, ':. (.>*##.%"." 
"*&. *+ )+)'$%$, $& A7 #/ *()556 *%>. ")$56 ;%'$5 "$&.)&. 
-(*/(.&&$*% *( %* 5*%/.( '*5.()'." ,6 ':. -)'$.%'8  It is felt that the use of the 30 mg dose of 
afatinib in this vulnerable patient population (elderly) reflects actual clinical practice.
The daily dose will be modified following careful monitoring of a patient’s drug-related 
adverse events. Refer to Section 4.4 for dose reductions to be made in response to the 
occurrence of adverse events. Dose escalation will not be allowed during this study.
4.1.4
Drug assignment and administration of doses for each patient
Patients will take a single oral dose of afatinib each day starting at a dose of 30 mg 
continuously. The dose of afatinib must be reduced if certain adverse events occur (see 
Section 4.4).


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Afatinib should be taken at approximately the same time each day without food (at least one 
hour before a meal or at least two hours after a meal).  
Missed doses of afatinib can be made up within 12 hours of the scheduled time.  Otherwise, 
the dose must be skipped and patients should take the next scheduled dose at the usual time. 
Patients with emesis must not take a replacement dose.
If dosing of whole tablets is not possible, afatinib tablets can also be dispersed in
approximately 100 ml of non-carbonated drinking water. No other liquids should be used. 
The tablet should be dropped in the water, without crushing it, and occasionally stirred for up 
to 15 min until the tablet is broken up into very small particles. The dispersion should be 
drunk immediately. The glass should be rinsed with approximately 100 ml of water which 
should also be drunk. The dispersion can also be administered through a naso-gastric tube. 
Afatinib will be prescribed by the investigator and may be dispensed either by the 
investigator, site staff or affiliated pharmacy via Interactive Response Technologies (IRT) at 
the beginning of each treatment course.  For administrative purposes, a treatment course is 
defined as 28 days.  Treatment will start when the patient takes the first dose of afatinib 
(Course 1 Day 1) and continue until the criteria for stopping trial medication in Section 
3.3.4.1 are met. 
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This open-label, single-arm study will be handled in an open fashion throughout, i.e., also for 
the purpose of data cleaning and preparation of the analysis. No blinding is necessary in this 
trial, because all patients receive the same treatment.
4.1.5.2 Procedures for emergency unblinding
Not applicable
4.1.6
Packaging, labelling, and re-supply
For details of packaging and the description of the label, refer to the product package insert 
provided in the ISF.
Afatinib will be supplied as film-coated tablets. Available dosage strengths will be 20 mg and 
30 mg.
Medication numbers which will be recorded by the site in the eCRF (Electronic Case Report 
Form) are used for tracking purposes only. 
As study medications will be commutable between studies 1200.208 and 1200.209, both 
study numbers will be pre-printed on the study medication labels.  Upon enrolment at Visit 1, 


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IRT will issue a report showing the study number and patient number for each patient.  The 
report should be filed in the ISF.
4.1.7
Storage conditions
Drug supplies, should be maintained according to the current drug label, must be kept in a 
secure, limited access storage area under the storage conditions defined on the label 
instructions. Where necessary, temperature logs must be maintained to make certain that the 
drug supplies are stored at the correct temperature. If storage temperature is out of range at 
any time, this has to be reported in the ISF and the sponsor must be notified.
Afatinib must be stored in the original package in order to protect from light. Film-coated 
tablets are humidity-sensitive; therefore, bottles must be kept tightly closed to protect from 
moisture.
4.1.8
Drug accountability
The investigator or delegate (e.g. pharmacist or investigational drug storage manager) will 
utilize sponsor provided afatinib when the following requirements are fulfilled:

Approval of the study protocol by the institutional review board (IRB) / ethics 
committee, 

Availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal investigator,

Availability of a signed and dated clinical trial protocol (CTP) or immediately 
imminent signing of the clinical trial protocol, 

Availability of the proof of a medical licence for the principal investigator (if 
applicable).

Availability of the Form 1572 (if applicable)
The Investigator or delegate investigational drug storage manager must maintain records of 
the product’s delivery to the trial site, the inventory at the site, the use by
each patient, and the return to the Sponsor or alternative disposal of unused products.
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates,
and the unique code numbers assigned to the investigational product and trial patients. The
Investigator / Pharmacist / investigational drug storage manager will maintain records that
document adequately that the patients were provided the doses specified by the CTP and
reconcile all investigational products received from the Sponsor. At the time of return to the
Sponsor, the Investigator / Pharmacist / investigational drug storage
manager must verify that all unused or partially used drug supplies have been returned by the
clinical trial patient and that no remaining supplies are in the Investigator’s possession.   


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatments
4.2.1.1
Rescue medication
Rescue medications to reverse the actions of afatinib are not available. There is no specific 
antidote for over dosage with afatinib. Potential adverse events should be treated 
symptomatically. Common adverse events of treatment with afatinib with specified 
management recommendations and/or requirements include diarrhoea, and rash/acne. To 
improve tolerability and the probability of clinical benefit, patients should receive prompt and 
appropriate supportive care at the first signs of symptoms. Suggested treatments for AEs are 
described in Section 4.4.2.
4.2.1.2
Emergency procedures
Careful assessment of all patients with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude ILD. Afatinib 
should be interrupted pending investigation of these symptoms. If interstitial lung disease is 
diagnosed, study drug must be permanently discontinued and appropriate treatment instituted 
as necessary. 
Patients who present with symptoms of keratitis, such as acute or worsening eye 
inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be 
referred promptly to an ophthalmic specialist. If a diagnosis of ulcerative keratitis is 
confirmed, treatment with afatinib should be interrupted or discontinued. If keratitis is 
diagnosed, the benefits and risks of continuing treatment with afatinib should be carefully 
considered. Afatinib should be used with caution in patients with a history of keratitis, 
ulcerative keratitis or severe dry eye. Contact lens use is a risk factor for keratitis and 
ulceration.
Dermatologic adverse events and diarrhoea are the most common side-effects associated with 
treatment with afatinib. Treatment of these side-effects should be proactive and should be 
started as early as possible after onset of symptoms.
4.2.1.3
Additional treatments
Concomitant medications or therapy to provide adequate supportive care may be given as 
clinically necessary. 
After study enrollment, palliative radiotherapy may be given for bone pain or for other 
reasons (e.g. bronchial obstruction, skin lesions), provided that the total dose delivered is in a 
palliative range according to institutional standards. The irradiated area cannot be used for 
tumor response assessment. During palliative radiotherapy, study treatment should be delayed 
and may be resumed once the patient has recovered from any radiation-associated toxicity.  If 
medication is interrupted for more than 14 days, the decision to continue will be made by the 
BI clinical monitor in agreement with the investigator.  Patients who are dose interrupted for 


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>28 days due to palliative radiotherapy must be permanently discontinued from study 
medication.
All concomitant therapy, including anaesthetic agents, vitamins, homeopathic/herbal 
remedies, nutritional supplements, must be recorded in the eCRF during the screening and 
treatment period, starting from the date of signature of informed consent, and ending at the 
EOT (end of treatment) visit. After the EOT visit, only concomitant therapy indicated for 
treatment of an AE has to be reported. 
In case of major surgery (as judged by the investigator), it is recommended to stop treatment 
with afatinib around one week prior to the surgery, and to restart treatment after complete 
wound healing. If afatinib is interrupted for more than 14 days, the decision to continue will 
be made by the BI Clinical Monitor in agreement with the investigator.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Concomitant medications or therapy to provide adequate supportive care may be given as 
clinically necessary. 
Palliative radiotherapy may be given as described in Section 4.2.1.3.
Additional experimental anti-cancer treatment and/or standard chemo-, immunotherapy, 
hormone treatment (with the exception of megestrol acetate and use of anti-androgens and/or 
gonadorelin analogues for treatment of prostate cancer), or radiotherapy (other than palliative 
radiotherapy for symptom control) is not allowed concomitantly with the administration of 
afatinib. 
Afatinib is a substrate of the P-gp transporter. Caution should be exercised when combining 
afatinib with P-gp modulators.  For a list of potent P-gp inhibitors and inducers see Appendix 
10.2.
4.2.2.2
Restrictions on diet and life style
Patients should be advised to avoid any foods known to aggravate diarrhoea.
To prevent skin related adverse events it is recommended to avoid intense irradiation with 
UV light and harsh detergents, see also Section 4.4.2.
4.2.2.3
Men capable of fathering a child and pregnancy prevention
Men who are capable of fathering a child and whose partners have child bearing potential
must use adequate contraception throughout the trial (from screening until 28 days after last 
dose of trial medication). 
Acceptable methods of contraception include surgical sterilisation and double barrier method, 
and must be in accordance with local regulations where applicable. Double barrier method of 


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contraception is defined as two barrier methods used simultaneously each time the patient has 
intercourse. Accepted barrier methods include diaphragm, female condom, cervical cap, male 
condom and intrauterine device (IUD) (the diaphragm and cervical cap must be used in 
conjunction with spermicidal jelly/cream). Those with partners using hormonal 
contraceptives must also be using an additional approved method of contraception (as 
described above).  Natural “rhythm” and spermicidal jelly/cream are not acceptable methods 
of contraception.
Pregnancies that result from a male participating in this trial must be reported following BI 
internal SOP using the pregnancy monitoring form (refer to ISF).   
4.3
TREATMENT COMPLIANCE
The study medication will be given in accordance with the protocol and the instructions of a 
site investigator. 
The appropriate number of afatinib tablets for 28 days of treatment will be provided to 
patients to be self-administered at home.
Patients will be asked to bring the remaining trial medication to the investigator site for a 
compliance check according to the Flowchart. The remaining film-coated tablets will be 
counted by the investigator/site staff and recorded at the investigator site. Discrepancies 
between the number of tablets remaining and the calculated number of tablets the patients 
should have taken must be documented and explained. At the end of each 28 day period, any 
remaining medication will be collected. If the patient is eligible for further treatment, a new 
bottle of study medication must be dispensed. 
Patient’s repeatedly missing scheduled on-treatment study visits, unless due to exceptional 
circumstances, should be discussed with the BI trial monitor and be evaluated for 
compliance. A maximum of 25% of the dispensed afatinib doses may be missed for other 
reasons than drug-related AEs. Patients who miss afatinib treatment more frequently are 
considered non-compliant.  
The investigator and/or the sponsor can withdraw a patient from the study in the event of 
serious and persistent non-compliance which jeopardizes the patient’s safety or render study 
results for this patient unacceptable. 
4.4
MANAGEMENT OF DOSE REDUCTION AND EXPECTED ADVERSE 
EVENTS
4.4.1
Management of dose reduction for afatinib
Afatinib treatment related toxicities will be managed by treatment interruptions and 
subsequent dose reductions according to the schedule described in Table 4.4.1: 1. Dose 
reductions will apply to individual patients only. Once the dose has been reduced, it cannot 
be increased later.


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To prevent the development of more severe adverse events, treatment related diarrhoea, 
dermatologic adverse events or mucositis/stomatitis should be managed early and proactively 
as described in Section 4.4.2.
Table 4.4.1: 1 Dose reduction scheme for afatinib
CTCAEa Adverse Events
related to afatinib
Action
Dose reduction scheme
Grade 1 or Grade 2
No interruptionb
No dose adjustment
Grade 2 (prolongedc or 
intolerable)
or Grade 2 renal dysfunction
or Grade ≥ 3
Interrupt until Grade ≤1b
Resume treatment with dose 
reduction by 10mg 
decrementsd
a NCI Common Terminology Criteria for Adverse Events V 4.0 (R12-2532)
b In case of diarrhoea, anti-diarrhoeal medicinal products (e.g. loperamide) should be taken 
immediately and continued for persistent diarrhoea until loose bowel movements ease.
c >48 hours of diarrhoea and/or >7 days of rash
d If patient cannot tolerate 20mg/ day, afatinib should be permanently discontinued
Interstitial Lung Disease (ILD) should be considered if a patient develops acute or worsening 
of respiratory symptoms in which case treatment should be interrupted pending evaluation. If 
ILD is diagnosed, afatinib should be discontinued and appropriate treatment initiated as 
necessary.
In the event of any unrelated adverse events, the investigator may choose to interrupt the 
medication for up to 14 days, but no dose reduction should occur.  If the medication is 
interrupted for more than 14 days for any reason, the decision to continue with afatinib will 
be made by the BI clinical monitor in agreement with the investigator.
4.4.2
Management of expected adverse events
4.4.2.1 Management of diarrhoea and hydration status following treatment with afatinib
Diarrhea occurs at a high frequency and generally begins within 2 weeks of exposure to 
afatinib. Although usually mild to moderate, diarrhea may lead to dehydration and require 
treatment modification or discontinuation, so early management is essential (Table 4.4.1:1). 
At the time of initiation of treatment with afatinib, patients should be given a supply of 
loperamide to keep with them at all times or access to loperamide should be confirmed; and 
patients should be counselled on the appropriate use. 
Patients must be advised to drink an adequate amount of fluid to make up for the fluid lost 
through diarrhea. 


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Table 4.4.2.1: 1 Grade specific treatment recommendations for afatinib related diarrhea 
Severity 
(CTCAE Grading)
Description 
Intervention 
concerning afatinib
treatment
Specific intervention
Mild (Grade 1)
Increase of < 4 stools per 
day over baseline; mild 
increase in ostomy output 
compared with baseline
Continue same dose
Stop laxatives and advise 
patient to drink at least 8-10 
glasses of water or clear fluids 
per day;
4 mg (2 tablets) of loperamide 
to be taken immediately, 
followed by 2 mg (1 tablet) 
after each loose stool until 
bowel movements cease for 12 
hours
Moderate (Grade 2)
Increase of 4-6 stools per 
day over baseline; i.v. 
fluids indicated < 24 
hours; moderate increase 
in ostomy output 
compared with baseline; 
not interfering with ADL
Continue same dose 
unless Grade 2 
diarrhoea continues 
for ≥ 2 days (48 hours)
in which case treatment 
must be interrupted 
until recovered to ≤
Grade 1 followed by 
dose reduction*
Continue loperamide; 
assess for dehydration and 
electrolyte imbalance;
consider IV fluids and 
electrolyte replacement 
Severe (Grade 3) 
Increase of ≥7 stools per 
day over baseline; 
incontinence; IV fluids > 
24 hours; hospitalization; 
severe increase in ostomy 
output compared with 
baseline; interfering with 
ADL
Dose interruption until 
recovered to ≤Grade 1 
followed by dose 
reduction*
See Grade 2; plus:
an infectious process should be 
ruled out with stool cultures; 
aggressive iv fluid replacement 
≥ 24 hours; hospitalization to 
monitor progress;
consider prophylactic 
antibiotics if patient is also 
neutropenic; 
Life threatening 
(Grade 4)
Life-threatening 
consequences (e.g. 
haemodynamic collapse) 
Dose interruption until 
recovered to ≤Grade 1 
followed by dose 
reduction*
See Grade 3
* If despite optimal supportive care and a treatment interruption, diarrhea does not resolve to CTC AE Grade ≤ 
1 within 14 days, treatment with afatinib must be permanently discontinued. In the event that the patient is 
deriving obvious clinical benefit according to the investigator’s judgement, further treatment with afatinib will 
be decided in agreement between the sponsor and the investigator.
4.4.2.2 Management recommendations for dermatological AEs following treatment with 
afatinib
Dermatologic AEs of afatinib include rash, acne, dermatitis acneiform, and dry skin. General 
recommendations for prophylaxis are summarized in Table 4.4.2.2: 1 and grade-specific 
treatment recommendations are summarized in Table 4.4.2.2: 2. For dose adjustment of 
afatinib refer to Table 4.4.1: 1.  
Specific interventions should be reassessed at least after 2 weeks or at any worsening of 
symptoms, in which case the specific intervention should be adjusted and, depending on own 


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clinical experience, early involvement of a dermatologist should be considered (adapted from 
R11-0826).
Table 4.4.2.2: 1 General recommendation for prophylaxis while receiving afatinib
Personal hygiene
Use of gentle soaps and shampoos for the body, e.g. pH5 neutral bath and 
shower formulations and tepid water.
Use of very mild shampoos for hair wash.
Only clean and smooth towels are recommended because of potential risk of 
infection. The skin should be patted dry after a shower, whereas rubbing the skin 
dry should be avoided.
Fine cotton clothes should be worn instead of synthetic material.
Shaving has to be done very carefully.
Manicure, i.e. cutting of nails, should be done straight across until the nails no 
longer extend over the fingers or toes. Cuticles are not allowed to be trimmed 
because this procedure increases the risk of nail bed infections
Sun protection
Sunscreen should be applied daily to exposed skin areas regardless of season. 
Hypoallergenic sunscreen with a high SPF (at least SPF30, PAPA free, 
UVA/UVB protection), preferably broad spectrum containing zinc oxide or 
titanium dioxide are recommended
Patients should be encouraged to consequently stay out of the sun.
Protective clothing for sun protection and wearing a hat should be recommended.
Moisturizer treatment
It is important to moisturize the skin as soon as anti-EGFR therapy is started.
Hypoallergenic moisturizing creams, ointments and emollients should be used 
once daily to smooth the skin and to prevent and alleviate skin dryness. 
Note: avoid greasy creams (e.g. petrolatum, soft paraffin, mineral oil based) and 
topical acne medications
Prevention of paronychia 
Patients should keep their hands dry and out of water if ever possible.
They should avoid friction and pressure on the nail fold as well as picking or 
manipulating the nail.
Topical application of petrolatum is recommended around the nails due to its 
lubricant and smoothing effect on the skin.
Table 4.4.2.2: 2 Grade specific treatment recommendation of skin reactions to afatinib
Severity 
(CTCAE Grading)
Description
Specific intervention
ACNEIFORM RASH
Mild (Grade 1)
Macular or papular eruptions or 
erythema without associated 
symptoms
Consider topical antibiotics, e.g. 
clindamycin 2% or topical erythromycin 1% 
cream of metronidazole 0.75% or topical 
nadifloxacin 1%;
Isolated scattered lesion: cream preferred
Multiple scattered areas: lotion preferred
Moderate (Grade 2)*
Macular or papular eruptions with 
pruritus or other associated 
symptoms; localized desquamation 
or other lesions covering <50% of 
BSA 
Topical treatment as for Grade 1 
plus short term topical steroids, e.g. 
prednicarbate cream 0.02% plus
an oral antibiotic (for at least 2 weeks) e.g. 
Doxycycline 100mg b.i.d. or Minocycline 
hydrochloride 100mg b.i.d


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Severe (Grade 3)
Severe, generalized erythroderma or 
macular, popular or vesicular 
eruption; desquamation covering ≥ 
50% of BSA; associated with pain, 
disfigurement, ulceration or 
desquamation
Topical and systemic treatment as for   
Grade 2.
Consider referral to dermatologist
Consider systemic steroids
Life threatening 
(Grade 4)
Generalized exfoliative, ulcerative, 
or bullous dermatitis
See Grade 3
Systemic steroids are recommended
EARLY AND LATE XEROTIC SKIN REACTIONS - PRURITUS
Mild (Grade 1)
Mild or localized
Topical polidocanol cream.
Consider oral antihistamines, e.g. 
diphenhydramine, dimethindene, cetirizine, 
levocetirizine, desloratidine, fexofenadine 
or clemastine)
Moderate (Grade 2)
Intense or widespread
See Grade 1 plus oral antihistamines;
Consider topical steroids, e.g. topical 
hydrocortisone
Severe (Grade 3)
Intense or widespread and interfering 
with activities of daily living (ADL)
See Grade 2.
XEROSIS (DRY SKIN)
Mild (Grade 1)
Asymptomatic
Soap-free shower gel and/or bath oil.
Avoid alcoholic solutions and soaps.
Urea- or glycerin-based moisturizer.
In inflammatory lesions consider topical 
steroids (e.g. hydrocortisone cream)
Moderate (Grade 2)
Symptomatic, not interfering with 
ADL
See Grade 1.
In inflammatory lesions consider topical 
steroids (e.g. hydrocortisone cream)
Severe (Grade 3)
Symptomatic,
interfering with ADL
See Grade 2.
Topical steroids of higher potency (e.g. 
prednicarbate, mometasone furoate)
Consider oral antibiotics
FISSURES
Mild (Grade 1)
Asymptomatic
Petroleum jelly, Vaseline® or Aquaphor for 
30 minutes under plastic occlusion every 
night, followed by application of 
hydrocolloid dressing; antiseptic baths (e.g. 
potassium permanganate therapeutic baths, 
final concentration of 1:10,000, or 
povidone-iodine baths)
Topical application of  aqueous silver 
nitrate solutions to fissures
Moderate (Grade 2)
Symptomatic, not interfering with 
ADL
See Grade 1. 
Consider oral antibiotics.
Severe (Grade 3)
Symptomatic,
Interfering with ADL
See Grade 2.
*If Grade 2 rash persists for ≥7 days despite treatment and is poorly tolerated by the patient, the investigator 
may choose to pause treatment up to 14 days followed by a reduction in the dose of afatinib according to the 
dose reduction scheme in Table 4.4.1: 1


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4.4.2.3
Management of mucositis/stomatitis 
General and grade specific recommendations are described in Table 4.4.2.3:1. For dose 
adjustment refer to Section 4.4.1 and for restrictions on concomitant therapies refer to Section 
4.2.2.
Treatment is supportive and aimed at symptom control. These may include atraumatic 
cleansing and rinsing with non-alcoholic solutions such as normal saline, diluted salt and 
baking soda solution (e.g. one-half teaspoonful of salt and one teaspoon of baking soda in one 
quart of water every four hours); avoidance of agents containing iodine, thyme derivatives 
and prolonged use of hydrogen peroxide; dietary manoeuvres such as promotion of soft, non-
irritating foods like ice-creams, mashed/cooked vegetables, potatoes and avoidance of spicy, 
acidic or irritating foods such as peppers, curries, chillies, nuts and alcohol. If the patient is 
unable to swallow foods or liquids, parenteral fluid and/or nutritional support may be needed. 
Examples of some of the agents suggested in Table 4.4.2.3:1 include: topical analgesics –
viscous lidocaine 2%; mucosal coating agents - topical kaolin/pectin; oral antacids, 
maltodextrin, sucralfate; topical antifungals – nystatin suspension (adapted from P11-09424).
Table 4.4.2.3: 1
Grade specific treatment recommendations of study-drug related 
mucositis/stomatitis 
Severity 
(CTCAE grading)
Description 
Treatment recommendations
Intervention concerning 
afatinib treatment/ dose 
modification
Mild (Grade 1)
Minimal 
symptoms; 
normal diet 
Oral rinses with agents such as non-
alcoholic mouth wash, normal saline, 
diluted salt and baking soda solution.
No change.
Moderate (Grade 
2)
Symptomatic, but 
can eat and 
swallow 
modified diet
Addition of topical analgesic mouth 
treatments, topical corticosteroids, 
antiviral therapy if herpetic infection 
confirmed, antifungal therapy 
preferably topical on a case by case 
basis.
Maintain dose if 
tolerable; Hold dose if 
intolerable until recovery 
to grade ≤1, then restart 
at the same dose.
Severe (Grade 3) 
Symptomatic and 
unable to 
adequately 
aliment or 
hydrate orally
Same as for Grade 2; institute 
additional symptomatic therapy (topical 
or systemic) as clinically indicated .
Hold dose until recovery 
to grade ≤1 or baseline, 
then restart at the 
reduced dose according 
to Section 4.4.1.
Life threatening 
(Grade 4)
Symptoms 
associated with 
life-threatening 
consequences 
Same as for Grade 2; institute 
additional symptomatic therapy (topical 
or systemic) as clinically indicated.
Hold dose until recovery 
to grade ≤1 or baseline, 
then restart at the 
reduced dose according 
to Section 4.4.1


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5.
VARIABLES AND THEIR ASSESSMENT
There are three categories of endpoints in this trial: 1) the primary endpoint, 2) secondary 
endpoints and 3) other endpoints. The primary endpoint of this study is a safety endpoint, the 
occurrence of AEs leading to the dose reduction of afatinib. The secondary endpoints are 
also safety endpoints. The category of “other endpoints” includes specific safety and efficacy 
endpoints.
5.1
EFFICACY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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5.2
SAFETY
5.2.1
Endpoints of safety
The primary endpoint of the study is the occurrence of AEs leading to dose reduction of 
afatinib. Patients without AEs leading to dose reduction of afatinib will be considered as “no” 
for the primary endpoint. No confirmatory analysis is planned (i.e. no formal hypothesis 
testing will be performed.)
The secondary endpoints of the study are:

Occurrence of CTCAE grade≥3 diarrhea

Occurrence of CTCAE grade≥3 rash/acne+ 

Occurrence of CTCAE grade ≥3 stomatitis+

Occurrence of CTCAE grade ≥3 -)(*%6>:$)H

Time to first dose reduction of afatinib caused by AEs, defined as time from the date 
of the first administration of afatinib to the first dose reduction of afatinib caused by 
AEs.
In the study, MedDRA preferred terms that describe AEs of similar nature will be grouped 
together as “grouped term” to ensure that important events will not be underestimated. These 
grouped terms are flagged by a ‘+’.
Endpoints for safety belonging to the category of ‘other endpoints’ are:

Adverse events evaluated according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 (R12-2532).
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.
Serious adverse event


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A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for 
any other reason if it is an important medical event when based upon appropriate medical 
judgement which may jeopardise the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions.
Intensity of adverse event
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 and recorded in the eCRF.
Causal relationship of adverse event
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms (CRF). 
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE. 
Worsening of the underlying disease or other pre-existing conditions
Disease Progression in oncology trials is a study endpoint for analysis of efficacy. Disease 
progression is exempted from reporting as a (S)AE. Progression of the patient's underlying 
malignancy will be recorded in the appropriate pages of the (e)CRF as part of efficacy data 
collection. Death due to disease progression is to be recorded on the appropriate (e)CRF page 
and not on a SAE form. 
Examples of exempted events of PD are: Progression of underlying malignancy (Progressive 
disease PD): if PD is clearly consistent with the suspected progression of the underlying 
malignancy as defined by the respective response criteria. 
• Hospitalization/Procedures due solely to the progression of underlying malignancy (PD) 
• Clinical symptoms and/or signs of progression (with or without confirmation by objective 
criteria e.g. imaging, clinical measurement): if the symptom can exclusively be determined to 
be due to the progression of the underlying malignancy and does meet the expected pattern of 
progression for the disease under study. 
When there is evidence suggesting a causal relationship between the drug and the progression 
of the underlying disease, the event must be reported as (S)AE on the eCRF and SAE form. 
Worsening of other pre-existing conditions will be recorded as an (S)AE in the eCRF and 
SAE form (if applicable).


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Changes in vital signs, ECG, physical examination, and laboratory test results
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an (S)AE in the eCRF, if they are judged clinically relevant by the investigator.
Adverse Event of Special Interests (AESIs)
No AESIs have been defined for this trial.
Expected Adverse Events
For expected (listed) AEs of afatinib, see the current version of the IB (Investigator’s Brochure) 
(U03-3218-13).
5.2.2.2
Adverse event and serious adverse event reporting
All adverse events, serious and non-serious, occurring during the course of the clinical trial 
(i.e., from signing the informed consent onwards through the follow-up period of 28 days 
after the last drug administration, Table 5.2.2.2:1) will be collected, documented and reported 
to the sponsor by the investigator on the appropriate eCRFs / SAE reporting forms. Reporting 
will be done according to the specific definitions and instructions detailed in the ‘Adverse 
Event Reporting’ section of the Investigator Site File. 
For each adverse event, the investigator will provide the onset date, end date, intensity, 
treatment required, outcome, seriousness, and action taken with the investigational drug. The 
investigator will determine the relationship of the investigational drug to all AEs as defined in 
Section 5.2.2.1. 
The Residual Effect Period (REP), defined as the period of time after the last dose of 
medication when measureable drug levels or pharmacodynamic effects are still likely to be 
present, is 28 days for Afatinib. All events reported within 28 days of the last study 
medication will be considered on-treatment. 
The investigator does not need to actively monitor patients for adverse events once the 
clinical trial has ended. However, if the investigator becomes aware of an SAE that occurred 
after the patient has completed the clinical trial, it should be reported by the investigator to 
the sponsor if considered relevant by the investigator.
All AEs, including those persisting after end of study treatment must be followed up until 
they have resolved or have been sufficiently characterized or the principal investigator 
decides to not further pursue them.
Table 5.2.2.2:1 AE/SAE reporting requirements
Time period
Reporting requirements
For screen failures; From signing of informed 
consent to the timepoint where ineligibility is 
Report all AEs and SAEs. This includes all 


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confirmed
deaths.
For treated patients; From signing of 
informed consent to the end of the follow-up 
visit (28 days after last trial drug 
administration)
Report all AEs and SAEs regardless of 
relatedness or whether the trial drug is 
administered. This includes all deaths.
After the 28 day followup visit until vital 
status followup (VS) is completed
Report all related SAEs. 
After the patient has completed the study
Active monitoring for adverse events is not 
required. If the investigator becomes aware of 
an SAE that occurred after the patient has 
completed the clinical trial it should be 
reported to the sponsor if considered relevant 
by the investigator.
If not stipulated differently in the ISF, the investigator must report the following events using
the SAE form via fax immediately (within 24 hours) to the sponsor: SAEs and non-serious 
AEs relevant to an SAE. The same timeline applies if follow-up information becomes 
available. In specific occasions, the investigator could inform the sponsor via telephone. This 
does not replace the requirement to complete and fax the BI SAE form.
BI has set up a list of AEs which are defined to be always serious. In order to support the 
investigator with the identification of these “always serious adverse events”, if a non-serious 
AE is identified to be serious per BI definition, a query will be raised. The investigator must 
verify the description and seriousness of the event.  If the event description is correct, the 
item “serious” needs to be ticked and an SAE has to be reported in expedited fashion 
following the same procedure as above.
The list of these adverse events can be found via the Remote Data Capture (RDC) system.
With receipt of any further information to these events, a follow-up SAE report has to be 
provided. SAEs and non-serious AEs must include a causal relationship assessment made by 
the investigator.
The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU 
(operative unit) (country-specific contact details will be provided in the Investigator Site 
File). This immediate report is required irrespective of whether the investigational product 
has been administered or not and irrespective of causal relationship. It also applies if new 
information to existing SAEs becomes available. 
Pregnancy
In this study, pregnancy is not expected to occur in female participants with the age of 70 
years or older. In rare cases, pregnancy might occur in a female partner of a male participant
with drug exposure to afatinib; in which case, pregnancy must be reported following BI 
internal SOP using the pregnancy monitoring form (refer to ISF).   


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5.2.3
Assessment of safety laboratory parameters
Safety laboratory samples will be analysed at the investigator’s local laboratory. Safety 
laboratory examinations will include hematology, biochemistry and urine examinations. 
Table 5.2.3: 1 Laboratory tests to be performed
Category
Parameters 
Hematology
Hemoglobin, hematocrit, platelet count, white 
blood cell count (WBC), with differential 
(neutrophils and bands)
Coagulation*
International Normalized Ratio (INR), activated 
Partial Thromboplastin Time (aPTT)
Chemistry
Electrolytes
Sodium, potassium, calcium, magnesium, 
chloride, bicarbonate (HCO3)
Liver function tests
Alkaline phosphatase, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), γ-
glutamyltransferase (GGT), total  bilirubin
Table 5.2.3: 1 Laboratory tests to be performed (continued)
Category
Parameters 
Renal function parameters
Blood urea nitrogen (BUN), creatinine; Creatinine 
clearance (see Appendix 10.3)
Other
Glucose, albumin
Urinalysis*
The following will be tested at baseline and at the 
EOT visit: pH, protein, glucose, ketones, blood, 
leucocytes, nitrite, bilirubin, urobilinogen, and 
specific gravity.  In case of pathological finding 
further evaluation should be performed and 
results documented 
           * tested at Screening and EOT only
The investigator should complete additional evaluations of laboratory tests as clinically 
indicated.  Any abnormal findings from these investigations need to be reported as an 
Adverse Event.


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5.2.4
Electrocardiogram
Electrocardiogram (ECG) is only required at screening. If any additional ECG is performed 
as part of routine clinical care and clinically significant results are found, this will be 
documented in accordance with the adverse event process. 
5.2.5
Assessment of other safety parameters
5.2.5.1 Physical examination, vital signs, height and weight
A full physical exam must include cardiopulmonary examination, examination of the regional 
lymph nodes, and examination of the abdomen and an assessment of the mental and 
neurological status. Additional symptoms which have not been reported during a previous 
examination must be clarified. Wherever possible the same investigator should perform this 
examination.
A complete physical examination will be done at Screening, on Day 1 of each treatment 
course and at the End of Treatment visit. A symptom-directed examination is to be performed 
at all other visits. 
5.2.5.2 Vital Signs
Vital sign measurements should include blood pressure [systolic blood pressure, diastolic 
blood pressure], pulse rate, respiratory rate, temperature and measurement of height (in cm, at 
screening) and body weight (in kg at screening and end of trial). Evaluation of the ECOG PS
(see Appendix 10.1) will be performed at the times specified in the Flowchart.  
 
 
 
 
     
 
 
 
 


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questionnaire that each contains several short measurement tools. In the final GAM, 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


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5.4
APPROPRIATENESS OF MEASUREMENTS
Both CTCAE and 
 criteria used in the study are standard methods. The present 
trial will use CTCAE version 4.0.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Please refer to the Flowchart and Figure 3.1:1 for the visit schedule. All patients are to adhere 
to the visit schedule as specified in the Flow Chart.  
In case a patient misses the scheduled study visit but reports to the investigative site before 
the next scheduled study visit, the missed visit will be performed.  The current date and 
reason for the delayed visit will be noted in the source documentation.  All subsequent study 
visits should take place at the start of the next treatment course per the flow chart.  In the 
event of any study drug interruption or delay of treatment, the tumour assessment scheduled 
will not be changed.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Please refer to the Flowchart and section 5 for details of the procedures performed at each 
visit. 
6.2.1
Screening period
All patients must have documented Deletion 19 and/or L858R EGFR mutation prior to the 
signing of the informed consent. All Screening procedures must be performed within 28 days 
of the first dose of afatinib. Assessments required for study participation which were 
completed as part of Standard of Care before the patient signed the informed consent may be 
used for the screening assessments if they were completed within the allowed timeframe.  
However, presence of Deletion 19 and/or L858R mutation may have been determined prior 
to the 28-day screening window. 
Patients who meet the inclusion criteria and not violate the exclusion criteria at enrolment are 
allowed to take part in this study.
6.2.2
Treatment periods
All patients will receive continuous daily treatment with afatinib until the criteria for stopping 
medication are met (Section 3.3.4.1). For administrative purposes, treatment is divided into 
courses, which are each 4 weeks (28 days) in duration. 
During the treatment phase, visits should be performed as scheduled whenever possible, but 
within the visit window. Deviation in scheduling for administrative purpose would be 
acceptable upon agreement between the investigator and the sponsor.
6.2.3
End of treatment visit
End of treatment visit should be performed within 7 calendar days after permanent 
discontinuation of treatment, regardless of the reason. If the decision to discontinue study 
treatment is taken during a scheduled visit, the EOT visit should be performed instead of the 
scheduled visit.


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6.2.4
Follow-up visit
The follow-up (FU) visit is performed 28-35 days after the last dose of afatinib and is 
primarily to collect follow-up safety information.  
6.2.5 
Vital Status 
For patients that agree to be followed, vital status will be collected every three months until 
the end of the trial. 
6.3
END OF TRIAL
The end of the trial is defined as approximately 12 months after the last patient is entered
(starts trial therapy). 


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
This study is an open-label, single arm study in elderly NSCLC patients with common EGFR 
mutations treated with afatinib.
7.2
NULL AND ALTERNATIVE HYPOTHESES
No formal hypothesis testing will be performed since this is a single arm, uncontrolled study.
This is an exploratory trial and all the statistical analyses will be descriptive.
7.3
PLANNED ANALYSES
All patients who receive at least one dose of afatinib will be included in the treated set.  The 
analyses of safety and efficacy will be performed on the treated set.
Corresponding to the three categories of endpoints, there are three categories of analyses in 
this trial: 1) the primary analysis, 2) secondary analysis, and 3) other analyses. The primary 
and secondary analyses are safety analyses. The category “Other analyses” includes both 
safety and efficacy analyses.
7.3.1
Primary analyses
As the primary endpoint is a safety endpoint, these analyses are described in Section 7.3.3.
7.3.2
Secondary and other analyses
7.3.2.1 Secondary analyses
The secondary safety analyses are described in Section 7.3.3.
 
 


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7.3.3
Safety analyses
Adverse events will be graded according to CTCAE, Version 4.0 (R12-2532).
Adverse events with an onset date from the date of first dose of afatinib until 28 days after the 
last dose of afatinib will be analyzed as ‘on-treatment’ AE.
7.3.3.1
Primary analysis
The proportion of patients with AEs leading to dose reduction of afatinib and an exact  95% 
Clopper-Pearson confidence interval for this proportion will be calculated. Standard 


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tabulations (arranged by MedDRA SOC and PT) for patients with AEs leading to dose 
reduction will also be produced.
7.3.3.2
Secondary analyses
Tables that describe the frequency, time to onset, and clinical consequences will be produced 
for:

CTCAE grade ≥ 3 diarrhoea

CTCAE grade ≥3 rash/acne+

CTCAE grade ≥3 stomatitis+

CTCAE grade≥ 3 paronychia+
Time to first dose reduction of afatinib caused by AEs is defined as follows: 
For patients with AEs leading to dose reduction: 
•
Time _1st_dose_reduction [days] = date of 1st dose reduction – (date of start 
treatment)+1
For patients without AEs leading to dose reduction: 
•
Time _1st_dose _reduction (censored)[days]=date of last intake of afatinib –
(date of start treatment) +1
The time to first dose reduction of afatinib caused by AE’s will be described by Kaplan-
Meier estimates and curve.
7.3.3.3
Other analyses
Standard tabulations arranged by MedDRA SOC and PT will include: 

The overall incidence and intensity of adverse events

AE judged to have been related to afatinib

AE leading to permanent treatment discontinuation

Drug related AE leading to permanent treatment discontinuation

SAE
These standard tables will be supplemented with tables in which MedDRA SMQ and HLT
(with some modifications) will be used to group MedDRA PT for the following:

rash/acne+

stomatitis+

conjunctivitis+

paronychia+

fatigue+
Tables that describe the frequency, intensity, time to onset, and clinical consequences will be 
produced for the following AEs:


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
diarrhea

rash/acne+

stomatitis+

-)(*%6>:$)H
7.3.3.4
Primary laboratory tests
Primary laboratory tests are defined as:

Low values (-): haemoglobin, total WBC, platelets, neutrophils, lymphocytes, 
potassium, magnesium, sodium, and GFR

High values (+): AST, ALT, Alkaline Phosphatase, aPTT, INR, Creatinine, Total 
Bilirubin,  and CPK
The following analyses will be presented for the primary laboratory tests:

descriptive statistics at each planned assessment 

frequency of patients with transitions in CTCAE grade from baseline to worst and last 
values during treatment

frequency of patients with possible clinically significant abnormalities
Possible clinically significant abnormalities are defined as CTCAE grade of 2 or greater, with 
an increase of at least one grade from baseline.
7.3.4
Interim analyses
No interim analyses are planned for this study.
7.4
HANDLING OF MISSING DATA
Handling of missing data will be defined in the TSAP. The category missing will be 
displayed in the frequency tables only if there are actually missing values.
7.5
RANDOMISATION
No randomization is necessary since this is a single arm study.
7.6
DETERMINATION OF SAMPLE SIZE
In the general population of the LUX-Lung 3 study, approximately 60% of the patients 
experienced AEs leading to dose reduction of afatinib. For 25 patients and a 60% dose 
reduction rate (caused by AEs), the 95% CI half-width for the dose reduction rate would be 
19.2% based on a normal approximation, resulting in a two-sided, 95% confidence interval of
(40.8%, 79.2%).  If a lower dose reduction rate of 50% is observed, the resulting 2-sided, 
95% confidence interval would be (30.4%, 69.6%). Similarly, if a higher dose reduction rate 
of 70% is observed the 2-sided, 95% confidence interval would be (52.0%, 88.0%).


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Sample size estimates were derived using nQuery Advisor® 7.0 statistical package by 
Statistical Solutions Ltd.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice and relevant BI Standard Operating Procedures (SOPs). Standard 
medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches
of the protocol/ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in the investigator contract. As a general rule, no trial results should be 
published prior to finalisation of the Clinical Trial Report.
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CRA) (Local Clinical Monitor / Clinical Research Associate ) or Clinical 
Quality Assurance auditors appointed by Boehringer Ingelheim, by appropriate IRB / IEC
members, and by inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance


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auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
8.3
RECORDS
Case Report Forms for individual patients will be provided by the sponsor via remote data 
capture. See Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, 
refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The 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 8.3.1.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not.
Therefore a unique reference document for the evaluation of listedness needs to be provided. 
For afatinib this is the currently approved drug label. The current versions of these reference 
documents are to be provided in the ISF. No AEs are classified as listed for study design, or 
invasive procedures.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File.


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8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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Moy B, Goss PE. Lapatinib-associated toxicity and practical management 
recommendations.  Oncologist 2007;12(7):756-765.
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Yang CH, Shih JX, Su WC, Hsia TC, Tsai CM, Ou SHI, et al.  A phase II 
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Seiwert TY, Fayette J, Campo JM del, Clement PM, Hitt R, Cupissol D, et al. 
Updated results of a randomized, open-label phase II study exploring BIBW 
2992 versus cetuximab in patients with platinum-refractory 
metastatic/recurrent head and neck cancer (SCCHN).  35th Ann Cong of the 
European Society for Medical Oncology (ESMO), Milan, 8-12 Oct 2010 Ann 
Oncol 2010;21(Suppl 8):VIII316 Abstr 1010PD.
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Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, et al.  Phase 
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+ BSC in patients failing 1-2 lines of chemotherapy and erlotinib/gefitinib 
(LUX-Lung 1).  35th Ann Cong of the European Society for Medical Oncology 
(ESMO), Milan 8-12 Oct 2010 (Oral Presentation).
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Porta C, Osanto S, Ravaud A, Climen MA, Vaishampayan U, White DA et al.  
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label, randomised phase 3 trial.  Lancet  Oncol. 2014 Feb;15(2):213-22.
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(Publish Date: 12 December 2003). 
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Heymach JV, Janne PA, Johnson BE, Johnson DH, Lilenbaum RC, Meyerson 
M, Sandler AB, Sequist LV, Settleman J, Wong KK, Hart CS. Summary 
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Cancer: Advances in EGFR-Targeted Agents, Cambridge, 23 - 24 Sep 2005 
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of non-small cell lung cancer. 3rd Cambridge Conf on Novel Agents in the 


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Treatment of Lung Cancer: Advances in EGFR-Targeted Agents, Cambridge, 
23 - 24 Sep 2005 Clin Cancer Res 2006;12 (14) (Suppl), 4441S - 4445S.
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Johnson BE, Janne PA. Epidermal growth factor receptor mutations in patients 
with non-small cell lung cancer. Cancer Res 2005;65(17):7525-7529.
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Doroshow JH. Targeting EGFR in non-small-cell lung cancer. N Engl J Med 
2005;353(2):200-202.
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Sequist LV, Bell DW, Lynch TJ, Haber DA.  Molecular predictors of response 
to epidermal growth factor receptor antagonists in non-small-cell lung cancer. 
J Clin Oncol 2007;25(5), 587-595.
R07-1134
Riely GJ, Politi KA, Miller VA, Pao W. Update on epidermal growth factor 
receptor mutations in non-small cell lung cancer. Clin Cancer Res 2006;12 
(24), 7232–7241.
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Giaccone G, Melosky B, Reck M. Epidermal growth factor receptor inhibitor 
(EGFRI)-associated rash: a suggested novel management paradigm. A 
consensus position from the EGFRI dermatologic toxicity forum. ECCO 14, 
14th Eur Cancer Conf, Barcelona, 23 - 27 Sep 2007 (Poster) 2007.
R07-4078
Lynch TJ, Kim ES, Eaby B, Garey J, West DP, Lacoutoure ME.  Epidermal 
growth factor inhibitor-associated toxicities:  an evolving paradigm in clinical 
management.  Oncologist 2007; 12(5): 610-621.
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Benson AB, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson 
JA, McCallum R, Mitchell EP, O'Dorisio TM, Vokes EE, Wadler S.
Recommended guidelines for the treatment of cancer treatment-induced 
diarrhea.  J Clin Oncol 2004;22 (14), 2918–2926.
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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 2009;45, 228 
– 247.
R09-2250
Wheatley-Price P, Ding K, Seymour L, Clark GM and Shepherd FA. Erlotinib 
for advanced non-small cell lung cancer in the elderly: an analysis of the 
National Cancer Institute of Canada Clinical Trials Group BR.21. J Clin Oncol 
2008;26(14), 2350-2357.
R11-0826
Potthoff K, Hoffheinz R, Hassel JC, Volkenandt M, Lordick F, Hartman JT, 
et al.  Interdisciplinary management of EGFR-inhibitor-induced skin 
reactions:  a German expert opinion.  Ann Oncol 2011;22(3):524-535.
R12-2532        Common terminology criteria for adverse events v4.0 (CTCAE) (publish date: 
May 28, 2009; v4.03: June 14, 2010). Website: 


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www.oncology.tv/.../NationalCancerInstituteUpdatesCTCAEtov403.aspx ; 
Common Terminology Criteria for Adverse Events, Version 4.03. , NCI, NIH, 
DHHS, Publish date: May 28, 2009; 4.0, Publish Date: June 14,2010 4.03.
R12-4000
Petrelli F, Borgonovo K, Cabiddu M, Barni S.  Efficacy of EGFR tyrosine 
kinase inhibitors in patients with EGFR-mutated non-small-cell lung cancer: a 
meta-analysis of 13 randomized trials. Clin Lung Cancer 2012;13 (2), 107 –
114.
R12-4710
American Joint Committee on Cancer (AJCC). Lung cancer staging. 
http://www.cancerstaging.org/staging/posters/lung12x15.pdf (access date: 23 
October 2012) ; (Cancer Staging Poster Series) American Joint Committee on 
Cancer (AJCC) 2009
R14-1350
Merimsky O, Cheng CK, Au JSK, Pawel J von, Reck M
Efficacy and safety of first-line erlotinib in elderly patients with advanced 
non-small cell lung cancer. Oncol Rep 2012; 28, 721–727.
R14-1781
Meoni G, Cecere FL, Lucherini E, Di Costanzo F. Medical treatment of 
advanced non-small cell lung cancer in elderly patients: a review of the role of 
chemotherapy and targeted agents. J Geriatr Oncol 2013;4(3), 282-290.
R14-1839
Lewis JH, Kilgore ML et al. Participation of patients 65 years of age or older 
in cancer clinical trials. J Clin Oncol 2003;21(7), 1383-1389.
R14-1840
Hutchins LF, Unger JM, et al. Underrepresentation of patients 65 years of age
or older in cancer-treatment trials. NEJM 1999;341:20161-7.
R14-2119
Siegelin MD, Borczuk AC. Epidermal growth factor receptor mutations in 
lung adenocarcinoma. Lab Invest. 2014 Feb; 94(2):129-37.
R15-0770
Kurishima K. Erlotinib for elderly patients with non-small-cell lung cancer: 
Subset analysis from a population-based observational study by the Ibaraki 
Thoracic Integrative (POSITIVE) Research Group. Molecular and Clinical 
Oncology 2013; 1:8928-832.
R15-0802
Hurria A, Togawa K, Mohile SG, Owusu C, Klepin HD, Gross CP et 
al. Predicting chemotherapy toxicity in older adults with cancer: a prospective 
multicenter study. J Clin Oncol. 2011;29(25):3457-65.
9.2
UNPUBLISHED REFERENCES
c01802941-09 Investigator’s brochure. Afatinib (BIBW 2992). Version 15. 03 Jul 2014.


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U03-3218-13
. Investigator's Brochure BIBW 2992; 
Indication:  Oral Treatment of Cancer.  Revised 04 July 2013
U07-3128-02
  A Phase I open-label dose escalation study of 
continuous once-daily oral treatment with BIBW 2992 in patients with 
advanced solid tumours.  Trial 1200.4.  30March 2007.  Revised 23 April 
2010.
U08-1023-02
.  A Phase I open-label dose escalation study of 
continuous once-daily oral treatment with BIBW 2992 in patients with 
advanced solid tumors.  Trial 1200.3. 30 January 2008. Revised 25 February 
2010.
<E7IJ7AKI7E 
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-5)>.,* -5;& TO= $% %*%I&#)55 >.55 5;%/ >)%>.( -)'$.%'& +)$5$%/ .(5*'$%$, *( 
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)>'$?)'$%/ #;')'$*%&8 7G Y.>.#,.( 
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11.
DESCRIPTION OF GLOBAL AMENDMENTS
Number of global amendment
1.0
Date of CTP revision
21DEC215
EudraCT number
BI Trial number
1200.209
BI Investigational Product(s)
afatinib
Title of protocol
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as 
changes involve logistical or 
administrative aspects only
Section to be changed
Protocol Synopsis – Test Product Dose
Description of change
Starting dose 30mg daily
Rationale for change
Consistent with clinical practice in 
vulnerable population
Section to be changed
Protocol Synopsis – Efficacy Endpoints
Description of change
Rationale for change
Section to be changed
Flow Chart 
Description of change
Vital Status added to assessments 
Rationale for change
Section to be changed
3.1
Overall Trial Design and Plan
Description of change
Starting dose 30mg daily for eligible 
patients
Rationale for change
All patients will start at 30 mg daily
Section to be changed
3.2
Discussion of Trial Design, Including the 
Choice of Treatment


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Number of global amendment
1.0
Description of change
Starting dose 30mg daily for eligible 
patients
Rationale for change
All patients will start at 30 mg daily
Section to be changed
3.3.3
Exclusion Criteria #10 
Description of change
Added additional language “Pathologically 
documented meningeal carcinomatosis
(i.e. cytology (+) lumbar puncture ; 
radiology reports alone raising this as a 
possibility, in the absence of true 
symptomatology, would not constitute an 
exclusion)”
Rationale for change
Clarification on definition of Meningeal 
Carcinomatosis
Section to be changed
3.3.3
Exclusion #12
Description of change
Previous or concomitant malignancies at 
other sites, except effectively treated non-
melanoma skin cancers, carcinoma in situ 
of the cervix, ductal carcinoma in situ or 
effectively treated malignancy that has 
been in remission for more than 2 years 
and is considered to be cured
Rationale for change
Changed number of years in remission 
from 3 to 2 years
Section to be changed
3.3.4
Removal of patients from therapy or 
assessments
Description of change
Patients that develop brain metastasis 
during the study may continue on trial 
treatment if there is lack of progression in 
other areas.  
Rationale for change
Changed to be consistent with current 
NCCN guidelines
Section to be changed
4.1
Treatments to be Administered
Description of change
Dose strengths 20mg and 30mg tablets 
Rationale for change
Starting dose changed to 30mg daily
Section to be changed
4.1.3
Selection of doses in the trial  
Description of change
Starting dose 30mg daily for eligible 
patients. The 30 mg dose of afatinib in this 
vulnerable patient population (elderly) 
reflects actual clinical practice.
Rationale for change
All patients  will start at 30 mg daily
Section to be changed
4.1.4
Drug assignment and administration of 
doses for each patient 
Description of change
Starting dose 30mg daily for eligible 
patients


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Number of global amendment
1.0
Rationale for change
All patients  will start at 30 mg daily
Section to be changed
4.1.6
Packaging, Labeling and Re-supply
Description of change
Available dosage strengths will be 20 and 
30mg
Rationale for change
All patients will start at 30 mg daily
Section to be changed
5.2.2 
Assessments of safety
Description of change
The intensity of adverse events should be 
classified and recorded according to the 
Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 
and recorded in the eCRF.
Rationale for change
Change in CTCAE version from 3.0 to 
4.0 
Section to be changed
5.2.2.1
Worsening of the underlying disease or 
other pre-existing conditions
Description of change
If progressive disease occurs and is 
associated with symptoms, the term 
“Progressive Disease” should not be 
reported as (S)AE. , however, signs Signs 
and symptoms of progressive disease will 
NOT be reported as an (S)AE (if 
applicable).
Rationale for change
Clarification on how PD is captured in 
the data set
Section to be changed
6.2.5
Vital Status Assessments
Description of change
Vital Status to be collected q3 months 
until the end of the trial. 
Rationale for change
 
Section to be changed
7.3.3
Safety Analysis
Description of change
CTC AE Version 4.0 


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Number of global amendment
1.0
Rationale for change
Change in CTC AE version from 3.0 to 
4.0 
Number of global amendment
2.0
Date of CTP revision
15 FEB 2018
EudraCT number
N/A
BI Trial number
1200.209
BI Investigational Product(s)
Afatinib
Title of protocol
A Single Arm Phase IV Study of Afatinib
in Elderly Patients with recurrent or Stage 
IV Non-Small Cell Lung Cancer (NSCLC) 
Whose Tumors Have Common Epidermal 
Growth Factor Receptor (EGFR) 
mutations (Exon 19 Deletions or Exon 21 
L858R Substitution Mutations)
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as 
changes involve logistical or 
administrative aspects only
Section to be changed
Title Page and Protocol Synopsis 
Description of change
Trial Clinical Monitor
Rationale for change
Change in personnel
Section to be changed
Protocol Synopsis 
Description of change
Number of patients
Rationale for change
Number of anticipated patients changed 
from approximately 50 to approximately 
25 given slow recruitment and identification 
of new potential patients.
Section to be changed
Flow Chart 
Description of change
AE collection
Rationale for change
Clarification that AE collection should 


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Number of global amendment
2.0
occur during screening visit and during 
followup for vital status to be consistent 
with CTP section 5.2.2.2 and Flowchart 
footnote n.
Section to be changed
Flowchart
Description of change
Footnote n
Rationale for change
Clarification that AEs are to be collected 
until 28 days after last trial drug 
administration and that it no longer 
required to collect AEs related to trial 
design.
Section to be changed
3.1
Overall Trial Design and Plan
Description of change
Number of patients
Rationale for change
Number of anticipated patients changed 
from approximately 50 to approximately 
25 given slow recruitment and identification 
of new potential patients.
Section to be changed
3.3
Selection of Trial Population
Description of change
Number of patients
Rationale for change
Number of anticipated patients changed 
from approximately 50 to approximately 
25 given slow recruitment and identification 
of new potential patients. Reference to 
section 3.3.4.2 added.
Section to be changed
3.3
Selection of Trial Population
Description of change
Number of patients enrolled per site
Rationale for change
Number of anticipated patients changed 
from approximately 3-4 patients per site to 
approximately 1-2 patients per site.
Section to be changed
4.1.2
Method of assigning patients to treatment 
groups
Description of change
Number of patients
Rationale for change
Number of anticipated patients changed 
from approximately 50 to approximately 
25 given slow recruitment and identification 
of new potential patients.
Section to be changed
3.3.2
Inclusion Criteria
Description of change
Inclusion Criteria #2 updated
Rationale for change
Text clarified due to typographical error in 
previous amendment
Section to be changed
3.3.2
Inclusion Criteria
Description of change
Inclusion Criteria #5 updated
Rationale for change
Text clarified due to typographical error to 
denote that AST and ALT are to meet 
defined criteria.


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Number of global amendment
2.0
Section to be changed
5.2.2.1
Definitions of adverse events
Description of change
Clarification that worsening will be 
recorded as an (S)AE in the eCRF and 
SAE form (if applicable).
Rationale for change
Addition of SAE form for SAE reporting 
(if applicable).
Section to be changed
5.2.2.2
AE and SAE Reporting
Description of change
Miscellaneous clarifications: 
1) Removal of AESI
2) Clarification of reporting period
3) Removal of electronic submission
process for SAE
Rationale for change
Reference to AESI removed as no AESIs 
are defined for the trial. Clarification that 
events are to be collected until 28 days 
after last administration of trial drug. 
Clarification of requirements for reporting 
during followup for vital status.Electronic 
submission process for SAE collection is 
no longer in effect.
Section to be changed
7.6
Determination of Sample Size
Description of change
Number of patients
Rationale for change
Number of anticipated patients changed 
from approximately 50 to approximately 
25, and sample size has been clarified.


APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
Title: 
 
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
c02364424
3.0
clinical-trial-protocol-revision-02
A Single Arm Phase IV Study of Afatinib in Elderly Patients with recurrent or Stage
IV Non-Small Cell Lung Cancer (NSCLC) Whose Tumors Have Common Epidermal
Growth Factor Receptor (EGFR) mutations (Exon 19 Deletions or Exon 21 L858R
Substitution Mutations)
Approval–Clinical Monitor
22 Feb 2018 17:03 CET
Author-Trial Statistician
22 Feb 2018 18:36 CET
Approval–Clinical Monitor
27 Feb 2018 21:50 CET
Approval-Team Member Medical
Affairs
27 Feb 2018 22:30 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
Technical Version Number:
 
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
c02364424
3.0

SAP_001.pdf: 
TRIAL STATISTICAL ANALYSIS PLAN
C03655893-01
BI Trial No.:
1200.209
Title:
A Single Arm Phase IV Study of Afatinib in Elderly Patients with 
recurrent or Stage IV Non-Small Cell Lung Cancer (NSCLC) 
Whose Tumors Have Common Epidermal Growth Factor Receptor 
(EGFR) mutations (Exon 19 Deletions or Exon 21 L858R 
Substitution Mutations)
(Including Protocol Amendment 1[U#: c02364424-02] and Protocol 
Amendment 2[U#: c02364424-03])
Investigational
Product(s):
Giotrif®/ Gilotrif® (Afatinib)
Responsible trial 
statistician(s):
Email:
Date of statistical 
analysis plan:
25-Mar-2019
Version:
Final
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1.
TABLE OF CONTENTS
1.
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................3
2.
LIST OF ABBREVIATIONS ...............................................................4
3.
INTRODUCTION..................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......7
5.
ENDPOINT(S)........................................................................................8
5.1
PRIMARY ENDPOINT(S) ..........................................................................................................8
5.2
SECONDARY ENDPOINTS.......................................................................................................8
5.2.1
Key secondary endpoints..............................................................................................................8
5.2.2
(Other) Secondary endpoints .......................................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS...........................................10
6.1
TREATMENTS...........................................................................................................................10
6.2
IMPORTANT PROTOCOL DEVIATIONS............................................................................10
6.3
PATIENT SETS ANALYSED ...................................................................................................12
6.5
POOLING OF CENTRES .........................................................................................................13
6.6
HANDLING OF MISSING DATA AND OUTLIERS ............................................................13
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS............................................14
7.
PLANNED ANALYSIS.......................................................................15
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS..................................15
7.2
CONCOMITANT DISEASES AND MEDICATION..............................................................15
7.3
TREATMENT COMPLIANCE ................................................................................................15
7.4
PRIMARY ENDPOINT(S) ........................................................................................................16
7.5
SECONDARY AND FURTHER ENDPOINTS.......................................................................16
7.5.1
Key secondary endpoints............................................................................................................16
7.5.2
(Other) Secondary endpoints .....................................................................................................16
7.7
EXTENT OF EXPOSURE.........................................................................................................18
7.8
SAFETY ANALYSIS..................................................................................................................18
7.8.1
Adverse events.............................................................................................................................18
7.8.2
Laboratory data ..........................................................................................................................20
7.8.3
Vital signs.....................................................................................................................................21
7.8.4
ECG..............................................................................................................................................21
7.8.5
Others...........................................................................................................................................21
8.
REFERENCES.....................................................................................22
10.
HISTORY TABLE...............................................................................24


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LIST OF TABLES
Table 6.1: 1 Study periods .......................................................................................................10
Table 6.2: 1 Important protocol deviations..............................................................................11
Table 10.1 History table...........................................................................................................24


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2.
LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the TSAP
Term
Definition / description
AE
Adverse event
BRPM
Blinded report planning meeting
CR
Complete response
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical trial protocol
CTR
Clinical trial report
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EGFR
Epidermal growth factor receptors
EOT
End of Treatment
ICH
International Conference on Harmonisation
iPD
Important protocol deviation
MedDRA
Medical Dictionary for Regulatory Activities
MQRM
Medical Quality Review Meeting
NSCLC
Non-small cell lung cancer


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Term
Definition / description
PT
Preferred term
Q1
Lower quartile
Q3
Upper quartile
REP
Residual effect period
SAE
Serious adverse event
SD
Stable disease
SOC
System organ class
StD
Standard deviation
TSAP
Trial statistical analysis plan


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol
Amendments. In particular, the TSAP is based on the planned analysis specification as
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., on 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, randomization.
SAS® Version 9.4 or later will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The following changes have been made in the planned analyses prior to database lock:

The trial protocol was amended on 15Feb2018 (global amendment 2) to document 
early study termination due to slow enrollment. The number of patients randomized in 
this trial is expected to be approximately 25 patients instead of 50. 
 
 
 
 
 

Per current standard operating procedures, important protocol violations will be 
summarized as important protocol deviations.


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5.
ENDPOINT(S)
5.1
PRIMARY ENDPOINT(S)
The primary endpoint of this study is the occurrence of adverse events (AEs) leading to dose
reduction of Afatinib. 
This endpoint is a safety endpoint; therefore, analyses are described in Section 7.8.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints 
This section is not applicable as no key secondary endpoints have been specified in the 
protocol.
5.2.2
(Other) Secondary endpoints
The secondary endpoints of the study are

Occurrences of CTCAE grade ≥3 diarrhea,

Occurrences of CTCAE grade ≥3 rash/acne+,

Occurrences of CTCAE grade ≥3 stomatitis+,

Occurrences of CTCAE grade ≥3 paronychia+,

Time to first dose reduction of Afatinib caused by AEs.
Refer to CTP Section 5.2.1 and Section 7.8 of this TSAP for more details. The terms flagged 
by a “+” represent MedDRA preferred terms reported together as one grouped term for 
analysis.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments administered, assignment of dose group and 
selection of doses, see CTP Section 4. All eligible patients will be assigned to receive
Afatinib 30 mg QD in this study. The dose may be reduced to 20 mg QD during the study as 
described in Section 4.4 of the CTP. Unless otherwise stated, treated patients will be 
presented under the starting dose, i.e. 30 mg Afatinib. 
Table 6.1:1 displays the study periods defined for 1200.209. In this study, treatment is 
administered in courses of 28 days. The follow-up period extends from the date of last 
administration of study treatment to the follow-up visit, which should occur 28 to 35 days 
after the last administration of study treatment. After completion of the follow-up period, 
vital status will be monitored every 3 months until the end of the trial, which is defined as 
approximately 12 months after the last patient enters the study.
Table 6.1: 1 Study periods 
Study Period
Start time
Stop time
Screening
Date of informed consent 
Date of 1st administration of 
study treatment – 1 day
On-treatment
Date of 1st administration of 
study treatment
Date of last administration 
of study treatment
Residual effect period
Date of last administration 
of study treatment + 1 day
Date of last administration 
of study treatment + 28 days
Follow-up period (includes 
residual effect period)
Date of last administration 
of study treatment + 1 day
Date of follow-up visit (28-
35 days after date of last 
administration of study 
treatment). 
Post-study vital status
Date of follow-up visit +1
End of trial
6.2
IMPORTANT PROTOCOL DEVIATIONS
The following table (Table 6.2: 1) defines the different categories of important protocol 
deviations (iPD) to be documented during the study. No per-protocol analyses will be 
performed for this study; however, patients identified with some iPDs may be excluded from 
certain analyses as specified in the table. Protocol deviations will be reviewed periodically at 
MQRMs and BRPMs prior to database lock.


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Table 6.2: 1 Important protocol deviations
Category
/ Code
Description
Example/Comment
Excluded 
from
Automatic
/Manual
A
Entrance criteria not met
A1
Inclusion criteria
not met
A1.1
Disease criteria 
not met
Inclusion criteria 1 or 2 not 
met as specified in the protocol 
per IE CRF.
None
Automatic
A1.2
ECOG not 0 or 1.
Inclusion criteria 4 not met or 
ECOG recorded on screening 
physical exam CRF not 0 or 1.
None
Automatic
A1.3
Age at enrollment 
not ≥ 70 years
Inclusion criterion 3 not met or 
AGE<70 years on 
demographics CRF. 
None
Automatic
A1.4
Failure to recover
from previous 
therapy-related 
toxicity
Inclusion criterion 6 not met.
None
Automatic
A1.5
Laboratory values 
do not meet 
inclusion criteria
Inclusion criterion 5 not met.
None
Automatic
A1.6
Other inclusion 
criteria not met
Inclusion criteria 7 or 8 not 
met.
IN7 
=None;
IN8 = see 
B1 below
Automatic
A2
Exclusion criteria not met
A2.1
Prior therapy not 
consistent with 
exclusion criteria
Exclusion criteria 1, 2, 3, 4, or 
5 not met.
None
Automatic
A2.2
Patient has 
excluded medical 
condition
Exclusion criteria 7, 8, 9, 10, 
11, 12, 13, 14, or 15 not met.
None
Automatic
A2.3
Other exclusion 
criteria not met
Exclusion criteria 6, 16 or 17.
None
Automatic
B
Informed consent
B1
Informed consent 
not available/not 
Informed consent date missing; 
no signature on ICF
All
Automatic
/Manual


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Category
/ Code
Description
Example/Comment
Excluded 
from
Automatic
/Manual
done
B2
Informed consent 
given late
Informed consent date <actual 
consent date> after Visit 1 date 
<Visit 1 date>
None
Automatic
/Manual
C
Trial medication
C1
Incorrect trial 
medication taken
Review of dose(s) recorded on 
the drug administration and 
dose change CRFs against 
IWRS reports at MQRM/RPM.
None
Manual
C2
Dose reduction or 
treatment 
discontinuation 
not according to 
protocol.
Review of reported dose 
changes and AEs at 
MQRM/RPM for compliance 
with Sections 3.3.4 and 4.4.1 
of the CTP.
None
Automatic
/Manual
C3
Non-compliance 
with trial 
medication.
Afatinib doses missed for 
reasons other than drug-related 
AEs is >25% of the dispensed 
doses as indicated on 
compliance CRF.
None
Automatic
/Manual
D
Concomitant medication
D1
Use of prohibited 
concomitant 
medication.
Review of concomitant 
medication listings at 
MQRM/RPM for prohibited 
medications as defined in 
Section 4.2.2 of the CTP.
None
Manual
Note: Missing visits, evaluations, and tests will be considered missing data, not protocol deviations.
6.3
PATIENT SETS ANALYSED
The following sets of patient data will be used for analyses:

Enrolled set:
This patient set includes all enrolled (screened) patients who signed informed consent, 
whether treated or not.

Treated set (TS):
This patient set includes all patients who were dispensed study medication and were 
documented to have taken at least one dose of study treatment. All planned efficacy 
and safety analyses will be based on the TS.


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6.5
POOLING OF CENTRES
Descriptive summaries will present data from all centers combined. Center/country will not 
be included in any statistical models.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing or incomplete AE dates will be imputed according to BI standards (see ‘Handling of 
missing and incomplete AE dates’). (4) A separate category for missing values will be 
displayed in frequency tables only if there are missing values for the variable being 
summarized.
 
 
 
 
 
 
 
 
 
Time since diagnosis of NSCLC will be calculated from the date of diagnosis and the date of 
screening. If a partial date of diagnosis is provided, the following imputation rules will be 
used:

If the day is missing but month and year are present, impute day as the first day of the 
month.

If only the year of diagnosis is present, impute month and day of diagnosis to January 
1.
For partial treatment discontinuation dates, the following logic will apply:

If the patient died within the same month and year as treatment discontinuation, use 
the date of death as the treatment discontinuation date.


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
Otherwise, if day is missing, but month and year are present, use the last day of the 
month.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
In general, baseline values are the last non-missing measurements collected prior to the first 
administration of study treatment. Typically, this is the value collected at the screening visit.
Nominal visit numbers as recorded in the eCRF will be used; there will be no windowing of 
visits. Study day will be calculated relative to the date of first administration of study 
treatment. The day prior to date of first administration will be ‘Day -1’, and the date of first 
administration of study treatment will be ‘Day 1’. There will be no ‘Day 0’.
 
 
 
 
 


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7.
PLANNED ANALYSIS
Unless otherwise specified, summary statistics for continuous data will include: N, mean, 
StD, minimum, median and maximum
Tabulations of categorical data will include all possible categories and will display the 
number of observations in each category with the percentage (%) of the respective treatment 
group, unless otherwise specified. Percentages will be rounded to one decimal place. A
category for missing values will be displayed only if there are actual missing values for a 
variable.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. Demographic and 
baseline characteristics to be summarized include:

Age [years]

Sex (male/female)

Race and ethnicity (as defined in the eCRF)

Smoking and alcohol use status (as defined in the eCRF)

Height [cm], weight [kg] and body mass index [kg/m2]

ECOG performance status

EGFR mutation status (negative, L858R, Del19, both, other)

Oncology history

Medical conditions,

Concomitant medications.

Treatment exposure and compliance

Vital signs
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. 
7.3
TREATMENT COMPLIANCE
Treatment compliance during each visit interval will be calculated as:


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Treatment compliance (%) =
	 
 
   
	 
 
  
   
Overall treatment compliance is the weighted average of available treatment compliance for 
each visit interval weighted by number of days within the interval. For example: patient 
whose compliance score=80% at Visit 3, 100% at Visit 4, 100% at Visit 5, the overall 
compliance for this patient is [(compliance score date at V3 – treatment start date at V2)*0.8 
+ (compliance score date at V4 - treatment start date at V3)*1 + (compliance score date at V5 
- treatment start date at V4)*1]/( compliance score date at V5 - treatment start date).  
Overall compliance will be summarized descriptively, and the number and percentage of 
treated patients reported as compliant with study treatment, defined as overall compliance >
75%, and non-compliance, defined as overall compliance ≤75%, will be summarized.
7.4
PRIMARY ENDPOINT(S)
Primary endpoint analysis is described in Section 7.8 (Safety Analysis).
7.5
SECONDARY AND FURTHER ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
(Other) Secondary endpoints
Secondary endpoints are described in Section 7.8 (Safety Analysis).


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7.7
EXTENT OF EXPOSURE
Total time on treatment (days and number of courses) will be calculated for each patient as 
follows:
Exposure time = (date of last administration of study treatment) – (date of first 
administration of study treatment) + 1
Periods of time reported as off study treatment due to non-compliance or toxicity prior to 
permanent discontinuation of study treatment will be included in the calculation of treatment 
time. Descriptive summaries of time on treatment and number of courses of treatment will be 
presented for all treated patients. Summary of exposure by dose level (30 mg and 20 mg) will 
also be provided.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set.
7.8.1
Adverse events
Adverse events will be coded using the most current MedDRA version at the time of database 
lock. The intensity of adverse events will be graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0. 
All the analyses of adverse events will be descriptive and will be based on the numbers of 
patients reported AEs, not on the number of events reported. For further details on 
summarization of AE data, please refer to the guideline ‘Analysis and presentation of adverse 
event data from clinical trials‘(5).
Analyses of adverse events will be based on the concept of treatment emergent events. As 
such, all adverse events with an onset date between the dates of first dose of study treatment 
until 28 days after the last dose of study treatment will be analyzed as on-treatment AEs. All 


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adverse events occurring before first dose of study treatment will be assigned to ‘screening’ 
and all adverse events occurring after last dose of study treatment + 28 days will be assigned 
to ‘post-treatment’.
An overall summary of adverse events will be presented. This summary will include the 
following event categories:

All AEs

Drug-related AEs

AEs leading to dose reduction

AEs leading to treatment discontinuation

Serious AEs (SAE)

Highest CTC grade
The frequency and percentage of patients with adverse events will be summarized by highest 
CTC grade, treatment, primary system organ class (SOC) and preferred term (PT) in each of 
the following tables:

All AEs

Drug-related AEs

AEs leading to dose reduction

AEs leading to treatment discontinuation

Drug-related AEs leading to treatment discontinuation

SAEs

Drug-related SAEs

AEs leading to death
Events in all tables will be sorted by SOC according to the standard sort order specified by 
the European Medicines Agency (EMA); PTs will be sorted by frequency within SOC.
Primary endpoint: AEs leading to dose reduction
The frequency and percentage of treated patients reporting the primary endpoint of an AE 
leading to dose reduction will be reported with an exact 95% Clopper-Pearson confidence 
interval for this proportion. No formal hypothesis testing will be performed.


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Secondary endpoint: Time to first dose reduction of study treatment caused by an AE
The following definitions will be used to analyze the secondary endpoint of time to first dose 
reduction of study treatment caused by an AE.
For patients with AEs leading to dose reduction:
Time to first dose reduction [days] = (date of first dose reduction) – (date of first 
administration of study treatment) + 1
For patients without AEs leading to dose reduction:
Time to first dose reduction (censored) [days] = (date of last administration of study 
treatment) – (date of first administration of study treatment) + 1
The Kaplan-Meier estimate of median time to first dose reduction of study treatment due to 
AE will be presented, if calculable. In addition, the cumulative percentage of patients with 
dose reductions due to each AE by time interval will be summarized..
Secondary endpoint: Occurrence of CTCAE grade 3 or higher diarrhea, rash/acne+, 
stomatitis+ and paronychia+
The frequency and percentage of treated patients reporting project-defined grouped terms, 
including diarrhea, rash/acne+, stomatitis+ or paronychia+, will be summarized. The 
frequency of events will be summarized by highest CTC grade, i.e. grade 3, 4 or 5, treatment, 
SOC and PT.
Events designated with a ‘+’ are project-defined grouped terms. Definitions of the project-
defined groupings are included in the technical TSAP. In the summary table, the grouped 
AEs will replace the MedDRA PTs for all AEs included in the grouped term. A reference 
table presenting the grouped terms and the MedDRA PTs within each grouping will also be 
produced.
Listings for events within the grouped terms of diarrhea, rash/acne+, stomatitis+ or 
paronychia+ will display intensity, time to onset and clinical consequences of these events.
7.8.2
Laboratory data
Analyses of laboratory data will be descriptive and will be based on BI standards (6).
Primary laboratory tests defined in the protocol include:

Low values (-): haemoglobin, total WBC, platelets, neutrophils, lymphocytes, 
potassium, magnesium, sodium, and GFR

High values (+): AST, ALT, alkaline phosphatase, aPTT, INR, creatinine, total 
bilirubin, and CPK


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The following analyses will be presented for the primary laboratory tests:

Descriptive statistics at each planned assessment

Frequency of patients with transitions in CTCAE grade from baseline to worst value 
and from baseline to last values collected during treatment

Frequency of patients with possible clinically significant abnormalities
Possible clinically significant abnormalities are defined as CTCAE grade 2 or higher with an 
increase of at least one grade from baseline.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report. Summaries of absolute 
values and changes from baseline will be presented for systolic blood pressure, diastolic 
blood pressure, pulse rate, respiratory rate, and body temperature.
7.8.4
ECG
Abnormalities observed on ECGs will be recorded as baseline conditions or adverse events, 
as appropriate. No additional analyses of ECG findings are necessary.
7.8.5
Others
Not applicable.


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8.
REFERENCES
1. CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9, Note For Guidance on Statistical Principles for Clinical Trials, current 
version.
2.
 
3. Common terminology criteria for adverse events v4.0 (CTCAE) (publish date:
May 28, 2009; v4.03: June 14, 2010). Website:
www.oncology.tv/.../NationalCancerInstituteUpdatesCTCAEtov403.aspx;
Common Terminology Criteria for Adverse Events, Version 4.03. , NCI, 
NIH,DHHS, Publish date: May 28, 2009; 4.0, Publish Date: June 14,2010 4.03
[R12-2532].
 
 
 


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10.
HISTORY TABLE
Table 10.1 History table 
Version
Date
(DD-Mmm-
YY)
Author
Sections 
changed
Brief description of change
Final
25-Mar 19
None
This is the final TSAP without 
any modification.