Real-World Effectiveness of Afatinib (Gilotrif) Following Immunotherapy in the Treatment of Metastatic, Squamous Cell Carcinoma of the Lung: A Multi-Site Retrospective Chart Review Study in the U.S.
Conditions: Squamous Non-small Cell Lung Cancer
Sponsor: Boehringer Ingelheim

001-MCS-90-124_RD-01 (4.0)
TITLE PAGE 
 
 
 
 
CONFIDENTIAL
Protocol for non-interventional studies based on existing data 
TITLE PAGE 
Document Number: 
<document number> 
BI Study Number: 
1200-0325 
BI Investigational 
Product(s): 
Gilotrif® (afatinib) 
Title: 
Real-World Effectiveness of Afatinib (Gilotrif) Following 
Immunotherapy in the Treatment of Metastatic, Squamous Cell 
Carcinoma of the Lung: A Multi-Site Retrospective Chart 
Review Study in the U.S. 
Protocol version 
identifier: 
v1.0 
Date of last version of 
protocol: 
20-SEP-2019 
PASS: 
Yes 
EU PAS register 
number: 
No 
Active substance: 
Afatinib 
Antineoplastic agents, tyrosine kinase inhibitors 
ATC code: L01XE13 
Medicinal product: 
Gilotrif 40 mg, 30 mg, 20 mg 
Product reference: 
20 mg: NDC: 0597-0141-30 
30 mg: NDC: 0597-0137-30 
40 mg: NDC: 0597-0138-30 
Procedure number: 
N/A 
Joint PASS: 
No 
Research question and 
objectives: 
1) To describe the demographic and clinical characteristics of
patients who, after failure of 1L pembrolizumab in
combination with chemotherapy, received either afatinib in 
2L or chemotherapy in 2L (single-agent, doublet, and by
specific regimen).
2)
To describe time on treatment for patients who, after
failure of 1L pembrolizumab in combination with
chemotherapy, received either afatinib in 2L or
chemotherapy in 2L (single-agent, doublet, and by specific 
regimen).
3) To describe the incidence of severe (grade 3 or higher)
irAEs of specific interest (including pneumonitis, colitis,
hepatitis, interstitial lung disease, higher indeterminate
pulmonary events, death, or discontinuation of therapy due
to toxicity) during 2L treatment with afatinib or

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chemotherapy following failure of 1L pembrolizumab in 
combination with chemotherapy. 
Country(-ies) of study: 
United States 
Authors: 
Marketing authorisation 
holder(s): 
MAH contact person: 
N/A 
Date: 
20-SEP-2019 
 
Page 1 of 29 
 
Proprietary confidential information 
© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission 
 

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1. 
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................. 1 
1. 
TABLE OF CONTENTS ....................................................................................... 3 
2. 
LIST OF ABBREVIATIONS ................................................................................ 5 
3. 
RESPONSIBLE PARTIES .................................................................................... 6 
4. 
ABSTRACT ........................................................................................................... 7 
5. 
AMENDMENTS AND UPDATES ..................................................................... 10 
6. 
MILESTONES ..................................................................................................... 11 
7. 
RATIONALE AND BACKGROUND ................................................................ 12 
8. 
RESEARCH QUESTION AND OBJECTIVES ................................................. 13 
9. 
RESEARCH METHODS .................................................................................... 14 
9.1 
STUDY DESIGN ............................................................................................ 14 
9.2 
SETTING ........................................................................................................ 14 
9.2.1 
Provider/Site/Patient Selection ................................................................ 15 
9.3 
VARIABLES .................................................................................................. 16 
9.3.1 
Exposures ................................................................................................ 17 
9.3.2 
Outcomes ................................................................................................. 18 
9.3.2.1 Primary outcomes .................................................................................. 18 
9.3.2.2 Secondary outcomes .............................................................................. 18 
 
 
9.3.3 
Covariates ................................................................................................ 18 
9.4 
DATA SOURCES ........................................................................................... 18 
9.4.1 
Source Documents ................................................................................... 19 
9.4.2 
Dataset and Records ................................................................................ 19 
9.5 
STUDY SIZE .................................................................................................. 19 
9.6 
DATA MANAGEMENT ................................................................................ 19 
9.7 
DATA ANALYSIS ......................................................................................... 20 
9.7.1 
Main analysis ........................................................................................... 20 
 
 
9.8 
QUALITY CONTROL ................................................................................... 20 
9.8.1 
eCRF Functionality Testing .................................................................... 20 
9.8.2 
Data Validation ....................................................................................... 21 
9.9 
LIMITATIONS OF THE RESEARCH METHODS ...................................... 22 
9.10 
OTHER ASPECTS ......................................................................................... 23 

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9.11 
SUBJECTS ...................................................................................................... 23 
9.11.1 
Cases ........................................................................................................ 23 
9.11.2 
Controls ................................................................................................... 23 
9.12 
BIAS ................................................................................................................ 23 
10. 
PROTECTION OF HUMAN SUBJECTS .......................................................... 24 
11. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ....................................................................................................... 25 
12. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS ............................................................................................................ 29 
13. 
REFERENCES .................................................................................................... 30 
13.1 
PUBLISHED REFERENCES ......................................................................... 30 
13.2 
UNPUBLISHED REFERENCES ................................................................... 30 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS .............................................. 31 
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS ................................. 32 
ANNEX 3. ADDITIONAL INFORMATION .............................................................. 33 

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2. 
LIST OF ABBREVIATIONS 
1L 
First-line 
2L 
Second-line 
3L 
Third-line 
AE 
Adverse Event 
CHSS 
Cardinal Health Specialty Solutions 
CI 
Confidence Interval 
CRF 
Case Report Form 
CTR 
Clinical Trial Report 
DOT 
Duration of Treatment 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EMR 
Electronic Medical Record 
HIPAA 
Health Insurance Portability and Accountability Act 
irAE 
Immune-related adverse events 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ISPE 
International Society for Pharmacoepidemiology 
I-O 
Immuno-oncology 
KM 
Kaplan-Meier 
NSCLC 
Non-small cell lung cancer 
OS 
Overall survival 
OPU 
Operative Unit 
PD-L1 
Programmed death-ligand 1 
PHI 
Protected Health Information 
PFS 
Progression-free survival 
PS 
Performance Status 
SAE 
Serious Adverse Event 
SPC 
Summary of Product Characteristics 
SqCC 
Squamous cell carcinoma of the lung 
Sq NSCLC 
Squamous non-small cell lung cancer 
STROBE 
Strengthening the Reporting of Observational Studies in 
Epidemiology 
US 
United States 
 

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3. 
RESPONSIBLE PARTIES 
 
Principal Investigator 
Clinical Investigator 
 
Study Statistician 
Project 
 
Research 
 
Clinical Analyst 

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4. 
ABSTRACT 
Name of company: 
 
 
 
Boehringer Ingelheim 
Name of finished medicinal 
product:  
Gi(l)otrif® 
 
Name of active ingredient: 
afatinib 
Antineoplastic agents, tyrosine kinase 
inhibitors 
ATC code: L01XE13 
 
Protocol date: 
Study 
number: 
Version/Revision: 
Version/Revision 
date: 
20 September 2019 
 
1.0 
 
Title of study: 
Real-World Effectiveness of Afatinib (Gilotrif) Following 
Immunotherapy in the Treatment of Metastatic, Squamous Cell 
Carcinoma of the Lung: A Multi-Site Retrospective Chart Review 
Study in the U.S. 
 
Rationale and 
background: 
Pembrolizumab in combination with platinum-doublet chemotherapy 
is the only U.S. Food and Drug Administration approved, first-line 
(1L) treatment for patients with squamous non-small cell lung cancer 
(Sq NSCLC) and is now considered the standard of care based on 
results from KEYNOTE-407 presented at the American Society of 
Clinical Oncology annual meeting in June 2018. The effectiveness of 
afatinib or single-agent chemotherapy as second-line (2L) treatment 
following exposure to pembrolizumab in combination with platinum-
doublet chemotherapy is unknown as no clinical trials have evaluated 
safety and efficacy of 2L treatments in this setting. This study will use 
real-world data to examine differences in patient characteristics 
leading to disease progression and subsequent treatment in 2L with 
either afatinib or chemotherapy (either single-agent or doublet), 
evaluate and describe time on treatment between these cohorts, and 
examine the rate of occurrence of immune-related adverse events 
(irAEs) during 2L afatinib or chemotherapy.  

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Research question 
and objectives: 
1) To describe the demographic and clinical characteristics of 
patients who, after failure of 1L pembrolizumab in combination 
with chemotherapy, received either afatinib in 2L or chemotherapy 
in 2L (single-agent, doublet, and by specific regimen).  
2) To describe time on treatment for patients who, after failure of 1L 
pembrolizumab in combination with chemotherapy, received 
either afatinib in 2L or chemotherapy in 2L (single-agent, doublet, 
and by specific regimen). 
3) To describe the incidence of severe (grade 3 or higher) irAEs of 
specific interest (including pneumonitis, colitis, hepatitis, 
interstitial lung disease, higher indeterminate pulmonary events, 
death, or discontinuation of therapy due to toxicity) during 2L 
treatment with afatinib or chemotherapy following failure of 1L 
pembrolizumab in combination with chemotherapy. 
Study design: 
This is a non-interventional, multi-site cohort study based on existing 
data from electronic medical records of patients with advanced or 
metastatic Sq NSCLC treated with pembrolizumab in combination 
with platinum doublet chemotherapy as 1L treatment followed by 
either afatinib as 2L treatment or chemotherapy as 2L treatment. 
Population: 
U.S.-based community oncologists will select patients meeting the 
study eligibility criteria as describe below.  
 
Inclusion Criteria: 
 
Diagnosis of squamous or mixed histology non-small cell lung 
cancer. 
 
Treated with pembrolizumab in combination with platinum-based 
chemotherapy as initial therapy for advanced or metastatic disease 
(stage IIIB or IV). 
o First cycle of pembrolizumab containing therapy 
received after 06/01/2018. 
o Permanently discontinued 1L pembrolizumab 
containing treatment. 
 
Initiated second-line treatment at least 3 months prior to data 
collection with either: 
o Afatinib 
o Any chemotherapy 
 
Age ≥ 18 years  
          Exclusion Criteria: 
 
Received pembrolizumab in combination with platinum-based 
chemotherapy as part of an interventional clinical trial. 
Variables: 
Primary Outcome(s): 
1) Demographics, clinical characteristics and treatment history of 
patients who receive 2L afatinib or 2L chemotherapy 
2) Time on treatment in 2L with afatinib and time on treatment in 
2L with chemotherapy  
3) Incidence rates of severe (grade 3 or higher) irAEs of specific 
interest during 2L treatment (including pneumonitis, colitis, 
hepatitis, interstitial lung disease, indeterminate pulmonary 
events, death or discontinuation of 2L therapy due to toxicity) 

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Data sources: 
Data will be collected from patients’ medical records and recorded in 
an electronic case report form by the patient’s treating provider. 
Providers will be recruited to participate from a list of over 7,000 
oncologists, haematologists and urologists from across the US.  
Study size: 
Total enrolled: approximately 200 patients including 100 patients 
treated in 2L with afatinib and 100 patients treated in 2L with 
chemotherapy. 
Data analysis: 
Descriptive analysis of demographics, clinical characteristics, and 
treatment history of patients treated in 2L with afatinib and those 
treated in 2L chemotherapy. 
Time on treatment will be described in each 2L cohort (with no 
comparisons made)  using the Kaplan-Meier method, and the median, 
along with two-sided 95% confidence intervals, and 3-, 6-, 9- and 12-
month rates of discontinuation will be reported. Time on treatment is 
defined in months as the interval from the start of 2L treatment until 
the end of 2L treatment or death date by any cause. 
Incidence rates of severe irAEs of specific interest during 2L afatinib 
treatment or 2L chemotherapy will be estimated as the number of 
events divided by the total person-years of follow-up. Additionally, the 
incidence rates among patients who completed 2L therapy will be 
reported.  
Milestones: 
Start of data collection January 2020 
End of data collection in March 2020* 
Study progress report in February 2020 
Final report of study results expected in May 2020 
*The results of this descriptive study may be used to inform a follow-
up comparative study for which additional data collection time may be 
required. 
 

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5. 
AMENDMENTS AND UPDATES 
None 

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6. 
MILESTONES 
Milestone 
Planned Date 
Start of data collection 
13 January 2020 
End of data collection  
10 February 2020 
Study progress report/interim results* 
28 February 2020 
End of data collection (quality control 
assessment and update completed) 
27 March 2020 
Final report of study results 
29 May 2020 
* The results of this descriptive study may be used to inform a follow-up comparative study for which 
additional data collection time may be required. The protocol may be amended at that time. 

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7. 
RATIONALE AND BACKGROUND 
Squamous cell carcinoma (SqCC) of the lung accounts for 20-30% of non-small cell lung 
cancer (NSCLC) cases.1 The underlying molecular pathogenesis of SqCC of the lung is less 
well understood than other histologies.2 Historically, the standard of care in first-line (1L) has 
been platinum-doublet chemotherapy which provides a response rate of approximately 20% 
and a median overall survival (OS) of less than 8 months.3,4 Upon disease progression, three 
targeted agents, afatinib, erlotinib, and ramucirumab, are approved as second-line (2L) 
therapy. Afatinib (Gilotrif) is an irreversible kinase inhibitor of EGFR (ErbB1), HER2 
(ErbB2), and HER4 (ErbB4). Aberrations in the ErbB/HER family have been found in 
approximately 22% of patients with advanced, squamous non-small cell lung cancer 
(NSCLC).5 Afatinib was approved in 2016 for the treatment of patients with metastatic, 
squamous NSCLC progressing after platinum-based chemotherapy based on the findings of 
the LUX-Lung-8 trial that demonstrated improved overall survival (OS) and progression-free 
survival (PFS) in comparison to those who received erlotinib in 2L.6  
 
In October 2018 pembrolizumab in combination with carboplatin and either paclitaxel or nab-
paclitaxel was approved by the U.S. Food and Drug Administration for 1L treatment of 
metastatic SqCC of the lung. In the Keynote-407 trial, the median OS in the 
pembrolizumab/chemotherapy combination arm was 15.9 months compared to 11.3 months 
in the placebo-combination group (with consistent results regardless of PD-L1 expression 
level).7 Results of the Keynote-407 trial were initially presented at the American Society of 
Clinical Oncology (ASCO) annual meeting in June 2018.8 Subsequently the National 
Comprehensive Cancer Network guidelines for 1L treatment of squamous NSCLC were 
updated with the combination receiving a category 2A recommendation establishing a new 
1L standard of care within one month of the ASCO presentation.9 Pembrolizumab in 
combination with chemotherapy remains the only approved 1L treatment at this time.    
 
Randomized controlled trials of afatinib following any 1L immuno-oncology (I-O) treatment 
for metastatic SqCC of the lung have yet to be undertaken. However, preliminary feasibility 
and market research have shown utilization of afatinib as 2L and third-line (3L) therapy 
following 1L I-O monotherapy or 1L I-O in combination with chemotherapy. As such, there 
is a significant need to describe the patient types and effectiveness of afatinib, as 2L, 
following 1L I-O plus chemotherapy, given that LUX-Lung-8 was specific to afatinib 
following initial chemotherapy only. Moreover, while IO therapy and EGFR tyrosine-kinase 
inhibitors have demonstrably different mechanisms of action severe immune-related adverse 
events (irAEs) have occurred in patients who have received sequential I-O to EGFR therapy 
or concurrent IO/EGFR combination therapy.10-11 These events include grade 3 or higher 
pneumonitis, colitis, hepatitis, interstitial lung disease, or indeterminate pulmonary events.  
Therefore, real-world data from patients treated in community oncology clinics in the U.S. is 
needed to further examine the incidence and outcomes of these severe irAEs of specific 
interest. 
 
 
 

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8. 
RESEARCH QUESTION AND OBJECTIVES 
With a new 1L standard of care for patients with SqCC of the lung, the profile and outcomes 
for patients who progress and receive afatinib as 2L therapy have not been characterized. The 
proposed research study will aim to answer the following key questions: 
 
1) What are the demographic and clinical differences between patients who received 
afatinib following pembrolizumab combination with chemotherapy (e.g. afatinib 
as 2L) versus those who receive 2L chemotherapy and are never treated with 
afatinib? 
2) What is the real-world time on treatment for patients who receive afatinib after 
failure following 1L pembrolizumab combination with chemotherapy? What is the 
time on treatment for those receiving 2L chemotherapy after prior pembrolizumab 
plus chemotherapy? 
3) What are the real-world rates of severe irAEs during 2L treatment with afatinib or 
chemotherapy following 1L pembrolizumab plus chemotherapy?  
 
To address these research questions the following objectives are proposed for this 
retrospective, observational study: 
 
1) To describe the demographic and clinical characteristics of patients, who after failure 
of 1L pembrolizumab in combination with chemotherapy, received either afatinib in 
2L or chemotherapy in 2L (single-agent, doublet, and by specific regimen).  
2) To describe time on treatment in 2L for patients who, after failure of 1L 
pembrolizumab in combination with chemotherapy, received either afatinib or 
chemotherapy in 2L (single-agent, doublet, and by specific regimen). 
3) To describe the incidence of severe (grade 3 or higher) irAEs of specific interest 
(including pneumonitis, colitis, hepatitis, interstitial lung disease, higher 
indeterminate pulmonary events, death, or discontinuation of therapy due to toxicity) 
during 2L treatment with afatinib or chemotherapy following failure of 1L 
pembrolizumab in combination with chemotherapy. 
 

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9. 
RESEARCH METHODS 
9.1 
STUDY DESIGN 
This is a non-interventional, retrospective, multi-site cohort study based on existing data from 
medical records of patients with metastatic SqCC of the lung treated with pembrolizumab in 
combination with platinum doublet chemotherapy as 1L treatment followed by either afatinib 
as 2L treatment or chemotherapy as 2L treatment. Data collection will begin after December 
2019 and complete in February 2020. All patients are required to have initiated 1L 
pembrolizumab and platinum combination chemotherapy after 01 June 2018 (post release of 
the Keynote-407 trial results at ASCO Annual Meeting), discontinued 1L therapy, and 
initiated 2L treatment at least 3 months prior to the date of data collection. As such the 
maximum follow-up period for patients is approximately 15 months. The index date is the 
date of initiation of 2L therapy with either afatinib or chemotherapy. The proposed research 
design allows for nearly real-time data collection with no lag, abstraction of detailed clinical 
and treatment-related data points, and determination of the date of death. 
 
In total, approximately 200 patients will be selected for this study of whom approximately 
100 are 2L afatinib treated and 100 who are treated in 2L with chemotherapy. The objectives 
of this study are to describe patient demographics and clinical characteristics at diagnosis and 
discontinuation of 1L therapy for each cohort. As a retrospective, descriptive study no direct 
comparisons between cohorts will be made. In addition to describe the patient cohort 
characteristics time on treatment will be estimated. Time on treatment is defined as the 
interval from the start of 2L treatment until the end of 2L treatment or death date by any 
cause. Finally, the frequency and timing of irAEs during afatinib treatment will be assessed. 
The results of this descriptive study may be used to inform a follow-up comparative study for 
which additional data collection time may be required. 
 
The limitations of this approach include provider selection bias, patient selection bias, and the 
inability to perform source document verification. As only providers who meet the study 
eligibility requirements and who volunteer to participate in the research study are known the 
representativeness of the providers to all oncologists in the U.S. cannot be verified directly. 
Second, providers will select the patients meeting the study eligibility criteria and providers 
may not include all patients who could be eligible. The representativeness of the patient 
sample to all patients in the U.S. cannot be verified. Source document verification cannot be 
performed, however quality assessment/quality control procedure to minimize 
misclassification errors are described in Section 9.8 – Quality Control. 
9.2 
SETTING 
Approximately 20 or more unique providers will participate in this research study. To 
minimize potential bias the maximum number of patients each provider may select and 
complete data abstraction is capped at 10. Data will be collected through an electronic case 
report form (eCRF) completed by the patient’s providers volunteering to participate in the 
study. Providers will be compensated at fair market value for the time to complete data 
abstraction and quality control procedures which is assumed to take approximately 1 hour per 
patient.  
 

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Recruitment of providers will be conducted electronically. Providers who responded to an 
initial feasibility request who reported treating potentially eligible patients will be contacted 
and invited to participate. Recruitment to fill the 200 patient quota will run for 4 weeks from 
the data of recruitment launch. During that time the per cohort quotas will be electronically 
monitored to ensure that the final samples are balanced with 100 patients in each arm. As 
recruitment for a cohort is completed no further patient data entry will be allowed for that 
cohort, however providers actively completing an eCRF at the time of quota close for a 
cohort will be allowed to complete that eCRF and the total number of patients per cohort may 
exceed 100.  
 
Providers will be asked to identify all eligible patients, and chronologically, starting with the 
earliest index date, select consecutive patients meeting the eligibility criteria and complete 
data abstraction. The eCRF is structured to allow data collection regarding patient clinical 
history at the time of initial diagnosis of lung cancer, initiation of 1L therapy, initiation of 2L 
therapy, treatment regimens (including dates of starts, stops, interruptions) during 1L and 2L, 
dates of disease progression, severe irAEs of specific interest, subsequent regimens used in 
3L and beyond, and date of death. For severe irAEs the physician will be provided with 
information regarding the CTCAE definition of each of the specific events of interest. The 
provider will make the final determination as to whether the event occurred (e.g. distinction 
between severe diarrhea and colitis) and the attribution of the event or substantiation of either 
the event grade or attribution cannot be completed. Events are considered a bonafide irAE if 
documented as immune-mediated in real time by the primary oncologist involved in the care 
of the patient and supported by radiologic and/or pathologic evidence. Adverse events that 
were possibly immune-mediated but had alternative or mixed etiologies will be termed 
“indeterminate irAEs” and considered separately. 
9.2.1 
Provider/Site/Patient Selection 
Providers 
Provider will be eligible to participate in this research study who meet the following criteria: 
1) Board certified hematologist/oncologist.  
2) Have treated/are treating at least two patients with Sq NSCLC in 1L with I-
O/platinum chemotherapy combination. 
3) Have treated at least two NSCLC patients with afatinib since 2016. 
4) Able to participate in research covered by a central institutional review board (IRB). 
 
Patients 
Providers will select patients meeting the study eligibility criteria as describe below. 
Providers will be asked to select eligible patients chronologically, starting with the first 
patient who first initiated 2L afatinib or chemotherapy on or after 06/01/2018 but at least 3 
months prior to data collection, and then randomly from that point forward until they have 
submitted their maximum number of patients or no further patients are evaluable. 
 
 
Inclusion Criteria: 
 Diagnosis of squamous or mixed histology non-small cell lung cancer. 
 Treated with pembrolizumab in combination with platinum-based chemotherapy as 
initial therapy for advanced or metastatic disease (stage IIIB or IV). 
o First cycle of pembrolizumab received after 06/01/2018  

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o Permanently discontinued 1L pembrolizumab treatment. 
 Initiated second-line treatment at least 3 months prior to the date of data collection. 
with either : 
o Afatinib 
o Any chemotherapy 
 Age ≥ 18 years  
 
 
Exclusion Criteria: 
 
 Received pembrolizumab in combination with platinum-based chemotherapy as part 
of an interventional clinical trial. 
 
Patients who were treated with pembrolizumab in combination with platinum-based 
chemotherapy as part of a clinical trial will not be selected to ensure the non-interventional 
nature of the study design and that no differential care was received. 
9.3 
VARIABLES 
The patients treated/managing provider is the chart data abstractor in this study. The provider 
will review the patients EHR and abstract the data points described below from the EHR into 
the eCRF. Source documents (e.g. the structured fields of the EMR database) will not be 
provided to Cardinal Health. All the variables described below will be transformed into a 
series of questions the provider will answer based on the data in the EHR. The data points 
described below will be collected for each of the study cohorts (2L afatinib and 2L other 
chemotherapy).  
Providers 
• 
Provider characteristics: practice location, practice size, urban versus rural location, 
years in practice, number of Sq NSCLC patients treated/treating, medical specialty 
 
Patient Demographics/Clinical Characteristics 
• 
Patient demographics: sex, year of birth, payer at initiation of 2L, region of primary 
residence, race/ethnicity, Hispanic 
• 
Smoking history at time of diagnosis: never, former, current 
• 
Date of initial lung cancer diagnosis, date of diagnosis of advanced/metastatic disease 
• 
NSCLC histology 
• 
Stage (pathological and clinical) at initial diagnosis 
• 
Molecular/genetic mutations reported: Erb1/Her2 (ErbB2)/3 (ErbB3)/4 (ErbB4), PD-
1(L1), if available 
• 
Method of testing (e.g., NGS, etc.) 
• 
ECOG-PS at 1L initiation, 2L initiation 
• 
Clinically relevant comorbidities including Charlson components at initiation of 1L, 
2L 
• 
Sites of metastatic disease at 1L, 2L 
• 
Counts of metastatic sites at 1L, 2L 
 
Patient Treatment Regimens 
• 
Surgical resection of tumor and date 
• 
Receipt of radiation therapy overall and by line of therapy 

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• 
Treatment regimens received as neoadjuvant, adjuvant, maintenance therapy, 1L, 2L, 
and 3L or greater 
• 
Dates of initiation  
• 
Dates of discontinuation 
• 
Total number of cycles received 
• 
Starting dose/ ending dose 
• 
Days of supply of last prescription for afatinib during the follow-up period 
• 
Dose reduction(s)/number, dose interruption(s)/ number during 1L, 2L 
• 
Rationale for discontinuation of 1L, 2L, 3L or greater 
• 
Progression, toxicity/adverse event, patient choice, death, other 
 
If death cited as rationale for discontinuation then provider will abstract data related to date 
of death, cause of death – see bottom of next section. Death during treatment and toxicity/AE 
as the rationale for discontinuation of 2L therapy is considered a severe AE of specific 
interest for this study. 
 
Patient Clinical/ Follow-up Outcomes 
• 
Diagnosis, time, grade, and attribution (treatment-related or not per provider 
interpretation) of any of the following severe (grade 3 or greater) irAEs during 1L/2L  
• 
Pneumonitis, colitis, hepatitis, interstitial lung disease, or indeterminate 
pulmonary event 
• 
Hospitalization(s)/number during 1L, 2L 
• 
Emergency department visit/ number during 1L, 2L 
• 
Date of disease progression in 1L, 2L, 3L and greater (provider reported and/or 
radiographically confirmed) 
• 
Attribution of disease progression/death due to treatment 
• 
Date of last clinic visit 
• 
Referral to hospice/ date 
• 
Date of death 
• 
Cause of death: cancer related, non-cancer related 
 
Providers will only be queried if the severe irAE’s (grade 3 or higher) listed above, occurred 
during therapy. No other severe irAEs will be captured in structured fields of the eCRF. 
Should the provider notify Cardinal Health of another adverse drug reaction/adverse event, 
Cardinal Health will follow the procedures outlined in Section 11 for reporting.  
9.3.1 
Exposures 
 Pembrolizumab in combination with platinum-based doublet chemotherapy 
 Afatinib as 2L therapy following discontinuation of pembrolizumab in combination 
with platinum-based doublet chemotherapy 
 Any chemotherapy as 2L therapy following discontinuation of pembrolizumab in 
combination with platinum-based doublet chemotherapy 

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9.3.2 
Outcomes 
9.3.2.1 
Primary outcomes 
To describe the demographic and clinical characteristics of and between patients receiving 2L 
afatinib or 2L chemotherapy all variables listed as Patient Demographics /Clinical 
Characteristics will be reported in terms of frequencies and proportions for categorical 
variable and means or medians (as appropriate) for continuous variables.  
 
Time on treatment with afatinib or chemotherapy during 2L. Time on treatment is defined as 
the interval from the start of 2L treatment until the end of 2L treatment or death date by any 
cause. 
 
The incidence of severe irAE of specific interest during 2L treatment will be reported as the 
proportion of patients experiencing the event among all patients who completed 2L therapy 
(e.g. discontinued) and as an incidence rate when including all patients in the 2L afatinib or 
chemotherapy cohort. Any discontinuation of 2L therapy due to toxicity or death will be 
reported in aggregate as a frequency/proportion. 
9.3.2.2 
Secondary outcomes 
NA 
 
9.3.3 
Covariates 
As a descriptive, retrospective study no formal comparisons between 2L afatinib and 
chemotherapy-treated patients will be made. For evaluation of the incidence of irAEs during 
afatinib treatment covariates of interest include patients’ history or irAE during 1L treatment 
along with the previously described demographics, clinical characteristics, and patient 
treatment regimens. 
 
9.4 
DATA SOURCES 
Data will be collected from patients’ medical records and recorded in the eCRF. Providers 
will be recruited to participate from a list of over 7,000 oncologists, haematologists and 
urologists from across the US, with varying levels of time in practice, from practices both 
within and outside of group purchasing organizations.  
 
Provider recruitment and patient identification activities are conducted over the span of 4 
weeks from the date of recruitment launch. During this 4-week interval, providers who 
responded to a feasibility assessment conducted prior to the launch of the study will be 
invited to participate first followed by recruitment from the maximum list of providers as 
needed. Should recruitment from the larger network be required, the research team will 

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identify providers caring for patients with a diagnosis of lung cancer based on ICD-9/10-CM 
diagnosis codes through the overlay of an internal administrative claims database with the 
provider list. Should this recruitment strategy not complete recruitment, the research team 
will invite all remaining providers known via electronic mail to participate in the research. 
9.4.1 
Source Documents 
Source documents will not be reviewed by the study research team for validation of the data 
points. Providers who elect to participate will abstract all relevant data from the patients’ 
medical record into the eCRF. See Section 9.8 – Quality Control for details describing the 
approach to data validation in the absence of source document verification. 
 
9.4.2 
Dataset and Records 
Individual eCRF’s will not be provided to the study sponsor for review. An analytical, 
patient-level dataset will not be provided to the study sponsor. The research team will retain 
the source documents according to the contract between the research team and the study 
sponsor.  
9.5 
STUDY SIZE 
A priori the study size was determined to be 200 patients with 100 patients each included in 
the 2L afatinib and 2L chemotherapy cohorts. The sample size was determined based on 
resources available for provider honoraria payment and the number of potentially eligible 
patients that were identified during a feasibility assessment. As a descriptive study with no 
formal hypothesis tests or comparisons no formal sample size/power analysis has been 
conducted. The primary sample size consideration for this study is the ability to measure the 
time on treatment in 2L and the precision of that point estimate. The LUX-Lung 8 trial 
demonstrated a median PFS of 2.4 months in the afatinib treated patients and 1.9 months in 
the erlotinib treated patients. Based on the planned data collection period we anticipate that 
sufficient patients to measure the 2L PFS will be available.  
9.6 
DATA MANAGEMENT 
All study data will be entered into the eCRF. The eCRF captures data for each of the study 
variables described in Section 9.3 - Variables. The eCRF is designed to allow providers to 
efficiently move through the patient chart or electronic medical record (EMR) based on the 
journey of the patient through the course of their disease. The eCRF conforms to the rules and 
regulations of the Health Insurance Portability and Accountability Act (HIPAA) of 1996 
governing the abstraction and storage of protected health information (PHI).  
 
The research team will be responsible for the programming, testing, and hosting of data from 
submitted eCRFs. Providers will access the eCRF through a secure web-based portal with all 
data stored on encrypted, password protected, and HIPAA-compliant servers housed within the 
Cardinal Health electronic data storage infrastructure. These processes and systems are vetted 
during the field-testing procedures. The software used to program the eCRF is the Qualtrics 
Survey Software.  

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9.7 
DATA ANALYSIS 
9.7.1 
Main analysis 
Demographic and clinical characteristics of the 2L afatinib treated and 2L chemotherapy 
treated cohorts will be summarized using counts and frequencies for dichotomous and 
categorical variables, while measures of centrality (mean, median) and spread (min, max, 
standard deviation, interquartile range, as appropriate) will be used for continuous variables.  
These techniques will also be used to describe the occurrence of selected toxicities during 
treatment in cohorts according the length of follow-up for the patient. The frequency of 
occurrence of these events will only be reported in total among those patients who had 
discontinued afatinib therapy. Events are considered a bonafide irAE if documented as 
immune-mediated in real time by the primary oncologist involved in the care of the patient 
and supported by radiologic and/or pathologic evidence. Adverse events that were possibly 
immune-mediated but had alternative or mixed etiologies will be termed “indeterminate 
irAEs” and considered separately. In addition, the incidence rate of each toxicity will be 
estimated using the length of follow-up or time on treatment during specific lines of therapy. 
All analyses will be conducted in SAS v9.4. 
 
The primary outcome to be measured in this study is the time on treatment in 2L for the 
afatinib and 2L chemotherapy cohorts. Time on treatment is defined in months as the interval 
from the start of 2L treatment until the end of 2L treatment or death date by any cause. The 
end of 2L treatment is defined as the date of last treatment order for afatinib plus the days of 
supply on the last known treatment order up to the date of data collection (but not exceeding). 
The Kaplan-Meier (KM) method will be used to estimate the median and 95% confidence 
interval for time on treatment. In addition the proportion of patients still receiving 2L afatinib 
or 2L chemotherapy at 3, 6, 9, and 12 months post 2L initiation will be reported from the 
results of the KM analysis. Patients who are considered on therapy at the time of last visit 
will be censored on the last treatment date as previously described. Patients who have 
discontinued treatment for any reason will be considered events and the date of the event will 
be captured as previously described.  
9.8 
QUALITY CONTROL 
9.8.1 
eCRF Functionality Testing 
Prior to data collection, during the field test, or actual study launch, Cardinal Health will test 
the eCRF. This quality control process begins with extensive testing of the eCRF to ensure 
functionality across web-based user environments, looping logic to ensure proper alignment 
of data-related fields (required responses to certain fields prior to entering data into 
subsequent field), and other programmatic checks to ensure the reduction of the input of 
erroneous data (such as specifying maximums for year of birth or initiation of first-line 
treatment within the dates of the enrollment period). Data ranges consistent with known 
clinical parameters will only be allowed to be entered into the eCRF.  

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In addition, the eCRF will be field-tested among 4 providers to ensure its functionality, the 
correct interpretation of the questions in relation to the data points of interest, and the length of 
time required for completion for a single patient. Field-testing includes a Cardinal Health 
researcher viewing the screen of the provider completing the eCRF with actual patient data and 
asking probing questions regarding the functionality, interpretability (variables are aligned 
with clinical definitions or clinical interpretations), and availability of the variables requested. 
No data from the pre-testing phase will be used in the analysis for this research. Pre-testing of 
the eCRF will not commence until receiving IRB approval for the conduct of the study. The 
pre-test results will be reviewed by the study sponsor with Cardinal Health staff, however, the 
study sponsor will not have access to the individual data collected. Any changes made to the 
eCRF document as a result of the pre-test will require the resubmission of the eCRF and study 
protocol to the IRB.   
9.8.2 
Data Validation 
During data collection Cardinal Health clinical research staff review all submitted eCRFs for 
quality control. The CHS Cardinal Health S clinical research team will inspect each submitted 
eCRF for implausible dates (i.e., date of death prior to last date of treatment), non-standard 
treatments (e.g., treatment regimens unknown to be used for the cancer under study), lab and 
radiology results which are inconsistent with known clinical parameters, or other clinical data 
that are inconsistent with known standards and outcomes. In addition to review of the submitted 
data by the clinical research team, the study statistician will conduct an analysis of submitted 
data to identify any data points inconsistent (outliers) with the study population average. This 
analysis will include a descriptive analysis of the provider characteristics, demographics, 
baseline clinical and disease characteristics, and characteristics of treatment patterns (e.g. 
DOT). Data points flagged as outliers will be delivered to the clinical research team. 
 
Should outliers be discovered, Cardinal Health clinical research will contact the provider 
submitting the eCRF for data validation. All providers are informed in their contractual 
agreement that follow-up with clinical staff at Cardinal Health may be required. Participating 
providers are asked to create a 4-digit unique identifier code per patient that is provided to 
Cardinal Health through the eCRF and used for identifying the patient record for validation 
between Cardinal Health and the provider. Individual eCRFs that cannot be validated will be 
removed from the study dataset; a provider unable to validate a data point will not be 
compensated for the patient record that was removed and re-sampling will not occurr without 
an amendment to the statement of work. All other data will be considered valid provided 
additional patients from that provider are not selected for random validation.  
 
Random data validation occurs by selecting a random eCRF from each provider submitting a 
patient. Providers who have been previoulsy verified by Cardinal Health will not be subject to 
completion of the random validation. A verified provider is any physician abstractor who has 
completed at least two of the following: (1) completed and acknowledged our web-based chart 
data abstraction training in the past 2 years, (2) particpated in a chart review pre-test with screen 
sharing, (3) participated in 2 previous chart review studies in the past 2 years and accurately 
validated data, and (4) have completed a phone interview with the Cardinal Health team for 
data validation. A provider may be verfiied but still required to answer questions regarding 
patients with data flagged by Cardinal Health research operationa or research analytics groups. 
Providers subject to random validation are asked to complete a 3-data point validation exercise 

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for the patient whereby the provider is given the unique patient identifier but no other 
information. The provider is asked to re-enter the data elements. The 3 data points may include: 
month/year of 2L treatment initiation, stage at diagnosis, and date of 2L treatment 
discontinuation (or date of last treatment/prescription if patient still on therapy). A provider 
who fails to validate all data points for a selected patient will be required to submit to further 
clinical data review. Patients for whom the data are deemed questionable by the researh team 
staff will be excluded; providers will not be compensated for exlcuded data. No resampling to 
replace the excluded eCRF will occur. Provider who are non-responsive to any validation 
request will have all data submitted excluded from the study.  
 
Should data quality checks and confirmation with providers reveal discrepancies corrections 
will be made to the database. These corrections will be documented in an audit trail.  
9.9 
LIMITATIONS OF THE RESEARCH METHODS 
There are several limitations to this research which should be noted.  
1) As an exploratory, retrospective, non-randomized study with a sample size of 100 
patients per cohort post-hoc propensity score matching cannot be conducted and 
comparisons between the two cohorts cannot be made as underlying 
demographic/clinical characteristics may exist between the cohort. Therefore, no 
numerical comparisons of endpoints between the two cohorts should be made at this 
time.  
2) Not all patient characteristics will be included in the data collection (e.g., income and 
other variables which may influence physician-prescribing behavior or treatment 
decisions) and cannot be accounted for in the descriptive or multivariate analyses. 
3) Loss to follow-up during the study period may occur if patients transfer care to other 
providers and centers. As such, treatments, visits, and outcomes occurring after the 
date of last visit may be missing. 
4) Treatment patterns reflected in the study represent only the practices of physicians who 
have agreed to participate, and may vary from non-responding physicians, i.e., those 
who refused study participation or who were unresponsive to the screening invitation. 
No data is available to describe non-responders. 
5) This study employs purposive sampling that selects physicians and patients based on 
pre-specified selection criteria and hence this may not be representative of all patients 
diagnosed with NSCLC treated with the drugs of interest or representative of all 
physicians treating these types of patients. In particular we require that patients have 
discontinued 1L treatment and received 2L therapy therefore any long-term responders 
to 1L therapy are excluded. Furthermore, by requiring that patients initiated 2L therapy 
at least 3 months prior to data cut-off we may bias our results in favor of longer 2L 
treatment durations as it is likely that early discontinuers may not be selected. We have 
attempted to mitigate this by asking for consecutive patients starting with the earliest 
and capping the maximum number of patient charts submitted per provider to 10.  

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6) Adverse events may be underreported/under-documented in a routine clinical setting 
as they may occur outside of the office setting and often go unreported compared to 
what would be expected from a controlled trial or prospective observational study 
setting. Moreover, providers may not be able to verify the severe irAEs evaluated in 
this study meet the criteria as established by CTCAE or other bodies. Therefore, the 
frequency of occurrence of severe irAEs signal cannot be confirmed by this dataset. 
7) Although physicians will be required to record all patient experiences in the medical 
charts, there may be some undercounting of events that are unknown to physicians 
which occurred outside the office. Thus, the accuracy and completeness of data 
collected in this study is limited by the quality of data in the patient’s medical chart. 
9.10 
OTHER ASPECTS 
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited.  
9.11 
SUBJECTS 
Please see Section 9.2 – Provider/Site/Patient Selection for a description of the patients to 
be studied in this research.  
9.11.1 
Cases 
NA 
9.11.2 
Controls 
NA 
9.12 
BIAS 
Provider and patient selection bias may exist in this study. Provider selection bias will be 
minimized by only allowing providers to contribute up to 10 patients each therefore the 
minimum number of providers participating is 20. It is expected however given the rarity of 
the patient profile included in this study that the mean number of patients each provider will 
contribute is approximately 5 and the total number of providers participating will be greater 
than 30. Patient selection bias will be minimized to the extent possible by requesting 
providers complete eCRFs for eligible patients starting chronologically with the earliest 
patient meeting the criteria and selecting patients consecutively thereafter.  
 
In addition the extent of both provider and patient selection bias is likely minimized by the 
stringent study selection criteria. Because of the relatively recent approval granted to 
pembrolizumab in combination with platinum-doublet chemotherapy as initial treatment for 
Sq NSCLC, the relative rarity of squamous as opposed to non-squamous NSCLC histology, 
and the requirement that all patients had initiated 2L therapy the total prevalence of this 
patient population is likely small minimizing potential selection biases. 

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10. 
PROTECTION OF HUMAN SUBJECTS 
All study materials including the research protocol and paper-version of the eCRF will be 
reviewed by a central IRB prior to any data abstraction including field-testing of the eCRF. 
Providers are required to be able to participate in research covered by a central IRB. At all 
times, patients’ protected health information (PHI) will be kept confidential in accordance with 
HIPAA. The eCRF will not capture any data related to the patient’s name, full date of birth, 
social security number, health insurance plan number, medical record number, or other such 
PHI. However, date of disease diagnosis, date(s) of treatment(s) administered (including dates 
of dose changes), , date of the development of health states of interest (i.e. an adverse event, 
disease progression), and date of death (if available) will be collected in the eCRF. These items 
are  considered PHI under HIPAA. At no time will the study sponsor be provided PHI in the 
form of a dataset or otherwise; all study results will be reported in aggregate. 
 
This study was designed and shall be implemented and reported in accordance with the 
Guidelines for Good Pharmacoepidemiology Practices of the International Society for 
Pharmacoepidemiology (ISPE 2008), the STROBE (Strengthening the Reporting of 
Observational Studies in Epidemiology) guidelines, and with the ethical principles laid down 
in the Declaration of Helsinki.  
 

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11. 
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS 
This is a retrospective, non-interventional, non-randomized study using data contained in 
structured and unstructured areas of the patients EHR previously collected as part of routine 
clinical care. We are asking chart abstractors (i.e. the patients treating physician) to abstract 
information regarding severe (grade 3 or higher) irAEs of specific interest (including 
pneumonitis, colitis, hepatitis, interstitial lung disease, higher indeterminate pulmonary events, death, 
or discontinuation of therapy due to toxicity) during 1L and 2L for both patients treated with 
afatinib in 2L and those treated with chemotherapy in 2L. Providers/abstractors will be asked 
only if these specific immune related events occurred. Reporting of these events will be 
conducted in the manner described in section 11.2. Events are considered a bonafide irAE if 
documented as immune-mediated in real time by the primary oncologist involved in the care 
of the patient and supported by radiologic and/or pathologic evidence. Adverse events that 
were possibly immune-mediated but had alternative or mixed etiologies will be termed 
“indeterminate irAEs” and considered separately.  
 
In addition, reporting requirements and procedures for other AEs identified during the course 
of the chart review are described in 11.2. 
 
11.1 
DEFINITIONS OF ADVERSE EVENTS 
Adverse event 
AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (e.g., abnormal laboratory 
findng), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.  
Adverse reaction 
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an AE is at least a reasonable possibility. Adverse reactions may arise from the 
use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorisation include off-
label use, overdose, misuse, abuse, and medication errors. 
Serious adverse event 
SAE is defined as any AE which 
- results in death 
- is life-threatening  
- requires in-patient hospitalisation, or prolongation of existing hospitalisation  
- results in persistent or significant disability or incapacity, or 

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- is a congenital anomaly/birth defect 
 
Life-threatening in this context refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe. 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious events, such as important medical events that might not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation 
or development of drug dependency or drug abuse. Any suspected transmission via a 
medicinal product of an infectious agent is also considered a serious adverse reaction. 
11.2 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING 
11.2.1 
Collection of AEs 
The study design is of non-interventional nature, and the study is conducted within the 
conditions of the approved marketing authorisation. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
afatinib. For this reason, the following AE collection and reporting requirements have been 
defined. 
The following must be collected by the investigator in the eCRF from start of data extraction 
once informed consent is signed (if required) onwards until the end of data extraction: 
- all adverse drug reaction (ADRs) (serious and non-serious), 
- all AEs with fatal outcome,  
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below. Causal relationship of adverse event 
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an AE. An adverse reaction, in 
contrast to an AE, is characterised by the fact that a causal relationship between a medicinal 
product and an occurrence is suspected.  
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including the pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases, and relevant 
history.  
Arguments that may suggest a reasonable causal relationship could be: 
 The event is consistent with the known pharmacology of the drug  
 The event is known to be caused by or attributed to the drug class 

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 A plausible time to onset of the event relative to the time of drug exposure 
 Evidence that the event is reproducible when the drug is re-introduced 
 No medically sound alternative etiologies that could explain the event (e.g., pre-
existing or concomitant diseases, or co-medications) 
 The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g., Stevens-Johnson syndrome) 
 An indication of dose-response (i.e., greater effect size if the dose is increased, 
smaller effect size if the dose is diminished) 
 
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be: 
 No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g., pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned) 
 Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g., after 5 half-lives).  
Of note, this criterion may not apply to events whose time course is prolonged despite 
removing the original trigger. 
 Additional arguments amongst those stated before, like alternative explanation (e.g., 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned). 
 Disappearance of the event even though the study drug treatment continues or remains 
unchanged. 
Intensity of adverse event 
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) criteria version 5.0 in the eCRF. 
Pregnancy: 
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the 
study, after having taken afatinib, the investigator must report any drug exposure during 
pregnancy, which occurred in a female subject or a partner to a male subject to the Sponsor 
by means of Part A of the Pregnancy Monitoring Form. The outcome of the pregnancy 
associated with drug exposure during pregnancy must be followed up and reported by means 
of Part B of the Pregnancy Monitoring Form. 
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed. 
Otherwise, the NIS AE form is to be completed and forwarded as well within the respective 
timelines. 
Expedited reporting of AEs and drug exposure during pregnancy 

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The following must be reported by the investigator on the NIS AE form and/or Pregnancy 
Monitoring Form from start of data extraction once informed consent is signed (if required) 
onwards until the end of data extraction and provide to BI unique entry point: 
Type of Report 
Timeline 
All serious ADRs associated with afatinib  
immediately within 24 hours 
All AEs with fatal outcome in patients 
exposed to afatinib  
*Exemption applies 
immediately within 24 hours 
All non-serious ADRs associated with 
afatinib  
7 calendar days 
Drug exposure during pregnancy 
7 calendar days 
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions, the Investigator could inform the Sponsor upfront via 
telephone. This does not replace the requirement to complete and fax and/or email the NIS 
AE form. 
*Exemption 
Death due to disease progression of the underlying malignancy is a study endpoint and the 
natural course of the disease. As such it is exempted from reporting as an SAE. Progression 
of the subject's underlying malignancy will be recorded on the appropriate pages of the eCRF 
only and will not be reported on the NIS AE Form. However, when there is evidence 
suggesting a causal relationship between afatinib and the progression of the underlying 
malignancy, the event must be reported as an SAE on the NIS AE Form and on the eCRF. 
Information required 
For each reportable AE, the investigator should provide the information requested on the 
appropriate CRF pages and the NIS AE form. 
Reporting of related AEs associated with any other BI drug 
The investigator is encouraged to report all AEs related to any BI drug other than afatinib 
according to the local regulatory requirements for spontaneous AE reporting at the 
investigator’s discretion by using the locally established routes and AE report forms. The 
term AE includes drug exposure during pregnancy, and, regardless of whether an AE 
occurred or not, any abuse, off-label use, misuse, medication error, occupational exposure, 
lack of effect, and unexpected benefit. 
11.3 
REPORTING TO HEALTH AUTHORITIES 
AE reporting to regulatory agencies will be done by the Marketing Authorisation Holder 
(MAH) according to local and international regulatory requirements.  
Exemptions are described in section 11.2, if applicable. 
 

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12. 
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS 
The study sponsor will disseminate the results internally as appropriate. The study sponsor 
will not release final results until finalization of the study report. The study sponsor will plan 
to publish the results (both effectiveness and safety/tolerability) from this study peer-review 
publications such as abstracts, posters, podium presentations and manuscripts. 
 

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13. 
REFERENCES 
13.1 
PUBLISHED REFERENCES 
1) Stinchcombe TE. Unmet needs in squamous cell carcinoma of the lung: potential role 
for immunotherapy. Med Oncol 2014;31:960. 
2) Hirsh V. New developments in the treatment of advanced squamous cell lung cancer: 
focus on afatinib. Onco Targets Ther 2017;10:2513-26. 
3) Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy 
regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-8. 
4) Davis KL, Goyal RK, Able SL, Brown J, Li L, Kaye JA. Real-world treatment 
patterns and costs in a US Medicare population with metastatic squamous non-small 
cell lung cancer. Lung Cancer 2015;87:176-85. 
5) Goss GD, Felip E, Cobo M, et al. Association of ERBB mutations with clinical 
outcomes of afatinib- or erlotinib-treated patients with lung squamous cell carcinoma. 
JAMA Onc, 2018; 4(9):1189-1197. 
6) Soria JC, Felip E, Cobo M, et al. Afatinib versus erlotinib as second-line treatment of 
patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-
label randomised controlled phase 3 trial. Lancet Oncol 2015;16:897-907. 
7) Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus Chemotherapy for 
Squamous Non-Small-Cell Lung Cancer. N Engl J Med 2018;379:2040-51. 
8) Paz-Ares L, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaaxel/nab-
paclitaxel (Chemo) with or without pembrolizumab (Pembro) for patients (Pts) with 
metastatic squamous (Sq) non-small cell lung cancer (NSCLC). J Clin Oncol 2018; 
36 (no. 15 supplemental), abstract #105.  
9) Ettinger dS, Aisner DL, Wood DE, et al. NCCN Guidelines Insights: Non-small cell 
lung cancer, version 5.2018. J Natl Compr Canc Netw, 2018; 16(7):807-821. 
10) Schoenfeld AJ, Arbour KC, Rizvi H, et al. Sever immune-related adverse events are 
common with sequential PD-(L)1 blockage and osimertinib. Ann Oncol, 2019; 
30(5):839-844. 
11) Riess J, KellyK, Schalper K, et al. Immunomodulatory effects of afatinib and 
pembrolizumab in EGFR-mutant NSCLC with progression on prior EGFR-
TKI:P1.04-09. J Thorac Oncol, 2019; 13(10):S528. Abstract from the 2019 World 
Lung Cancer Conference,  
 
13.2 
UNPUBLISHED REFERENCES 
NA 

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS 
None 
 

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ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS 
Not applicable 
 

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ANNEX 3. ADDITIONAL INFORMATION 
None