Clinical trial NCT03157089
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Boehringer Ingelheim
Start date: 2017-11-02; Completion date: 2020-01-13
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main objective is to assess the efficacy of afatinib in combination with pembrolizumab, as measured by objective response (OR) in patients with locally advanced or metastatic squamous NSCLC who progressed during or after first line platinum-based treatment.

The secondary objectives are to confirm the RP2D, assess the safety profile, and the secondary measures of clinical efficacy including disease control (DC), duration of objective response (DoR), progression-free survival (PFS), overall survival (OS), and tumour shrinkage.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Afatinib intervention 2: pembrolizumab
Intervention descriptions: intervention 1: Film-coated tablet intervention 2: Solution for infusion

Protocol documents:
Prot_002.pdf: 
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 October 2016
Clinical Trial Protocol
TITLE PAGE
Document Number:
c13055147-03
EudraCT No.:
EU Trial No:
2016-005042-37
BI Trial No.:
1200.283
BI Investigational 
Product(s):
Afatinib in combination with pembrolizumab
Title:
LUX-Lung IO: A phase II, open label, non-randomised study of 
afatinib in combination with pembrolizumab in patients with 
locally advanced or metastatic squamous cell carcinoma of the 
lung
Lay Title:
A phase II study that tests afatinib in combination with 
pembrolizumab in patients with squamous cell carcinoma of the 
lung
Clinical Phase:
II
Trial Clinical 
Monitor:
Phone: 
/ Fax: 
Coordinating 
Investigators:
Status:
Final Protocol (Revised Protocol (based on global amendment 2)
Version and Date:
Version: 1.0
Version: 2.0
Version: 3.0
Date: 04 May 2017
Date: 12 Mar 2019
Date: 11 Apr 2019
Page 1 of 115
Proprietary confidential information.
2019 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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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name:
Boehringer Ingelheim
Finished product name:
Giotrif/Gilotrif 
Active ingredient name: Afatinib + pembrolizumab
Protocol date:
04 May 2017
Revision date:
11 Apr 2019
Trial number:
1200.283
Title of trial:
LUX-Lung IO: A phase II, open label, non-randomised study of 
afatinib in combination with pembrolizumab in patients with locally 
advanced or metastatic squamous cell carcinoma of the lung
Coordinating 
Investigators:
Trial site(s):
International, multi-centre trial
Clinical phase:
II
Objective(s):
[Primary Objective]
▪
To assess the efficacy of afatinib in combination with 
pembrolizumab, as measured by objective response (OR) in 
patients with locally advanced or metastatic squamous NSCLC 
who progressed during or after first line platinum-based 
treatment
[Secondary Objectives]
▪
To confirm the Recommended Phase 2 Dose (RP2D), assess the 
safety profile, and the secondary measures of clinical efficacy 
including disease control (DC), duration of objective response 
(DoR), progression free survival (PFS), overall survival (OS), 
and tumour shrinkage


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Methodology:
Open-label, non-randomised, single arm, phase II study. Eligible 
patients have locally advanced or metastatic squamous NSCLC who 
progressed during or after first line platinum-based treatment and 
who are immune checkpoint inhibitor naïve. Prior treatment with 
EGFR targeted therapy is not allowed
Number of patients 
entered:
Approximately 60 patients
Number of patients on 
each treatment:
Approximately 60 patients
Diagnosis:
Locally advanced (stage IIIb) or metastatic (stage IV) squamous 
NSCLC
Main in- and exclusion 
criteria:
1. Pathologically confirmed diagnosis of NSCLC considered to be 
of squamous histology, including mixed histology, in the opinion 
of the investigator
2. Locally advanced (stage IIIb) or metastatic (stage IV) NSCLC 
not considered eligible for curative therapy
3. Documented disease progression or relapse (based on 
investigator’s assessment) during or after completion of at least 
2 cycles of platinum-based chemotherapy as first line treatment 
of Stage IIIB/IV SCC of the lung. This includes patients 
relapsing within 6 months of completing (neo)
adjuvant/curative-intent chemotherapy or definitive 
chemoradiotherapy. Patients should be eligible to receive second
line therapy in the opinion of the investigator.
4. At least one target lesion (outside the brain), that can be 
accurately measured per RECIST v 1.1. In patients who only 
have one target lesion and a biopsy of the lesion is required; the 
baseline imaging must be performed at least two weeks after the 
biopsy
5. Availability and willingness to provide a fresh tumour tissue 
sample obtained after relapse or progression on or after prior 
therapy. In case a fresh biopsy cannot be obtained (e.g. 
inaccessible lesions or patient safety concern), an archived 
specimen may be submitted
6. ECOG performance status of 0 or 1
7. Adequate organ function defined as all of the following (all 
screening labs should be performed within 10 days of treatment 
initiation):
System
Laboratory Value
Hematological
Absolute neutrophil count 
(ANC)
≥1.5 x 109/L
Platelets
≥75 x 109/L
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L
Renal
Creatinine OR
≤ 1.5 x ULN OR 


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Measured or calculateda
creatinine clearance 
(Glomerular Filtration Rate 
(GFR) can also be used in 
place of creatinine or CrCl)
≥50 mL/min for patients with creatinine levels >1.5x 
ULN
Hepatic
Total bilirubin
≤1.5 times the upper limit of normal (ULN)
AST (SGOT) and ALT 
(SGPT)
≤2.5 x ULN OR ≤5 x ULN for patients with liver 
metastases
Coagulation

International Normalised 
Ratio (INR) or 
Prothrombin Time (PT)

≤1.5xULN unless patient is receiving 
anticoagulant therapy as long as PT is within 
therapeutic range of intended use of 
anticoagulants

Activated Partial 
Thromboplastin Time 
(aPTT)

≤1.5xULN unless patient is receiving 
anticoagulant therapy as long as PTT is within 
therapeutic range of intended use of 
anticoagulants
a Creatinine clearance should be calculated per institutional standard
8. No prior therapy with any immune checkpoint inhibitor or 
EGFR targeted therapy; however prior (neo) adjuvant 
checkpoint inhibitor and EGFR-targeted therapy is allowed if
completed at least 12 months before relapse
9. No history of (non-infectious) ILD/pneumonitis that required 
steroids or current ILD/pneumonitis
10. No active infection requiring intravenous systemic therapy
Test product(s):
Afatinib
dose:
Safety run in: The starting dose of afatinib is 40 mg once daily in 
combination with pembrolizumab. In case the RP2D for afatinib is 
not confirmed as 40 mg, 12 more patients will be included in the 
safety run in with a starting dose of afatinib 30 mg once daily. In 
addition, ongoing patients on afatinib 40 mg will have their dose 
reduced to 30 mg.
Main study part: at RP2D of afatinib 40 mg or 30 mg once daily in 
combination with pembrolizumab as determined during the safety 
run in
mode of 
administration:
Oral, once daily, continuous
Comparator product:
Pembrolizumab (given in combination with test product)
dose:
Fixed dose pembrolizumab: 200 mg once every 3 weeks
mode of 
administration:
Intravenous infusion over 30 minutes (25-40 minutes is permitted) 
once every 3 weeks
Duration of treatment:
Both afatinib and pembrolizumab will be given until documented 
disease progression (per RECIST 1.1 and confirmed with 
irRECIST), or unacceptable adverse events, or other reasons 


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requiring treatment discontinuation, or for up to 35 treatment cycles, 
which is the approved treatment duration for pembrolizumab 
monotherapy. In case of early discontinuation of one agent, the other 
agent may be continued as monotherapy for up to 35 cycles. After 
study treatment completion, further therapy will be decided by the 
investigator including continuation of afatinib (using commercial 
product), alternative therapy, or best supportive care
Endpoints:
Primary endpoint:

Objective response (OR)*
Secondary endpoints:

Disease control (DC)*

Duration of objective response (DoR)*

Progression-free survival (PFS)*

Overall survival (OS)

Tumour shrinkage*

Recommended Phase 2 Dose (RP2D)
*By investigator assessment according to RECIST 1.1
Safety criteria:
Intensity and incidence of reported AEs (AEs will be assessed using 
the US National Cancer Institute [NCI] Common Terminology 
Criteria for Adverse Events [CTCAE] version 4.03)
Safety is overseen by a Safety Monitoring Committee (SMC)
Statistical methods:
Efficacy Endpoints
Efficacy endpoints will be summarised descriptively. For OR and 
DC the frequency, proportion, and percentage of patients and 95% 
two-sided confidence interval will be presented. For survival 
variables, the median survival time and 95% two-sided confidence 
interval will be presented using the Kaplan-Meier method. Tumour 
shrinkage measured as the difference between the minimum post-
baseline sum of diameters of target lesions (longest for non-nodal 
lesions, short axis for nodal lesions) and the baseline sum of 
diameters of the same set of target lesions will be summarised 
descriptively
Dose confirmation
Dose confirmation is guided by a Bayesian Logistic Regression 
Model (BLRM) with overdose control that will be fitted to binary 
toxicity outcomes. The estimate of parameters will be updated as 
data are accumulated using the BLRM. At the end of the dose 
confirmation part, the toxicity probability at each dose level will be 
calculated to determine an estimate of the RP2D


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FLOWCHART
Screening
Cycle1a
Cycle 2 and 
onwardsa
End of Trial 
Treatmentb
End of REP c
Follow-up 
Progressiond
Follow-up 
Survivale
End of 
Trial
Visit abbreviation
SV
C1_V1
C1_V2
Cx_Vf
EOT
EOR
FU-PDyg
FU-OSzh
FV18
Time point
Day
-28 to 0
Day 1
Day 8
±2
Day 1i ±3
of each cycle
(every 3 weeks)
Day 0-14 after 
discontinuation 
of both study 
medications
Day 30-35 after 
last trial drug
Every 9 weeks 
± 1 after 
C1_V116
Every 9 
weeks ± 2 
after last FU
Informed Consent1
X
Demographics
X
Medical History
X
Review of In-/Exclusion criteria
X2
Safety lab and urinalysis3
X3
X
X3
X
X
Pregnancy test4
X
X
Thyroid function testing5
X
X5
12 Lead ECG6
X
Blood sample for PK analysis7
X7
Tumour biopsy8
X
Biomarker blood sampling9
X
X9
X9
X9
Full physical examination10
X
X
Limited physical examination10
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
X
Concomitant therapy11
X
X
X
X
X
X
X
Adverse events12
X
X
X12
X12
X12
X12
X12
X12
X12
Start of treatment
X
Dispense afatinib
X
X
Afatinib treatment
Continuous
Pembrolizumab treatment13
Day 1 of each cycle
Compliance check afatinib14
X14
X
X
Termination of trial medication15
X
Tumour assessment16
X
X16
X16
Vital status17
X
X
X
X
Completion of patient participation18
X18


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a
All cycles are 21 days in duration. Patients may continue on treatment for up to 35 cycles or until any other criteria for stopping medication are met (see Section 3.3.4.1).
C1V1 can be done on the same day as the screening visit only if all screening assessments are completed.
b
This refers to completion of study treatment (as scheduled) as well as premature treatment withdrawal. If the decision to permanently discontinue both trial medications is taken during 
a scheduled visit (also in case afatinib had been taken in the morning prior to the visit), the EOT (End of Treatment) visit should be performed instead of the scheduled visit. The EOT 
visit must be performed as soon as possible (at latest, within 14 days) after the last study drug administration (afatinib, pembrolizumab, or both whichever is later); however, the 
individual termination of trial medication eCRF page must be completed when either is discontinued. In case only one trial treatment is discontinued and the other is continued, the 
Cx_V should be performed instead of the EOT, and the EOT is performed when also the other trial treatment has been discontinued. Please also see Section 3.3.4.1. The imaging 
schedule should continue as described under footnote 16 and as indicated.
c
The EOR (End of Residual Effect Period) visit is performed at least 30 days (30-35 days) after permanent discontinuation of afatinib and pembrolizumab trial treatment. 
In case only one of the trial treatments is discontinued the patient continues the treatment cycles i.e. Cx_V 
d
Follow-up for progressive disease (FU-PD) visits are only for patients who have not progressed and/or not started subsequent anti-cancer treatment at EOR. FU-PD visits will take 
place as per the imaging schedules (see footnote 16) until confirmed PD or start of subsequent anti-cancer treatment. With the early termination of the study, there is no more follow-
up for progressive disease after a patient discontinues treatment.
e
After documented PD or start of subsequent anti-cancer treatment and EOT and EOR have been completed, patients will enter follow-up for overall survival (FU-OS). No visits will be 
performed for the purposes of the trial, but data on subsequent anti-cancer treatment and vital status will be collected from medical records or via telephone. The FU-OS period ends 
when the patient dies, is lost to follow-up, withdraws consent for collection of overall survival data, or completion of the whole trial. With the early termination of the study, there is no 
more follow-up for overall survival after documented PD or start of subsequent anti cancer therapy.
f
x is the number of the treatment cycle.
g
y is the number of the follow-up progression assessment, starting with FU-PD1. With the early termination of the study, there is no more follow-up for progressive disease.
h
z is the number of the follow-up survival assessment. With the early termination of the study, there is no more follow-up for overall survival.
i
Starting at cycle 2, day 1 of each cycle may be postponed for up to 3 days for administrative reason, but 14 days will be accepted when the patient is recovering from an AE. This 
should not affect the imaging schedule - the patients still have to come in for the tumour assessments based on the date of first drug intake.
1
Written informed consent must be obtained before any protocol specific screening assessments are performed. Re-consenting may become necessary when new relevant information 
becomes available and should be conducted according to the sponsor’s instructions. The consent to collection of a blood sample for biomarkers is optional and so is the testing for 
exploratory tumour tissue biomarkers.
2
In-/exclusion criteria should be re-confirmed before treatment start. Lab tests do not need to be repeated if performed within 10 days prior to treatment start and there is no clinical 
reason to repeat lab tests.
3
All screening labs should be performed or repeated within 10 days prior to treatment initiation; all other screening assessments are performed within 28 days. Re-screening is 
permitted, if applicable. Refer to Section 5.2.3 for an overview of the clinical laboratory tests. Starting at Cycle 13, lab tests will be performed every other cycle (C13V, C15V, C17V 
etc, – C35V.). After 35 cycles of trial treatment, lab tests will be performed at EOT, EOR, and as clinically indicated. In case of any elevation of ALT/AST and bilirubin, please see 
Section 10.5.
4
A pregnancy test is mandatory for female patients of childbearing potential within 72 hours prior to start of treatment and at EOT. Repeat as necessary during the treatment period as 
required per local regulation (refer to Section 4.2.2.3).
5
Thyroid function testing (TSH, T3, T4) at baseline, every six weeks during treatment with pembrolizumab, and as clinically indicated.
6
ECG is performed at screening and repeated as clinically indicated.
7
Pharmacokinetic (PK) sampling will take place in all patients at Cycle 2 and Cycle 3 before trial drug administration as specified in Section 5.3 and Appendix 10.1.


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8
A fresh tumour biopsy (alternatively archived tissue) will be required at screening for central measurement of PD-L1 expression and correlative studies (see also Section 5.4.1). In case 
a fresh tumour biopsy cannot be obtained (e.g. inaccessible lesions or patient safety concern) an archived specimen obtained as part of routine clinical practice prior to treatment 
initiation may be submitted. A biopsy obtained upon PD after prior therapy for squamous NSCLC can be used. In patients who only have one target lesion according to RECIST 1.1 
and a biopsy of the lesion is required, the baseline imaging must be performed at least two weeks after the biopsy. Further exploratory biomarker analyses are optional and are only 
performed if the patients have given written informed consent for this.
9
Collection of blood samples for blood-born biomarkers is optional and is only performed if the patients have given written informed consent for this. It must be obtained at C1_V1 
prior to first drug administration, at C4V, and at the time of PD (either at EOT visit or FU-PD, dependent on the timepoint of PD). Refer to Section 5.4. With the early termination of 
the study, no blood samples for biomarkers will be collected at the time of PD.
10
Includes height (at screening only) and weight. Refer to Section 5.2.1 for details on complete and limited physical exam procedures.
11
For concomitant therapy and restrictions on concomitant therapy, see Sections 4.2.1.1 and 4.2.2.1.
12
For details on Adverse Event reporting after treatment discontinuation, refer to Sections 5.2.6.2 and 6.2.3. Early and proactive management of side effects is essential for retention and 
the site should call the patient a few days after starting treatment to discuss whether the patient has side effects and how these can be treated. In addition, a phone call around day 15 is 
recommended and the patient should be instructed to contact the sites if applicable. All AEs (non-serious and serious and all AESIs) are reported for a minimum of 30 days post 
permanent discontinuation of the afatinib and pembrolizumab trial treatment. After the end of the REP until the individual subject’s end of trial, 90 days after the last dose of 
pembrolizumab or 30 days following cessation of trial treatment if the patient initiates new anticancer therapy, whichever is earlier, all AESIs related to afatinib and all SAEs are 
reported. After this time, only related SAEs and AESIs related to afatinib are reported. Information about pregnancy should be collected for female patients of childbearing potential at
least up to 120 days after the last dose of pembrolizumab treatment and 2 weeks after last afatinib treatment.
13
Pembrolizumab must be administered on day 1 of each cycle, but a time window of ±3 days will be allowed. Pembrolizumab may be continued for up to 35 cycles, which is the 
approved treatment duration for pembrolizumab monotherapy. After EOT for individual patient, further therapy will be decided by the investigator including continuation of afatinib 
(using commercial product), alternative therapy, or best supportive care.
14
After one week on study medication, treatment compliance should be discussed with the patient, to ensure that afatinib is being taken correctly (no compliance calculation is
performed). At the end of each 21 day cycle, treatment compliance is calculated and entered in the eCRF.
15
Afatinib and pembrolizumab study treatment combined or as monotherapy is allowed up to 35 cycles if, in the opinion of the investigator, the patient continues to derive clinical 
benefit, despite the other being discontinued.
16
Tumour assessments should include computed tomography (CT) scans of chest and abdomen and a brain MRI at screening. If clinically indicated, imaging of any other known or 
suspected sites of disease (e.g. pelvis, bone) using an appropriate method (CT scan, MRI, or bone scan) should be performed. The same radiographic procedure must be used 
throughout the study. If bone lesions are already known or confirmed at screening, correlative imaging (X-ray, CT scan, MRI, or bone scan) should be performed and repeated at each 
tumour assessment (see Appendix 10.3 and Appendix 10.4 for more details). Assessments will be performed at the following time points, irrespective of scheduled visits, until PD
and/or start of subsequent anti-cancer treatment for disease:

Screening visit (within 28 days prior to first drug intake). A scan performed as part of routine clinical practice and prior to provision of informed consent and within the screening 
timeframe can be used

During week 9 (56-63 days after C1_V1)

Every 9 weeks (63 ± 7 days) thereafter until PD or start of subsequent anti-cancer treatment.
After PD per RECIST, repeat imaging for confirmation is required. Repeat imaging ≥4 weeks to confirm In the event of early discontinuation or interruption/delay of treatment the 
tumour assessment schedule should not be changed. With the early termination of the study, tumour assessment is done per local standard and the timing and methods of imaging 
should follow local practice until PD, start of subsequent anti-cancer treatment for disease or withdrawal from trial treatment.
17
Vital status (overall survival data) can be collected from the patient notes etc. or by telephone contact with the patient; a formal study visit is not required (see also Section 6.2.3).
Exception: In case the patient is still in the EOR/FU or FU-PD, the patient needs to attend trial visits. With the early termination of the study, collection of vital status is no longer 
necessary.
18
When stopping trial participation, Final Visit (FV) must be completed for all patients who received study medication (see Section 3.3.4). However, a formal study visit is not required.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOWCHART.........................................................................................................................6
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................15
1.1
MEDICAL BACKGROUND.............................................................................15
1.2
DRUG PROFILE................................................................................................16
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................17
1.4
BENEFIT - RISK ASSESSMENT.....................................................................17
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................20
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........20
2.1.1
Main objectives....................................................................................................20
2.1.2
Primary endpoint(s)............................................................................................20
2.1.3
Secondary endpoint(s) ........................................................................................20
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................22
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................22
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................24
3.3
SELECTION OF TRIAL POPULATION .......................................................25
3.3.1
Main diagnosis for trial entry ............................................................................25
3.3.2
Inclusion criteria .................................................................................................25
3.3.3
Exclusion criteria ................................................................................................27
3.3.4
Withdrawal of patients from therapy or assessments .....................................29
3.3.4.1
Withdrawal from trial treatment ...........................................................................29
3.3.4.2
Withdrawal of consent for trial participation........................................................30
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................30
4.
TREATMENTS...................................................................................................31
4.1
INVESTIGATIONAL TREATMENTS ...........................................................31
4.1.1
Identity of the investigational medicinal products...........................................31
4.1.2
Selection of doses in the trial..............................................................................31
4.1.3
Method of assigning patients to treatment groups...........................................32
4.1.4
Drug assignment and administration of doses for each patient......................32
4.1.4.1
Afatinib treatment .................................................................................................33
4.1.4.2
Pembrolizumab treatment .....................................................................................34


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4.1.4.2.1
Dose modification and toxicity management for immune-related AEs associated 
with pembrolizumab .............................................................................................35
4.1.4.2.2
Other allowed dose interruption for pembrolizumab............................................38
4.1.5
Blinding and procedures for unblinding...........................................................38
4.1.5.1
Blinding.................................................................................................................38
4.1.5.2
Unblinding and breaking the code ........................................................................38
4.1.6
Packaging, labelling, and re-supply...................................................................38
4.1.7
Storage conditions...............................................................................................39
4.1.8
Drug accountability.............................................................................................39
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................40
4.2.1
Other treatments and emergency procedures..................................................40
4.2.1.1
Concomitant medications......................................................................................40
4.2.2
Restrictions ..........................................................................................................41
4.2.2.1
Restrictions regarding concomitant treatment ......................................................41
4.2.2.2
Restrictions on diet and life style..........................................................................42
4.2.2.3
Restrictions regarding women of childbearing potential......................................42
4.2.3
Management of side effects ................................................................................43
4.2.3.1
Management of dermatological AEs following treatment with afatinib...............44
4.2.3.2
Management of keratitis following treatment with afatinib..................................47
4.2.3.3
Management of diarrhoea and hydration status following treatment with afatinib 
and pembrolizumab...............................................................................................48
4.2.3.4
Management of interstitial lung disease/pneumonitis following treatment with 
afatinib/pembrolizumab ........................................................................................50
4.2.3.5
Management of type 1 diabetes mellitus following treatment with pembrolizumab
...............................................................................................................................50
4.2.3.6
Management of hypophysitis following treatment with pembrolizumab.............50
4.2.3.7
Management of hyperthyroidism or hypothyroidism following treatment with 
pembrolizumab......................................................................................................50
4.2.3.8
Management of hepatic events following treatment with pembrolizumab...........51
4.2.3.9
Management of renal failure or nephritis following treatment with 
pembrolizumab......................................................................................................51
4.2.3.10
Management of infusion reactions related to pembrolizumab..............................51
4.3
TREATMENT COMPLIANCE........................................................................53
5.
ASSESSMENTS..................................................................................................54
5.1
ASSESSMENT OF EFFICACY........................................................................54
5.1.1
Tumour imaging..................................................................................................54
5.1.2
Imaging review....................................................................................................55
5.2
ASSESSMENT OF SAFETY.............................................................................56
5.2.1
Physical examination ..........................................................................................57
5.2.2
Vital signs.............................................................................................................57
5.2.3
Safety laboratory parameters ............................................................................57
5.2.4
Electrocardiogram ..............................................................................................59
5.2.5
Other safety parameters.....................................................................................59
5.2.5.1
Dose limiting toxicities.........................................................................................59
5.2.5.2
Performance status ................................................................................................60


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5.2.6
Assessment of adverse events.............................................................................60
5.2.6.1
Definitions of AEs ................................................................................................60
5.2.6.2
Adverse event collection and reporting ................................................................63
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................67
5.3.1
Assessment of pharmacokinetics .......................................................................67
5.3.2
Methods of sample collection .............................................................................67
5.3.3
Analytical determinations ..................................................................................67
5.3.4
Pharmacokinetic – pharmacodynamic relationship........................................67
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................68
5.4.1
Tumour tissue samples .......................................................................................68
5.4.2
Blood samples for biomarker analyses..............................................................68
5.5
OTHER ASSESSMENTS...................................................................................69
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................69
6.
INVESTIGATIONAL PLAN.............................................................................70
6.1
VISIT SCHEDULE.............................................................................................70
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................70
6.2.1
Screening and run-in period(s)..........................................................................70
6.2.2
Treatment period(s)............................................................................................71
6.2.3
Follow-up period and trial completion..............................................................71
6.2.4
Trial completion for an individual patient .......................................................72
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................73
7.1
STATISTICAL DESIGN - MODEL.................................................................73
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................73
7.3
PLANNED ANALYSES.....................................................................................73
7.3.1
Primary endpoint analyses.................................................................................74
7.3.2
Secondary endpoint analyses .............................................................................74
7.3.4
Safety analyses.....................................................................................................76
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................77
7.3.6
Biomarker and pharmacogenetic analyses.......................................................77
7.4
INTERIM ANALYSES ......................................................................................77
7.5
HANDLING OF MISSING DATA ...................................................................77
7.6
RANDOMISATION ...........................................................................................78
7.7
DETERMINATION OF SAMPLE SIZE .........................................................78
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........79
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................79
8.2
DATA QUALITY ASSURANCE ......................................................................80
8.3
RECORDS...........................................................................................................80
8.3.1
Source documents ...............................................................................................80
8.3.2
Direct access to source data and documents.....................................................81
8.3.3
Storage period of records ...................................................................................81


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................81
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........82
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................82
8.6
TRIAL MILESTONES.......................................................................................82
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................83
9.
REFERENCES....................................................................................................85
9.1
PUBLISHED REFERENCES............................................................................85
9.2
UNPUBLISHED REFERENCES......................................................................87
10.
APPENDICES.....................................................................................................88
10.1
PHARMACOKINETIC ANALYSES...............................................................88
10.1.1
Handling procedure of blood samples for plasma concentration-time 
measurements......................................................................................................88
10.1.2
Time schedule for pharmacokinetic blood sampling.......................................89
10.2
TRIAL BIOMARKER PLAN............................................................................90
10.3
RECIST 1.1 CRITERIA.....................................................................................91
10.4
IMMUNE RELATED RECIST (IRRECIST)..................................................95
10.5
CLINICAL EVALUATION OF LIVER INJURY ..........................................96
10.5.1
Introduction.........................................................................................................96
10.5.2
Procedures ...........................................................................................................96
10.6
CREATININE CLEARANCE...........................................................................98
10.7
ECOG PERFORMANCE STATUS..................................................................99
10.8
P-GLYCOPROTEIN INHIBITORS AND INDUCERS ...............................100
10.9
BAYESIAN LOGISTIC REGRESSION MODEL WITH OVERDOSE 
CONTROL FOR DOSE CONFIRMATION .................................................101
10.9.1
Definition of the model and description of the prior derivation...................101
10.9.2
Operating characteristics .................................................................................106
10.9.3
Hypothetical data scenarios .............................................................................107
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................110
11.1
GLOBAL AMENDMENT 1 ............................................................................110
11.2
GLOBAL AMENDMENT 2 ............................................................................115


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
AUC
Area under the Curve
b.i.d.
bis in die (twice daily dosing)
BLRM
Bayesian Logistic Regression Model
CI
Confidence Interval
CML
Clinical Monitor Local
CRA
Clinical Research Associate
CrCl
Creatinine Clearance
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTR
Clinical Trial Report
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
DC
Disease Control
DOR
Duration of Objective Response
EOR
End of Residual Effect Period
EOT
End of Treatment
EudraCT
European Clinical Trials Database
FFPE
Formalin-fixed Paraffin Embedded
FV
Final Visit
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GI
Gastro Intestinal
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
INR
International Normalised Ratio
IRB
Institutional Review Board
ILD
Interstitial Lung Disease
irAEs
irRECIST
Immune-Related AEs
immune-related RECIST
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
intravenous
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
MedDRA
Medical Dictionary for Drug Regulatory Activities
NSAID
Non-Steroidal Anti-Inflammatory Drug
NSCLC
Non-Small Cell Lung Cancer
OPU
Operative Unit
OR
Objective Response


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OS
Overall Survival
PFS
Progression Free Survival
PD
Progressive Disease
PD-1
Programmed Cell Death Protein 1
PD-L1
Programmed Cell Death Ligand 1
PK
Pharmacokinetics
p.o.
per os (oral)
PT
Prothrombin Time
RP2D
Recommended Phase 2 Dose
REP
Residual Effect Period, after the last dose of medication with measurable 
drug levels or pharmacodynamic effects still likely to be present
SAE
Serious Adverse Event
SCC
Squamous Cell Carcinoma
SMC
Safety Monitoring Committee
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reactions
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
WHO
World Health Organization
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Squamous cell carcinoma (SCC) represents the second most common histologic subtype of 
lung cancer (preceded only by adenocarcinoma). In locally advanced unresectable or 
metastatic disease, doublet chemotherapy regimens (including cisplatin or carboplatin and a 
third-generation agent such as gemcitabine, taxanes, or vinorelbine) remain the cornerstone 
of front-line systemic treatment. Genomic alterations in SCC of the lung have not been 
comprehensively characterised, and no molecularly targeted therapies have been specifically 
developed for the treatment of this disease.
Molecular data suggest a role for overexpression or gene amplification of EGFR in the 
pathobiology of SCC. Several studies (R16-5728, R15-2034) suggest that EGFR 
overexpression is more common in squamous tumours (up to 82% of cases) than in 
adenocarcinomas. This feature might explain the sensitivity of some patients with SCC of the 
lung to EGFR-targeted treatments. The LUX-Lung 8 trial comparing afatinib versus the 
reversible EGFR TKI erlotinib for second-line treatment of patients with squamous NSCLC, 
showed that afatinib significantly improved progression-free survival (which was the primary 
endpoint) and key secondary endpoint of overall survival. In addition, longer-term survival at 
12 months and 18 months was significantly improved with afatinib. Afatinib was also 
associated with improvements in objective response (6% versus 3%) and duration of response 
(7.29 versus 3.71 months), significant improvements in disease control, patient-reported 
outcomes, and disease-related symptoms compared with erlotinib (P15-06906). Because 
EGFR mutations are rare (<5%) in SCC of the lung (R15-2035), it is unlikely that the 
improved survival outcomes observed with afatinib in this study were driven by molecular 
aberrations of EGFR. These improvements might be a result of afatinib’s higher potency and 
broader irreversible ErbB blockade in this setting compared with EGFR inhibition alone.
The development of immune checkpoint inhibitors has been revolutionary in the field of 
cancer immunotherapy. Blockade of programmed cell death protein 1 (PD-1) has
demonstrated durable responses across different tumour types, including SCC of lung. This 
led to the approval of three immune checkpoint inhibitors. Of them, pembrolizumab has 
demonstrated significant improvement in terms of PFS and OS compared to standard of care 
chemotherapy in both first and second line therapy of patients with PD-L1 expression score 
≥50% and ≥1% respectively (R16-4803, R16-0876).
Preclinical evidence suggests that PD-L1 tumour expression may be constitutively driven by 
EGFR signalling in EGFR mutant NSCLC. Treatment with anti-PD-1 antibodies in 
preclinical EGFR mutant lung cancer models have demonstrated delayed tumour growth and 
increased survival (R15-1556). In preclinical cell lines and genetically engineered mouse 
models (GEMM), EGFR-driven tumours expressed higher levels of PD-L1 with a more 
immunosuppressive tumour microenvironment (increased FoxP3+ T-cells, decreased 
CD8+/CD4+ ratio) (R15-1555).
In the clinical setting, a phase I trial combining the anti-PD-1 antibody, nivolumab with 
erlotinib in patients with EGFR mutant NSCLC, reported an encouraging anti-tumour activity 
along with a manageable safety profile (R16-0317). The Phase I study examined patients with 
Stage IIIB/IV EGFR mutant NSCLC who were chemotherapy naive or experienced 
progression after prior EGFR TKI therapy. Patients received nivolumab 3 mg/kg i.v. Q2W + 


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erlotinib 150 mg PO daily until progression of disease or unacceptable toxicity. Interim 
analysis included 21 patients who received treatment for >10 months prior to analysis. Of the 
20 patients who had acquired erlotinib resistance, 3 patients showed partial responses. 
Duration of responses was 6.1+, 16.3+, and 27.1+ weeks. Nine patients (45%) had stable 
disease and three patients (33%) responded. Similarly, an ongoing phase Ib trial combining 
full dose erlotinib with atezolizumab (anti PD-L1 antibody) in EGFR mutant NSCLC 
demonstrated a manageable safety profile (R17-0546). Globally considered, these findings 
suggest that concurrent inhibition of PD-1 and EGFR pathways may represent a rational and 
promising approach for EGFR-driven tumours, such as SCC of the lung, to increase response 
rate and duration of response, and delay development of resistance (R15-1555, R16-5263).
1.2
DRUG PROFILE
For a more detailed description of the afatinib profile please refer to the current Investigator’s 
Brochure (IB) (c01617169-04) and/or local product label information.
Afatinib (BIBW2992) is a small molecule, selective and irreversible ErbB family blocker. In 
preclinical models it effectively inhibits signalling from all homo- and heterodimers formed 
by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3, and ErbB4 resulting in 
tumour growth inhibition and regression of established subcutaneous tumours derived from 
four human cell-lines known to co-express ErbB receptors.
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 20-50 mg. The overall gMean 
terminal half-life at steady state was 37.2 hours in cancer patients. The major route of 
elimination of afatinib was via faeces.
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 % (AUC0-∞) and 22 % (Cmax), respectively. Caution should 
be exercised when combining afatinib with potent P-gp modulators (refer to Section 10.8). In 
pre-clinical studies afatinib is not irritant to intact skin but an ocular irritant.
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an intravenous (i.v.) immunotherapy for 
advanced malignancies. 
 (pembrolizumab) is indicated for the treatment of 
patients across a number of indications.


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Refer to the current local product label information and/or to the Summary of Product 
Characteristics (SmPC) or US Prescribing Information. For more details on specific 
indications refer to the Investigator brochure c16013985
1.3
RATIONALE FOR PERFORMING THE TRIAL
Although both afatinib and pembrolizumab have demonstrated effect in SCC patient
population (in terms of PFS and OS) it remains moderate and more treatment options are 
needed. This trial is combining both agents which are active in this setting in order to initially 
assess their tolerability and get indication about the preliminary anti-tumour activity.
To improve patient outcome, it is hypothesised that the combination of afatinib and 
pembrolizumab can lead to increased response rate with prolonged duration of response. This 
trial will assess the feasibility of such combination approach in terms of safety and 
tolerability, and eventually confirm whether it will achieve a better efficacy as compared to 
either agent alone.
This study aims to confirm the Recommended Phase 2 Dose (RP2D), the safety profile, and 
the efficacy of afatinib in combination with pembrolizumab in patients with squamous 
NSCLC, who are progressing during or after first line platinum-based standard therapy 
without any prior treatment with an immune checkpoint inhibitor or EGFR targeted therapy.
The potential therapeutic benefit or specific adverse events in patients cannot always be 
anticipated during the trial setup. Later on, there may be new scientific knowledge about 
biomarkers and other factors contributing to diseases or the action of a drug.
If clinically meaningful efficacy results are observed together with an acceptable safety and 
tolerability profile, further development of this treatment combination will be considered.
1.4
BENEFIT - RISK ASSESSMENT
Both afatinib and pembrolizumab are approved agents for the treatment of patients with SCC
of the lung and the combination of afatinib and pembrolizumab is hypothesised to increase 
response rate with prolonged duration of response as compared to each monotherapy.
The most common side effects from afatinib treatment are well characterized and include 
primarily diarrhoea, rash/acne, and stomatitis. For AE details please refer to the IB 
(c01617169-04). The severity of AEs is dose-dependent and potential side effects can be 
managed with treatment pauses, dose reductions, and administration of appropriate 
supportive care measures as described in Section 6.2.3. ILD/pneumonitis or ILD-like events 
are a known and infrequent risk associated with EGFR inhibitor therapy. Patients with known 
ILD/pneumonitis are not eligible for inclusion in the trial, and careful monitoring of 
pulmonary symptoms with sudden onset is warranted during the trial. A Safety Monitoring 
Committee (SMC) will oversee the trial and an external expert (e.g. ILD expert) may be 
appointed as needed to adjudicate potential ILD/pneumonitis cases. See Section 1.4.
In KEYNOTE-010, pembrolizumab was well tolerated, with primarily low-grade toxicities, 
most commonly fatigue, rash, and decreased appetite. Grade 3 or higher toxicities occurred in 
less than 17% of patients. Sixteen patients (5%) in the low dose level and fifteen patients 
(4%) in the higher dose level developed pneumonitis, including seven patients (2%) with 
grade 3 or higher pneumonitis in each dose level, three of whom died (<1% of all patients 


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treated with pembrolizumab) (R16-0876). Pembrolizumab immune-related events, as 
described in Section 4.2.3, are usually effectively managed with withholding or discontinuing 
pembrolizumab and initiating corticosteroid as outlined in the most recent version of the IB
(c16013985).
The combination of nivolumab (an immune checkpoint inhibitor) with erlotinib (a 1st
generation EGFR TKI) has previously been tested in a phase I trial CheckMate 012 (R16-
5545) in patients with EGFR mutation-positive NSCLC, and showed an encouraging anti-
tumour activity along with a manageable safety profile (R16-0317). Data from another trial 
indicated that the combination of full dose erlotinib with atezolizumab (PD-L1 inhibitor) is 
tolerable in advanced EGFR mutation-positive NSCLC. No new adverse events were 
identified and safety is similar to that of each agent alone (R17-0546).
In contrast, the combination of the 3rd generation EGFR TKI osimertinib and another PD-L1 
inhibitor durvalumab increased the frequency of ILD in EGFR mutation -positive NSCLC as 
compared to frequencies with either drug alone, although early data suggest encouraging 
clinical activity (R16-4467). Despite the fact that increased ILD frequency has not been 
reported when combining 1st or 2nd generation EGFR TKIs and immune checkpoint 
inhibitors, safety may still be a potential concern, thus careful safety measures have been 
implemented in this trial as further described in Sections: 1.4, 3.2, 5.2.6.1, and 8.7.
An ongoing phase I trial is assessing the combination of afatinib and pembrolizumab in 
patients with EGFR mutation-positive NSCLC with acquired resistance to erlotinib 
(NCT02364609). Information from this trial is taken into account for the determination of the 
recommended dose in the present trial (Appendix 10.9).
In the present trial, patients will receive afatinib and pembrolizumab at the approved 
recommended dose for the respective drugs. Twelve patients will be entered in the safety run 
in of the study and this data will be used to confirm the RP2D. Based on the observed safety 
profiles of both agents alone, it is expected that the combination can be initiated at 40 mg 
afatinib in combination with a fixed flat dose (200 mg every 3 weeks) of pembrolizumab. If 
excessive toxicities are observed at the 40 mg starting dose, the afatinib dose will be lowered 
to 30 mg as per the protocol, and twelve new patients will be entered in the safety run in to 
confirm the RP2D with afatinib 30 mg dose.
As mentioned above, patients will be monitored closely for adverse events and the dose of 
afatinib for individual patients will be interrupted or reduced, according to instructions 
provided in Table 4.1.4.1: 1.
Handling of the expected side effects is described in Section 4.2.3.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety, see also Section 5.2.6.1, adverse events of special interest (AESI).
During the trial, investigators are advised to manage treatment-related side-effects 
proactively. Suggested supportive care measures for the management of treatment related 
AEs and instructions for dose reductions for individual patients are provided in Section 4.1.4.
The patients will have frequent visits to ensure close monitoring of AEs. The safety of all 
patients, dose selection and benefit/risk assessment will be under constant surveillance by the 


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SMC (refer to Section 8.7) and by the Sponsor’s Medical Monitor and Drug Safety Physician. 
The SMC will review the safety analysis based on BLRM to confirm the RP2D, and also the 
available safety data from all trials evaluating the combination of afatinib and pembrolizumab
to confirm RP2D. The SMC will provide recommendations to either continue the trial 
without modification, or to stop recruitment, or to stop the trial at any of their meetings. The 
SMC may also provide recommendations to further minimize potential risks to patients, if 
required, e.g. regarding patient selection/ recruitment/dose adjustments, or request additional 
safety analysis. The SMC will operate under a Charter that will define membership, roles and 
responsibilities.
As part of the screening, patients are required to have a tumour tissue biopsy. In many cases 
this is standard clinical practice, and hence does not constitute an increased risk for the 
patients, but in case no fresh tissueis available this will be an additional procedure for some 
patients. As the results from the biopsy will provide more information which will assist 
clinical decisions for future patients, the benefit is assumed to outweigh the risks associated 
with the biopsy.
There will be regular and frequent examinations, including imaging every 9 weeks (63 ± 7 
days) until PD/start of subsequent anti-cancer treatment.
Based on the disease under study, the inclusion of women of childbearing potential, using 
contraception as described in Section 4.2.2.3, is justified. To minimize the risk of 
unintentional exposure of an embryo or foetus to the investigational drug, women of 
childbearing potential must agree to the requirements for pregnancy testing and contraceptive 
methods as described in this protocol and patient information.
In summary, considering the high unmet medical need for new treatment options in patients 
with advanced or metastatic SCC of the lung who are progressing during or after prior 
platinum-based chemotherapy, the anti-tumour activity and the well-known safety profiles of 
monotherapy with afatinib and pembrolizumab, and the existing data suggesting that a 
combination of PD-1 blockade with EGFR TKIs is a promising therapeutic strategy, the 
benefit risk assessment for patients included into this trial is considered to be favourable.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective is to assess the efficacy of afatinib in combination with pembrolizumab, 
as measured by objective response (OR) in patients with locally advanced or metastatic 
squamous NSCLC who progressed during or after first line platinum-based treatment.
The secondary objectives are to confirm the RP2D, assess the safety profile, and the 
secondary measures of clinical efficacy including disease control (DC), duration of objective
response (DoR), progression-free survival (PFS), overall survival (OS), and tumour 
shrinkage.
2.1.2
Primary endpoint(s)
The primary endpoint for this study is Objective Response (OR), defined as best overall 
response of complete response (CR) or partial response (PR) from first drug intake until the 
earliest of disease progression, death, or last evaluable tumour assessment before start of 
subsequent anti-cancer therapy, lost to follow-up, or withdrawal of consent.
All imaging related endpoints, including the primary endpoint will be investigator assessed 
primarily according to RECIST 1.1. Supportive summaries will also be produced with the 
supplemented immune-related RECIST (irRECIST) criteria. Refer to Sections 5.1, 7.3.1, 
10.3, and 10.4 for further details.
2.1.3
Secondary endpoint(s)
Secondary endpoints in this trial consist of

Disease control (DC), defined as best overall response of CR, PR, or stable disease 
(SD) from first drug intake until the earliest of disease progression, death or last 
evaluable tumour assessment before start of subsequent anti-cancer therapy, lost to 
follow-up or withdrawal of consent.

Duration of objective response (DoR), defined as the time from first documented CR 
or PR until the earliest of disease progression or death among patients with OR.

Progression-free survival (PFS), defined as the time from first drug intake until 
disease progression or death from any cause, whichever occurs earlier.

Overall survival (OS), defined as time from first drug intake until death from any 
cause.

Tumour shrinkage (in millimeters), defined as the difference between the minimum 
post-baseline sum of diameters of target lesions (longest for non-nodal lesions, short 
axis for nodal lesions) and the baseline sum of diameters of the same set of target 
lesions.

Recommended Phase II Dose (RP2D), defined by the SMC 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This trial is an open-label, single arm phase II study assessing the tolerability and anti-tumour 
activity of afatinib when given in combination with a fixed dose of pembrolizumab in 
patients with squamous NSCLC, who progressed during or after first line platinum-based 
standard therapy and had no prior treatment with an immune checkpoint inhibitor or EGFR 
targeted therapy.
The trial consists of two parts:
Safety run in: After the first 12 patients have been treated for at least one full cycle, the SMC, 
(see Section 8.7) will assess the overall safety profile and confirm the RP2D (refer to Section 
4.1.2).
The Bayesian Logistic Regression Model (BLRM) with overdose control will be fitted to 
binary toxicity outcomes to assess the risk for excessive toxicity. Please see Section 5.2.5.1
for the DLT definitions and Appendix 10.9 for details.
Based on the review of the clinical safety data together with the recommendations from the 
BLRM analysis, the SMC will decide if the starting dose of 40 mg of afatinib in combination 
with pembrolizumab should continue to be used for every new patient entering the study, or if 
it should be stopped and replaced by a dose of 30 mg afatinib. A stop of the 40 mg starting 
dose of afatinib is mandatory if this dose is considered too toxic according to the BLRM 
overdose criterion and all the available safety data. Hypothetical data scenarios have been 
performed for this purpose and are presented in Appendix 10.9.
The patients in the safety run in will continue in the trial during and after the SMC evaluation
and in case the SMC confirms a dose of 40 mg daily afatinib is too toxic, their afatinib dose 
will be reduced to 30 mg. SMC will provide guidance whether to continue patient recruitment 
at the defined dose prior to the RP2D definition.
In case the 40 mg is too toxic, 12 more patients will be included in the safety run in and they 
will receive a starting dose of afatinib of 30 mg. After they have been treated for at least one 
full cycle, the SMC will assess the overall safety profile and confirm the RP2D as stated above. 
In case the RP2D is confirmed as 30 mg, the patients will continue on this dose. However, in 
case this is considered too toxic, the trial will be stopped (see Figure 3.1: 2).
The SMC met to assess the overall safety profile and overall response rates. Although the 
BLRM analysis of afatinib in combination with pembrolizumab satisfies overdose control 
criterion, the data presented does not support the continuation of the combination of afatinib 
and pembrolizumab in this clinical setting. The SMC recommended stopping the trial, as it 
was felt that the benefit risk was not favorable.  The main part of the study will not open. 
Main part: Once the RP2D has been established, this will be the starting dose of afatinib for 
future patients entered to the main part of the trial. In total, 38 patients will be included in the 
main part.
If the RP2D is defined as the original starting dose of afatinib (40 mg daily) in combination 
with pembrolizumab, the trial will include 12 patients from the safety run in and 38 patients 
from the main part, leading to 50 patients in total. However if the RP2D is defined as 30 mg


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afatinib in combination with pembrolizumab, the trial will include 62 patients in total (12 
patients at 40 mg and 50 patients at 30 mg).
In both the safety run in and the main part, there is an option for dose adjustment in the 
individual patients (see Section 4.1.4.1).
Detailed guidance on AE reporting, assessments of efficacy, and patient visits is given in 
Sections 5 and 6.
* The trial will be closed as defined in Section 8.6
Figure 3.1: 1 Trial Design
The trial design is applicable for both the safety run in and the main part (see Figure 3.1: 2). 
For SMC evaluation, please see Appendix 10.9.3. The end of trial is defined in Section 8.6.


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Figure 3.1: 2 Safety run in and main part
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This study is a single arm, non-randomised, open-label, phase II study. A single arm design is 
justified as the trial is exploratory in nature to generate safety and efficacy data of afatinib 
when given in combination with pembrolizumab in patients with locally advanced or 
metastatic SCC of the lung. Sections 1.3 and 1.4 give the rationale and benefit risk 
assessment of this single arm combination therapy study, over what has been observed with
each of the single agents in previous studies. Section 1.3 also details the improvement in 
efficacy that is anticipated from the combination therapy to that observed in previous studies 
with each of the single agents (P15-06906, R15-6023).
The study will include a safety run in consisting of at least 12 patients, starting with afatinib 
40 mg once daily plus pembrolizumab 200 mg once every 3 weeks. A Bayesian Logistic 
Regression Model (BLRM) with overdose control will be implemented to confirm the RP2D. 
In case the RP2D is not established with afatinib 40 mg, dose de-escalation to afatinib 30 mg 
will be implemented. Ongoing patients on afatinib 40 mg will have their dose reduced to 30 
mg and any newly entered patients to the trial will start with afatinib 30 mg. In total, about 50 
patients will be included at the RP2D. The dose selection will be determined based on the 
recommendation of the SMC, guided by the aforementioned modelling approach. The BLRM 
with overdose control is not only an efficient method for dose finding studies but also for 
dose confirmation due to its flexibility to react to unforeseen toxicity rates (R13-4802). The 
use of Bayesian models has also been proposed by the European Medicines Agency (EMA) 
guideline on small populations (R07-4845) and by the US Food and Drug Administration 
(FDA) (R13-4881).
A variety of cancers were demonstrated to express abundant levels of PD-L1 (R15-6033,
R15-6038), which, via its interaction with the PD-1 receptor on tumour-specific T cells, plays 
a critical role in immune evasion by tumours (R15-6037). As a consequence, the PD-1/PD-L1 
pathway is an attractive target for therapeutic intervention in cancer. Although higher 
responses were observed with pembrolizumab in patients with PD-L1 expression score ≥ 
50%, the responses were also observed in patients with PD-L1 low (1-49%) or negative 


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(<1%) expression score. In addition, the significance of PD-L1 as a biomarker in predicting 
the effectiveness of checkpoint inhibition has been assessed with pembrolizumab 
monotherapy but not yet in combination with EGFR TKIs (R15-6023). Therefore no 
prospective patient selection based on PD-L1 expression score is planned; instead a 
retrospective assessment of PD-L1 expression score will be performed and its impact 
evaluated. Exploratory subgroup analyses for efficacy endpoints based on PD-L1 expression 
status will be performed.
Pembrolizumab and afatinib trial treatments as combination may be continued for up to 35 
cycles, which is the approved treatment duration for pembrolizumab monotherapy. In case of 
early discontinuation of one agent, the other agent may be continued as monotherapy for up 
to 35 cycles (including cycles with the combination treatment). After EOT, further therapy 
will be decided by the investigator including either continuation of afatinib (using 
commercial product), or alternative therapy, or best supportive care.
The primary endpoint of the study is Objective Response (OR), which is a well-accepted 
endpoint for a single arm phase II study. A response rate in excess of historical data in this 
population with demonstrated durability of such response can serve as a reasonable surrogate 
for clinical benefit in pre-treated locally advanced or metastatic squamous NSCLC.
3.3
SELECTION OF TRIAL POPULATION
This trial will be conducted at approximately 25 centres in about 6 countries. If a centre is 
unable to recruit patients, additional centres may be recruited and centres may be closed. 
Each centre is expected to recruit on average of 2-3 patients.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients has been screened. Sites will be 
notified about screening completion and will then not be allowed to screen additional patients 
for this trial. When the required number of patients has entered the study, patients who have 
already been screened for the trial are allowed to continue and be entered in case they meet 
all eligibility criteria.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site file (ISF) at the investigational site irrespective of whether 
they have been treated with investigational drug or not.
3.3.1
Main diagnosis for trial entry
This study will include patients with locally advanced or metastatic squamous cell carcinoma 
of the lung. Patients must have progressed during or after standard platinum-based 
chemotherapy, without prior treatment with any checkpoint inhibitor or EGFR targeted 
therapy.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.
3.3.2
Inclusion criteria
1. Pathologically confirmed diagnosis of NSCLC considered to be of squamous histology, 
including mixed histology, in the opinion of the investigator.


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2. Locally advanced (stage IIIb) or metastatic (stage IV) NSCLC not considered eligible for 
curative therapy.
3. Documented disease progression or relapse (based on investigator’s assessment) during or 
after completion of at least 2 cycles of platinum-based chemotherapy as first line 
treatment of Stage IIIB/IV SCC of the lung. This includes patients relapsing within 6 
months of completing (neo) adjuvant/curative-intent chemotherapy or definitive 
chemoradiotherapy. Patients should be eligible to receive second line therapy in the 
opinion of the investigator.
4. At least one target lesion (outside the brain) that can be accurately measured per 
Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. In patients who 
only have one target lesion and a biopsy of the lesion is required; the baseline imaging 
must be performed at least two weeks after the biopsy.
5. Availability and willingness to provide a fresh tumour tissue sample obtained after 
relapse or progression on or after prior therapy. In case a fresh biopsy cannot be obtained 
(e.g. inaccessible lesions or patient safety concern), an archived specimen may be 
submitted.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. Adequate organ function defined as all of the following (all screening labs should be 
performed within 10 days prior to treatment initiation):
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1.5 x 109/L.
Platelets
≥75 x 109/L.
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L.a
Renal
Creatinine OR
Measured or calculatedb creatinine 
clearance (Glomerular Filtration 
Rate (GFR) can also be used in 
place of creatinine or CrCl)
≤ 1.5 x ULN OR
≥50 mL/min for patients with creatinine levels >1.5x ULN.
Hepatic
Total bilirubin
≤1.5 times the upper limit of normal (ULN)
AST (SGOT) and ALT (SGPT)
≤2.5 x ULN OR ≤5 x ULN for patients with liver metastases.
Coagulation

International Normalised Ratio 
(INR) or Prothrombin Time (PT)

≤1.5xULN unless patient is receiving anticoagulant therapy as long 
as PT is within therapeutic range of intended use of anticoagulants.

Activated Partial 
Thromboplastin Time (aPTT)

≤1.5xULN unless patient is receiving anticoagulant therapy as long 
as aPTT is within therapeutic range of intended use of anticoagulants.
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion 
within last 2 weeks.
b Creatinine clearance should be calculated per institutional standard.
8. Recovery from major surgery or any previous anti-cancer or radiation therapy-related 
toxicity to ≤ CTCAE Grade 1 at C1_V1 (except for alopecia; stable sensory neuropathy 
must be ≤ CTCAE Grade 2).
9. At least 18 years of age or over the legal age of consent in countries where that is greater 
than 18 years at screening.


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10. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
11. Male or female patients. Women of childbearing potential (WOCBP)0F1 and men able to 
father a child must be ready and able to use highly effective methods of birth control per 
ICH M3 (R2) that result in a low failure rate of less than 1% per year when used 
consistently and correctly, starting with the screening visit and through 120 days after the 
last dose of pembrolizumab treatment and 2 weeks after last afatinib treatment, 
respectively, as listed in the protocol. A list of contraception methods meeting these 
criteria is provided in the patient information. For further details refer to Section 4.2.2.3.
Note: Female patients of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to taking study medication. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required. The 
serum pregnancy test must be negative for the patient to be eligible.
3.3.3
Exclusion criteria
1. Prior therapy with any immune checkpoint inhibitor; however, prior (neo) adjuvant 
checkpoint inhibitor therapy is allowed if completed at least 12 months before relapse.
2. Prior therapy with EGFR inhibiting drugs; however, prior EGFR-targeted (neo) adjuvant 
therapy is allowed if completed at least 12 months before relapse.
3. Treatment with prior chemotherapy, non-EGFR targeted therapy, or anti-cancer hormonal 
treatment within 2 weeks prior to the first dose of trial treatment.
4. Current or previous treatment with experimental therapy or use of an investigational 
device within 30 days prior to the first dose of trial treatment.
5. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the first dose of 
trial treatment.
6. Received a live vaccine within 30 days prior to the first dose of trial treatment. Seasonal 
flu vaccines that do not contain live virus are permitted.
7. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The 
use of physiologic doses of corticosteroids is allowed.
8. Any history of or concomitant condition that, in the opinion of the investigator, would 
compromise the patient’s ability to comply with the trial or interfere with the evaluation 
of the efficacy and safety of the test drugs.
9. Radiotherapy within 4 weeks prior to start of treatment except as follows:

Palliative radiotherapy to regions other than the chest is allowed up to 2 weeks prior 
to start of treatment;
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile.
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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
Single dose palliative radiotherapy for symptomatic metastasis within 2 weeks prior 
to start of treatment may be allowed but must be agreed with the sponsor.
10. Major surgery (according to the investigator’s assessment) performed within 4 weeks 
prior to start of treatment or planned during the projected course of the study.
11. Requirement or wish to continue the intake of restricted medications (see Section 4.2.2.1) 
or any drug considered likely to interfere with the safe conduct of the trial.
12. Known history of hypersensitivity to afatinib or any of its excipients.
13. Known history of hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its 
excipients.
14. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
Note: Patients with previously treated brain metastases may participate provided they are 
radiologically stable i.e. without evidence of progression for at least four weeks by repeat 
imaging (note that the repeat imaging should be performed during study screening), 
clinically stable, and without requirement of steroids treatment for at least 14 days prior 
to first dose of study treatment. This exception does not include carcinomatous meningitis 
which is excluded regardless of clinical stability.
15. Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with 
use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment and is allowed.
16. History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required 
steroids or current ILD/pneumonitis.
17. Any history or presence of uncontrolled gastrointestinal disorders that could affect the 
intake and/or absorption of the study drug (e.g. nausea, vomiting, Crohn’s disease, 
ulcerative colitis, chronic diarrhoea, malabsorption) in the opinion of the investigator.
18. Active infectious disease requiring systemic therapy or which puts the patient at increased 
risk in the opinion of the investigator.
19. Previous or concomitant malignancies at other sites than the lung, except:

Effectively treated non-melanoma skin cancers;

Effectively treated carcinoma in situ of the cervix;

Effectively treated ductal carcinoma in situ;

Other effectively treated malignancy that has been in remission for more than 3 years 
and is considered to be cured.
20. Known human immunodeficiency virus (HIV) (HIV 1/2 antibodies), hepatitis B (e.g. 
HBsAg reactive) or known active hepatitis C infection.
21. History of active TB (Bacillus Tuberculosis).
22. History or presence of cardiovascular abnormalities such as uncontrolled hypertension, 
congestive heart failure New York Heart Association (NYHA) classification of ≥3, 


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unstable angina or poorly controlled arrhythmia which are considered as clinically 
relevant by the investigator. Myocardial infarction within 6 months prior to start of 
treatment.
23. Psychiatric, substance abuse disorders, or chronic alcohol abuse or any condition that in 
the investigator’s opinion would interfere with cooperation with the requirements of the 
trial.
24. History or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the patient’s participation in the trial, 
or is not in the best interest of the patient to participate, in the opinion of the treating 
investigator.
25. Is pregnant or breastfeeding, expecting to conceive or father children within the projected 
duration of the trial or do not agree to submit to the pregnancy testing required by this 
protocol.
3.3.4
Withdrawal of patients from therapy or assessments
With the early termination of the study, there is no follow-up of patients who completed the 
trial. 
Patients may potentially be withdrawn from trial treatment or from the trial as a whole
(“withdrawal of consent”) with very different implications, please see Sections 3.3.4.1 and 
3.3.4.2 below.
Every effort should be made to keep the entered patients in the trial: if possible on treatment, 
or at least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial entry, as well as the
explanation of the consequences of withdrawal.
The decision to withdraw from trial treatment or from the whole trial as well as the reason
must be documented in the patient files and eCRF.
3.3.4.1
Withdrawal from trial treatment
With the early termination of the study there will be no follow-up for disease progression or 
overall survival after a patient is withdrawn from trial treatment. 
An individual patient is to be withdrawn from trial treatment if the patient:

Wants to withdraw from trial treatment, without the need to justify the decision.

Is diagnosed with Interstitial Lung Disease (ILD) / pneumonitis
o
afatinib: any grade
o
pembrolizumab: grade >2 or recurrent grade 2

Is required to stop treatment due to adverse events as described in Section 4.2.3 and 4.1.4.

Can no longer be treated with trial medication due to pregnancy or for other medical 
reasons (such as surgery, concomitant diagnoses, adverse events, or prohibited 
concomitant therapies (refer to Section 4.2.2).


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
Has repeatedly shown to be non-compliant with important trial procedures and, in the 
opinion of both, the investigator and sponsor representative, is not willing or not able to 
stick to the trial requirements in the future.

Has a significant deviation from the protocol procedures or eligibility criteria. The 
decision to continue or withdraw treatment will be made by the sponsor in agreement 
with the investigator.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow-up as outlined in the Flowchart and Section 6.2.3. FU/PD will be 
performed until confirmed PD, and FU/OS will be performed until the end of trial.
An individual patient will complete trial treatment if the patient:

Has radiological (or clinical) documentation of progressive disease on the current 
treatment (see Section 5.1.2).

Has completed the maximum 35 cycles of study treatment.
Given the patient’s agreement, the patient will undergo the procedures and follow-up as 
outlined in the Flowchart and Section 6.2.3. FU/PD will be performed until confirmed PD, 
and FU/OS will be performed until the end of trial.
For all patients the reason for discontinuation of trial treatment (e.g. adverse events) must be 
recorded in the eCRF. These data will be included in the trial database and reported.
3.3.4.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision.
This will however mean that no further information may be collected for the purpose of the 
trial and negative implications for the scientific value may be the consequence. Furthermore 
it may mean that further patient follow-up on safety cannot occur.
If a patient wants to withdraw consent, the investigator should explain the difference between 
treatment withdrawal and withdrawal of consent for trial participation and explain the options 
for continued follow-up after withdrawal from trial treatment, please see Section 3.3.4.1
above.
3.3.4.3
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:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3. Violation of GCP, the trial protocol, or the contract impairing 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
INVESTIGATIONAL TREATMENTS
Eligible patients will receive a combination of afatinib and pembrolizumab.
4.1.1
Identity of the investigational medicinal products
Table 4.1.1: 1
Afatinib (investigational medicinal product)
Substance (INN):
Brand name:
Afatinib
GIOTRIF®/ GILOTRIF®
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
40 mg tablet, 30 mg tablet, 20 mg tablet
Posology
Once daily
Route of administration:
Oral
Table 4.1.1: 2
Pembrolizumab (investigational medicinal product)
Substance (INN):
Brand name:
Pembrolizumab
Pharmaceutical formulation:
Solution for infusion
Source:
Unit strength:
Solution for infusion: 100 mg/4mL
Posology:
Infusion, once every 3 weeks
Route of administration:
Intravenous
4.1.2
Selection of doses in the trial
In this trial, afatinib will be given at the approved single-agent starting dose i.e. 40 mg once 
daily, in combination with pembrolizumab at the approved single-agent fixed dose of 200 mg 
every 3 weeks. Based on available data from an ongoing phase I trial in EGFR mutant 
NSCLC (NCT02364609), a starting dose of afatinib at 40 mg once daily in combination with 
pembrolizumab is considered feasible. The daily dose of afatinib may be adjusted following 


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careful monitoring of patients’ side effects, as depicted in Table 4.1.4.1: 1, with dose 
reduction to 30 mg or 20 mg for patients experiencing AEs (see Section 4.1.4).
The SMC will review the safety analysis based on BLRM to confirm the RP2D, which will 
be the starting dose of afatinib given in combination with pembrolizumab for any future 
patients entered to the trial. The starting dose of afatinib can be reduced to 30 mg based on 
the SMC recommendation.
4.1.3
Method of assigning patients to treatment groups
All eligible patients will receive afatinib in combination with pembrolizumab. The 
assignment of an afatinib medication number and a pembrolizumab medication number will 
occur via Interactive Response Technology (IRT). Patient numbers will be provided by the 
IRT system once the patient is registered in the system. Re-screening is allowed.
4.1.4
Drug assignment and administration of doses for each patient
Patients will receive continuous treatment from C1_V1 until progression or until other 
criteria for stopping medication are met (see Section 3.3.4.1). The SMC review of the safety 
analysis based on BLRM recommendations and additional safety data will confirm the RP2D 
(see Section 4.1.2). Patients will be monitored closely for adverse events and dose 
modifications may apply, according to instructions provided in Table 4.1.4.1: 1 and Table 
4.1.4.2.1: 1 below. In case of treatment related Adverse Events that cannot exclusively be 
attributed to one compound, the instructions for dose modification of both compounds should 
be taken into consideration. The starting dose of afatinib can be reduced to 30 mg based on 
the SMC recommendation.
Stopping rules and retreatment criteria for each compound should be considered separately. 
In case afatinib has to be (temporarily) interrupted, pembrolizumab treatment may continue at 
the investigator’s discretion.
After first documentation of PD and if the patient is clinically stable, the patient may continue 
study treatment at the physician discretion if it is felt patient is still deriving a benefit from 
treatment until confirmed PD (see Table 5.1.2: 1). This clinical judgment decision by the site 
should be based on the patients’ overall clinical condition, including performance status, 
clinical symptoms, and laboratory data. Tumour assessment should be repeated at least 4 weeks 
later in order to confirm PD by irRECIST. In case treatment is paused and disease progression 
is not confirmed on subsequent imaging, study treatment may be resumed.
Pembrolizumab and afatinib study medication will not be continued after the development of 
confirmed PD (see Section 5.1).
Refer to Section 4.2.3 for instructions on the management of treatment related AEs.
Dosing interruptions are permitted in case of medical / surgical events or logistical reasons 
not related to study therapy (e.g. elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Patients should be placed back on study therapy within 14 days of the 
scheduled interruption, unless otherwise discussed with the sponsor. The reason for 
interruption should be documented in the patient's study record.


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4.1.4.1
Afatinib treatment
Patients will take a single oral dose of afatinib each day starting at a dose of 40 mg, 
continuously, until the development of progressive disease or until other criteria for stopping 
medication are met. Dose reductions of afatinib can occur (see Table 4.1.4.1: 1). Once the 
SMC has confirmed the RP2D, this will be the starting dose of afatinib.
On day 1 of each treatment cycle, patients will be dispensed sufficient afatinib for the 
treatment cycle. Any medication remaining from the previous treatment cycle should be 
collected. If a dose reduction is necessary during a treatment cycle, any remaining medication 
from the higher dose should be collected from the patient and the new dose dispensed.
The afatinib tablet should be taken once daily (qd) at approximately the same time of the day, 
with a glass of water, and food should not be consumed for at least three hours before and at 
least one hour after taking the afatinib tablet. Missed doses of afatinib can be made up for 
during the same day, if taken within 8 hours of the regularly scheduled time. Otherwise, the 
dose should be skipped and patients should take the next scheduled dose at the usual time. 
Afatinib tablets should not be taken more than once a day and patients with emesis should not 
take a replacement dose. On the visit dates of Cycle 2 and Cycle 3, respectively, the patient 
should not take the dose at home before visiting the site, as the afatinib medication is taken at 
the study site shortly after the PK sampling and before start of pembrolizumab infusion (see 
Section 10.1).
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.
Patients will be monitored closely for adverse events and the dose of afatinib must be 
interrupted or reduced, according to instructions provided in Table 4.1.4.1: 1 below. Once the 
dose has been reduced, it may not be increased later.
Table 4.1.4.1: 1
Afatinib dose reduction scheme
AE type and CTCAE Grade
Action
Dose reduction scheme
Events related to afatinib:
Diarrhoea
Grade 2 persisting for 2 or 
more consecutive days (48 
hours) despite adequate anti-
diarrhoeal 
medication/hydration
Reduced renal function due to 
dehydration (i.e. pre-renal 
failure) secondary to diarrhoea
Pause afatinib until patient 
has recovered to CTCAE 
Grade ≤1 or baseline level1
Resume afatinib at reduced 
dose according to schedule 
opposite.
If patient has not 
recovered to CTCAE 
Grade ≤1 or baseline1
within 14 days afatinib 
If patient was receiving 40
mg, resume treatment at a 
dose of 30 mg
If patient was receiving 30
mg, resume treatment at a 
dose of 20 mg
If patient was receiving 20 
mg, discontinue afatinib.


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AE type and CTCAE Grade
Action
Dose reduction scheme
to ≥ Grade 2 as measured by 
serum creatinine, proteinuria,
or decrease in glomerular 
filtration rate of more than 
50% from baseline
Any drug related AE Grade ≥3
study treatment must be 
permanently discontinued2
Acute onset and/or unexplained 
worsening of pulmonary systems 
(dyspnoea, cough, fever)
Pause afatinib while 
clinical assessment to 
exclude ILD is completed
If ILD/pneumonitis is 
confirmed, discontinue 
afatinib
If ILD/pneumonitis is ruled 
out as a cause of symptoms, 
grade symptoms and 
relatedness and report as 
AEs unless there is another 
diagnosis
If AEs are not related, 
resume afatinib at current 
dose. If AEs are drug 
related, follow directions in 
row above
For pembrolizumab: refer to 
Table 4.1.4.2.1: 1
1.
Baseline is defined as the CTCAE Grade prior to the start of treatment.
2.
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.
In the event of a treatment pause, subsequent visits should not be delayed.
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, the decision to continue with afatinib will be made by the 
BI medical monitor in agreement with the investigator.
In case the criteria for discontinuing afatinib are met, treatment with pembrolizumab can 
continue until a maximum of 35 cycles, see Section 4.1.4.2.
4.1.4.2
Pembrolizumab treatment
Pembrolizumab will be administered on Day 1 of each 21 day treatment cycle after all study 
procedures and assessments have been completed. Pembrolizumab will be administered as a 
dose of 200 mg using a 30-minute i.v. infusion. Details on preparation and administration of 
pembrolizumab are provided in the Pharmacy Manual. Sites should make every effort to 
target infusion timing to be as close to 30 minutes as possible. However, given the variability 
of infusion pumps from site to site, a window between -5 minutes and +10 minutes is 
permitted i.e., infusion time is 30 minutes (-5 min/+10 min).


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Pembrolizumab and afatinib trial treatment may be continued, as combination or mono 
therapy, for a maximum period of 35 cycles (about two years) after which study 
medication(s) must be discontinued / completed. Further therapy will be decided by the 
investigator and may include: continuation of afatinib using commercial product according to 
current SPC/PI, or alternative therapy, or best supportive care.
4.1.4.2.1
Dose modification and toxicity management for immune-related AEs associated 
with pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 4.1.4.2.1: 1.
See Section 4.2.3 for supportive care guidelines, including use of corticosteroids.
Table 4.1.4.2.1: 1
Dose modification and toxicity management guidelines for immune-
related AEs associated with pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over 
at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot 
be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks.
3.
For severe and life-threatening irAEs, i.v. corticosteroid should be initiated first followed by oral 
steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids.
Immune-
related AEs
Toxicity grade 
or conditions 
(CTCAE v4.03)
Action taken to 
pembrolizumab1
irAE management 
with corticosteroid 
and/or other 
therapies
Monitor and follow-up
Pneumonitis
Grade 2
Withhold
Administer 
corticosteroids 
(initial dose of 1-2
mg/kg prednisone 
or equivalent) 
followed by taper
Monitor patients for 
signs and symptoms of 
pneumonitis
Evaluate patients with 
suspected pneumonitis 
with radiographic 
imaging and initiate 
corticosteroid treatment
Grade 3 or 4, or 
recurrent grade 
2
Permanently 
discontinue


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Immune-
related AEs
Toxicity grade 
or conditions 
(CTCAE v4.03)
Action taken to 
pembrolizumab1
irAE management 
with corticosteroid 
and/or other 
therapies
Monitor and follow-up
Add prophylactic 
antibiotics for 
opportunistic infections
Diarrhoea / 
Colitis
Grade 2 or 3
Withhold
Administer 
corticosteroids 
(initial dose of 1-2
mg/kg prednisone 
or equivalent) 
followed by taper
For afatinib: refer 
to Table 4.1.4.1: 1
Monitor patients for 
signs and symptoms of 
enterocolitis (i.e. 
diarrhoea, abdominal 
pain, blood or mucus in 
stool with or without 
fever) and of bowel 
perforation (i.e. 
peritoneal signs and 
ileus)
Patients with ≥ Grade 2 
diarrhoea suspecting 
colitis should consider 
GI consultation and 
performing endoscopy to 
rule out colitis
Patients with 
diarrhoea/colitis should 
be advised to drink 
liberal quantities of clear 
fluids. If sufficient oral 
fluid intake is not 
feasible, fluid and 
electrolytes should be 
substituted via i.v.
infusion
Grade 4
Permanently 
discontinue
AST / ALT
elevation or 
Increased 
Bilirubin1
Grade 2
Withhold
Administer 
corticosteroids 
(initial dose of 0.5-
1 mg/kg prednisone 
or equivalent) 
followed by taper
Monitor with liver 
function tests (consider 
weekly or more 
frequently until liver 
enzyme value returned 
to baseline or is stable
Grade 3 or 4
Permanently 
discontinue
Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper
In case of liver 
metastasis with 
baseline Grade 
2 elevation of 
AST or ALT, 
hepatitis with 
AST or ALT 
increases ≥ 50% 
and lasts ≥ 1 
week
Permanently 
discontinue
Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper


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Immune-
related AEs
Toxicity grade 
or conditions 
(CTCAE v4.03)
Action taken to 
pembrolizumab1
irAE management 
with corticosteroid 
and/or other 
therapies
Monitor and follow-up
Type 1 diabetes 
mellitus 
(T1DM) or 
Hyperglycaemia
Newly onset 
T1DM or 
Grade 
3 or 4
hyperglycemia 
associated with 
evidence of ß-
cell failure
Withhold
Initiate insulin 
replacement 
therapy for patients 
with T1DM 
Administer anti-
hyperglycemic in 
patients 
withhyperglycemia
Monitor patients for 
hyperglycemia or other 
signs and symptoms of 
diabetes
Hypophysitis
Grade 2
Withhold
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated
Monitor for signs and 
symptoms of 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue2
Hyperthyroidis
m
Grade 2
Continue
Treat with non-
selective beta-
blockers (e.g. 
propranolol) or 
thionamides as 
appropriate
Monitor for signs and 
symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue2
Hypothyroidism
Grade 2 to 4
Continue
Initiate thyroid 
replacement 
hormones (e.g. 
levothyroxine or 
liothyroinine) per 
standard of care
Monitor for signs and 
symptoms of thyroid 
disorders
Nephritis or 
renal 
dysfunction
Grade 2
Withhold
Administer 
corticosteroids 
(prednisone 1-2
mg/kg or 
equivalent) 
followed by taper
Monitor changes of renal 
function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 or 2
Withhold
Based on severity 
of AE administer 
corticosteroids
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes
Grade 3 or 4
Permanently 
discontinue
All Other 
Immune-Related 
AEs
Intolerable/ 
persistent Grade 
2
Withhold
Based on type and 
severity of AE 
administer 
corticosteroids
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes
Grade 3
Withhold or 
discontinue based 
on the type of 
event. Events that 
require 
discontinuation 
include and not 
limited to: 
Guillain-Barre 
Syndrome, 
encephalitis


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Immune-
related AEs
Toxicity grade 
or conditions 
(CTCAE v4.03)
Action taken to 
pembrolizumab1
irAE management 
with corticosteroid 
and/or other 
therapies
Monitor and follow-up
Grade 4 or 
recurrent Grade 
3
Permanently 
discontinue
Notes:
1 Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician.
2 For patients with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement 
therapy or achieved metabolic control (in case of T1DM).
In case the criteria for discontinuing pembrolizumab are met, treatment with afatinib can 
continue, see Section 4.1.4.
4.1.4.2.2
Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Patients should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the sponsor. The reason for interruption should be documented in the patient's 
study record.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
In this open-label trial, treatment allocation will not be concealed throughout the trial.
4.1.5.2
Unblinding and breaking the code
Not applicable.
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated CRO. They will be
packaged and labelled in accordance with the principles of Good Manufacturing Practice 
(GMP). Re-supply to the sites will be managed via an IRT system, which will also monitor 
expiry dates of supplies available at the sites.
Patients will be handed out afatinib trial medication for the upcoming treatment cycle during 
the planned and/or regular visit on day 1 of each treatment cycle. Medication not used in the 
previous treatment cycle and empty bottles will be collected.
For details of packaging and the description of the label, refer to the ISF.


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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
Details on storage conditions for pembrolizumab are provided in the Pharmacy Manual.
4.1.8
Drug accountability
The investigator or delegate (e.g. pharmacist or investigational drug storage manager) will 
receive the investigational drugs delivered by the sponsor when the following requirements 
are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee.

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site.

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.

Availability of the proof of a medical license for the Principal Investigator.

For US only: Availability of FDA Form 1572.
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator or delegate 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 warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal.
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 or delegate will maintain records that document adequately that the patients were 
provided the doses specified by the clinical trial protocol and reconcile all investigational 
products received from the sponsor. At the time of return to the sponsor or appointed CRO, 
the investigator or delegate 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
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed for afatinib.
Rescue medications to reverse the actions of afatinib are not available. There is no specific 
antidote for overdosage with afatinib. In cases of suspected overdose, afatinib should be 
withheld and supportive care initiated. If indicated, elimination of unabsorbed afatinib may 
be achieved by emesis or gastric lavage. Rescue medications to reverse the actions of 
pembrolizumab are not available. Potential adverse events should be treated symptomatically 
and must be recorded.
Common adverse events of treatment with afatinib with specified management 
recommendations and/or requirements include diarrhoea, stomatitis/mucositis, and rash/acne. 
For pembrolizumab, related adverse events are those with potential immunologic etiology. 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 4.2.3.
For pembrolizumab, patients should receive appropriate supportive care measures as deemed 
necessary by the treating investigator. Suggested supportive care measures for the 
management of AEs with potential immunologic etiology are outlined along with the dose 
modification guidelines in Section 4.1.4.2.1 (Table 4.1.4.2.1: 1). Where appropriate, these 
guidelines include the use of oral or i.v. treatment with corticosteroids, as well as additional 
anti-inflammatory agents if symptoms do not improve with administration of corticosteroids. 
Note that several courses of steroid tapering may be necessary as symptoms may worsen 
when the steroid dose is decreased. For each disorder, attempts should be made to rule out 
other causes such as metastatic disease or bacterial or viral infection, which might require 
additional supportive care. The treatment guidelines are intended to be applied when the 
investigator determines the events to be related to pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 4.1.4.2.1: 1 in 
Section 4.1.4.2.1 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
4.2.1.1
Concomitant medications
Concomitant medications or therapy to provide adequate supportive care may be given as 
clinically necessary.
After study enrolment, 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 
further tumour response assessment. During palliative radiotherapy, study treatment should 


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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 sponsor in agreement with the investigator.
All concomitant therapy, including anaesthetic agents, vitamins, homeopathic/herbal 
remedies and 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 visit. After the EOT visit, only concomitant therapy indicated for treatment of an AE 
has to be reported.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Patients are prohibited from receiving the following therapies or vaccination during the trial 
treatment:

Any other investigational agents apart from the study medication.

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), biological therapy, or radiotherapy (other 
than described in Section 4.2.1.1). The use of megestrol acetate to improve appetite 
and to increase weight in cancer-associated anorexia is allowed.
o
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may 
be considered on an exceptional case by case basis after consultation with the 
sponsor. The patient must have clear measurable disease outside the radiated 
field. 

Immunotherapy not specified in this protocol.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.
o
Seasonal influenza vaccines for injection are generally killed virus vaccines 
and are allowed.
o
However, intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated 
vaccines, and are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of suspected immunologic etiology or to treat adverse reactions to afatinib. The 
use of physiologic doses of corticosteroids may be approved after consultation with 
the sponsor.
o
Inhaled steroids are allowed for management of asthma.
o
Steroid pre-medications for contrast CTs are permissible if needed.
Patients who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be withdrawn from the trial
treatment. Patients may receive other medications that the investigator deems to be medically 
necessary. The final decision on any supportive therapy or vaccination rests with the 


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investigator and/or the patient's primary physician. However, the decision to continue the 
patient on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the sponsor and the patient.
The Exclusion Criteria describe other medications that are prohibited in this trial.
There are no prohibited therapies during the Post Treatment Follow-up Phase.
The following guidance is applicable for afatinib:

Afatinib is a substrate of the P-gp transporter. Caution should be exercised when 
combining afatinib with strong P-gp modulators. For a list of potent P-gp inhibitors 
and inducers see Appendix 10.8.

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 wound healing. If afatinib is interrupted for more than 14 days, the decision to 
continue will be made by the BI Medical Monitor in agreement with the investigator.
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 4.2.3.
Food should not be consumed for at least three hours before and at least one hour after taking 
the afatinib tablet.
On the visit dates of Cycle 2 and Cycle 3, respectively, the patient should not take the dose at 
home before visiting the site, as the afatinib medication is taken at the study site shortly after 
the PK sampling and before start of pembrolizumab infusion (see Section 10.1).
4.2.2.3
Restrictions regarding women of childbearing potential
Women of childbearing potential must use the contraception methods described in the patient 
information.
Women who are not of childbearing potential due to being postmenopausal (i.e. 12 months 
with no menses without alternative medical cause, predefined hormonal level according to 
local regulation) and patients (male or female) who are permanently sterilised (bilateral 
oophorectomy or hysterectomy confirmed with medical records of the actual procedure or 
confirmed by an ultrasound, bilateral salpingectomy, vasectomy) do not need to use 
contraception to be eligible for the trial.
All other patients (male or female) are considered to have childbearing potential and must use 
adequate contraception throughout the trial (from screening until 120 days after the last dose 
of pembrolizumab treatment and 2 weeks after last afatinib treatment).
Adequate contraception is defined per ICH M3 (R2) as highly effective or acceptable 
methods. Highly effective methods of birth control which should be used by women of 
childbearing potential are those, which alone or in combination, result in a low failure rate 
(i.e., less than 1% per year) when used consistently and correctly, and must be in accordance 
with local regulations where applicable.


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Based on the recommendations of the European Union Heads of Medicines Agency related to 
contraception and pregnancy testing in clinical trials (CTFG, 2014), the following 
contraception methods can achieve a failure rate of less than 1% per year when used 
consistently and correctly:
1. Use of hormonal methods of contraception associated with inhibition of ovulation
a.
Combined (estrogen and progestogen containing) hormonal contraception:
Oral
Intravaginal
Transdermal
b. Progestogen-only hormonal contraception:
Oral
Injectable
Implantable
2. Placement of intrauterine device or intrauterine system.
3. Bilateral tubal occlusion.
4. Male sterilization (with the appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate).
5. Complete sexual abstinence.
The list of acceptable contraception methods is also provided in the patient information.
Women who become pregnant while participating in the study must discontinue study 
medication immediately. The pregnancy must be reported following procedures detailed in 
Section 5.2.6.2.
4.2.3
Management of side effects
Management of treatment-related side-effects should be proactive and should be started as 
early as possible after onset of symptoms. Patients should be advised to report AEs promptly 
so that appropriate treatment can be initiated.
Suggested supportive care measures for the management of adverse events due to treatment 
with EGFR targeting agents or with potential immunologic etiology are outlined below.
When managing side effects, consider both afatinib and pembrolizumab instructions as 
provided below.
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, the 
measures for pembrolizumab adverse reactions include the use of oral or intravenous treatment 
with corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve 
with administration of corticosteroids. Note that several cycles of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab. Note: If after the evaluation the event is determined not to be related, the 
investigator does not need to follow the treatment guidance (as outlined below).


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It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. See also Table 4.1.4.2.1: 1 for more 
information about toxicity management and dose modification guidelines for irAEs 
associated with pembrolizumab.
Refer to the pembrolizumab IB (c16013985) for more information.
4.2.3.1
Management of dermatological AEs following treatment with afatinib
Dermatologic AEs observed with afatinib include rash, dermatitis acneiform, and dry skin 
(xerosis)/hyperkeratosis. General recommendations for prophylaxis are summarised in Table 
4.2.3.1: 1 and grade-specific treatment recommendations are summarised in Table 4.2.3.1: 2
(adapted from R11-0826).
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 
clinical experience, early involvement of a dermatologist should be considered.
Table 4.2.3.1:1
General recommendations for prophylaxis of dermatological AEs while 
receiving afatinib
Table 4.2.3.1: 1 General 
recommendation for 
prophylaxis of 
dermatological AEs while 
receiving afatinibPersonal 
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 Sun Protection Factor (SPF) (at least 
SPF30, PABA 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.
Moisturiser treatment
It is important to moisturise the skin as soon as anti-EGFR therapy is started.
Hypoallergenic moisturising 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.


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Table 4.2.3.1: 2
Grade specific treatment recommendations of skin reactions to afatinib
Intensity
(CTCAE Grading)
Description
Specific intervention
ACNEIFORM RASH
Mild (Grade 1)
Papules and/or pustules covering 
<10% Body Surface Area (BSA), 
which may or may not be 
associated with symptoms of 
pruritus or tenderness.
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)
Papules and/or pustules covering 
10 - 30% BSA, which may or 
may not be associated with 
symptoms of pruritus or 
tenderness; associated with 
psychosocial impact; limiting 
instrumental ADL.
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 100 mg 
(b.i.d.) or minocycline hydrochloride 100 
mg b.i.d.
Severe (Grade 3)
Papules and/or pustules covering 
>30% BSA, which may or may 
not be associated with symptoms 
of pruritus or tenderness; limiting 
self-care ADL; associated with 
local superinfection with oral 
antibiotics indicated.
Topical and systemic treatment as for 
Grade 2.
Consider referral to dermatologist.
Consider systemic steroids.
Life threatening (Grade 4)
Papules and/or pustules covering 
any % BSA, which may or may 
not be associated with symptoms 
of pruritus or tenderness and are 
associated with extensive 
superinfection with i.v. 
antibiotics indicated; life 
threatening consequences.
See Grade 3
Systemic antibiotics and steroids are 
recommended.
PRURITUS
Mild (Grade 1)
Mild or localised; topical 
intervention indicated.
Topical polidocanol cream.
Consider oral antihistamines, e.g. 
diphenhydramine, dimethindene, cetirizine, 
levocetirizine, desloratidine, fexofenadine 
or clemastine).
Moderate (Grade 2)
Intense or widespread; 
intermittent; skin changes from 
scratching (e.g., edema, 
papulation, excoriations, 
lichenification, oozing/crusts); 
oral intervention indicated; 
limiting instrumental ADL.
See Grade 1 plus oral antihistamines;
Consider topical steroids, e.g. topical 
hydrocortisone.


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Intensity
(CTCAE Grading)
Description
Specific intervention
Severe (Grade 3)
Intense or widespread; constant; 
limiting self-care ADL or sleep; 
oral corticosteroid or 
immunosuppressive therapy 
indicated.
See Grade 2
XEROSIS (DRY SKIN)/HYPERKERATOSIS
Hyperkeratotic skin rash was previously observed in patients treated with afatinib. It is characterised by 
dryness, feeling of “thickening of the skin” and appearance of desquamating hyperkeratotic plaques on palms 
and soles, on extensor surfaces of knuckles of fingers and toes and less frequently on elbows or knees.
Mild (Grade 1)
Covering <10% BSA and no 
associated erythema or pruritus.
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).
Over-the-counter moisturising cream or 
ointment to face b.i.d.
AND
Ammonium lactate 12% cream to body OR 
Urea 10-20% cream b.i.d.


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Intensity
(CTCAE Grading)
Description
Specific intervention
Moderate (Grade 2)
Covering 10 - 30% BSA and
associated with erythema or
pruritus; limiting instrumental
ADL.
Over-the-counter moisturising cream or 
ointment to face b.i.d.
AND
Ammonium lactate 12% cream OR 
Salicylic acid 3% cream to body b.i.d. OR 
Urea 10-20% cream b.i.d.
AND
Topical steroid* to eczematous areas b.i.d.
Severe (Grade 3)
Covering >30% BSA and 
associated with pruritus; limiting 
self-care ADL.
Over-the-counter moisturising cream or 
ointment to face b.i.d.
AND
Ammonium lactate 12% cream OR 
Salicylic acid 3% cream to body b.i.d.
AND
Topical steroid* to eczematous areas b.i.d.
*Moderate/low strength topical steroids e.g. triamcinolone acetonide 0.025% cream, desonide 0.05% cream 
or lotion, aclometasone 0.05% cream, fluticasone propionate 0.05% cream or lotion.
FISSURES
NA
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.
NA
Symptomatic, not interfering 
with ADL
As above and also consider oral antibiotics.
NA
Symptomatic, interfering with 
ADL
As above and also consider oral antibiotics.
If a Grade 2 AE as described above persists for ≥7 days despite treatment and is poorly
tolerated by the patient, the investigator has the option to pause treatment and perform a dose 
reduction in accordance with Section 4.1.4.1.
4.2.3.2
Management of keratitis following treatment with afatinib
Keratitis has been reported following treatment with currently approved EGFR targeting 
agents. 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, 


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ulcerative keratitis, or severe dry eye. Contact lens use is a risk factor for keratitis and 
ulceration.
4.2.3.3
Management of diarrhoea and hydration status following treatment with afatinib 
and pembrolizumab
Following treatment with afatinib, diarrhoea occurs at a high frequency and although usually 
mild to moderate, it may lead to dehydration and require treatment modification or 
discontinuation, so early management is essential (Table 4.2.3.3: 1). At the time of initiation 
of trial treatment patients should be given a supply of anti-diarrhoeal medication such as 
loperamide or a prescription hereof to keep with them at all times or access to anti-diarrhoeal 
medication should be confirmed; and patients should be counselled on the appropriate use.
Following treatment with pembrolizumab, patients should be carefully monitored for signs 
and symptoms of enterocolitis (such as diarrhoea, abdominal pain, blood or mucus in stool, 
with or without fever) and of bowel perforation (such as peritoneal signs and ileus). Further 
instructions are provided in Table 4.1.4.2.1: 1.


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Table 4.2.3.3: 1
Management guidelines for diarrhoea for patients taking the 
combination of afatinib and pembrolizumab
Intensity
(CTCAE Grading) and 
Description
Intervention 
concerning afatinib 
treatment
Intervention 
concerning 
pembrolizumab 
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
Continue same 
dose
Stop laxatives and advise patient to 
drink at least 8-10 glasses of water 
or clear fluids per day
Anti-diarrhoeal medication such as 
loperamide 4 mg (2 tablets) 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
Continue same dose 
unless Grade 2 
diarrhoea continues 
for ≥ 2 days (48 
hours) or is 
intolerable despite 
starting anti-
diarrhoeal treatment, 
in which case 
treatment must be 
interrupted until 
recovered to ≤ Grade 
1 followed by dose 
reduction
Withhold
Continue anti-diarrhoeal 
medication.
Assess for dehydration and 
electrolyte imbalance. Consider i.v. 
fluids and electrolyte replacement.
In case Grade 2 diarrhoea continues 
despite interruption of afatinib for 
≥ 2 days (48 hours), administer oral 
corticosteroids (initial dose of 1-2
mg/kg prednisone or equivalent) 
followed by taper
Monitor patients for signs and 
symptoms of enterocolitis and of 
bowel perforation
In case colitis is suspected, 
consider GI consultation and 
performing endoscopy. For more 
details about colitis, see Table 
4.1.4.2.1: 1
Severe (Grade 3)
Increase of ≥7 stools per 
day over baseline
Incontinence
Hospitalization indicated
Severe increase in 
ostomy output compared 
with baseline
Limiting self-care 
Activities of Daily 
Living (ADL)
Dose interruption 
until recovered to 
≤Grade 1 followed 
by dose reduction*
Withhold
See Grade 2, plus:
An infectious process should be 
ruled out with stool cultures
Aggressive i.v. fluid replacement ≥ 
24 hours
Hospitalization to monitor progress
Consider prophylactic antibiotics if 
patient is also neutropenic or 
febrile
Start i.v. steroid treatment followed 
by high dose oral steroids
Life threatening (Grade 
4)
Life-threatening 
consequences; urgent 
intervention indicated
Dose interruption 
until recovered to 
≤Grade 1 followed 
by dose reduction*
Permanently 
discontinue
See Grade 3
* If despite optimal supportive care and treatment interruption, diarrhoea does not resolve to CTCAE 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.


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4.2.3.4
Management of interstitial lung disease/pneumonitis following treatment with 
afatinib/pembrolizumab
Careful assessment of all patients with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude interstitial 
lung disease (ILD)/pneumonitis. Afatinib and pembrolizumab should be interrupted pending 
investigation of these symptoms. If ILD/pneumonitis is diagnosed, both study drugs must be 
permanently discontinued and appropriate treatment instituted as necessary (see below).

For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks.

For Grade 3-4 events or recurrent Grade 2, immediately treat with intravenous 
steroids. Administer additional anti-inflammatory measures, as needed.

Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration.
If ILD is ruled out as a cause of symptoms, assess causality and apply the follow the 
instructions provided in Table 4.1.4.1: 1.
4.2.3.5
Management of type 1 diabetes mellitus following treatment with pembrolizumab
Provided that: new onset, including diabetic ketoacidosis (DKA) or ≥ Grade 3 
hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA)
For type I diabetes mellitus or Grade 3-4 Hyperglycemia

Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 

Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.
4.2.3.6
Management of hypophysitis following treatment with pembrolizumab

For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered.

For Grade 3-4 events, treat with an initial dose of i.v. corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered.
4.2.3.7
Management of hyperthyroidism or hypothyroidism following treatment with 
pembrolizumab
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.


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
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):

In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine 
or liothyroinine, is indicated per standard of care.

Grade 3-4 hyperthyroidism

Treat with an initial dose of i.v. corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered.
4.2.3.8
Management of hepatic events following treatment with pembrolizumab

For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).

Treat with i.v. or oral corticosteroids.

For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.

When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.
4.2.3.9
Management of renal failure or nephritis following treatment with 
pembrolizumab

For Grade 2 events, treat with corticosteroids.

For Grade 3-4 events, treat with systemic corticosteroids.

When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued for at least 4 weeks.
4.2.3.10
Management of infusion reactions related to pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion.
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 4.2.3.10: 1.


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Table 4.2.3.10: 1 Pembrolizumab infusion reaction dose modification and treatment 
guidelines 
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, i.v. fluids); 
prophylactic medications 
indicated for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
i.v. fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr). Otherwise 
dosing will be held until symptoms resolve 
and the patient should be premedicated for the 
next scheduled dose.
Patients who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
trial treatment administration.
Patient may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of pembrolizumab (MK-
3475) with:
Diphenhydramine 50mg 
p.o. (or equivalent dose of 
antihistamine).
Acetaminophen 500-1000
mg p.o. (or equivalent 
dose of analgesic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
i.v. fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should 
be used immediately
Patient is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration. For further information, please refer to the CTCAE v4.03 at 
http://ctep.cancer.gov


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4.3
TREATMENT COMPLIANCE
Patients should take the first dose of afatinib treatment at the trial site and subsequent doses 
will be taken at home. On day 8, the site personnel should discuss treatment compliance with 
the patient, to ensure that the medication is taken correctly. Patients are requested to bring all 
remaining trial medication including empty package material with them when attending visits
for a compliance check, i.e. at the end of each 21 day cycle.
Based on tablet counts, treatment compliance will be calculated as shown in the formula 
below. Compliance will be recorded at the investigator site and verified by the CRA
authorised by the sponsor.
Treatment compliance (%) =
Number of tablets actually taken 100
Number of tablets which should have been taken
Discrepancies between the number of tablets remaining and the calculated number of tablets 
the patients should have taken must be documented in the site file and explained. If the 
number of doses taken is not between 80-120%, site staff will explain to the patient the 
importance of treatment compliance. If the patient is eligible for further treatment, a new 
study medication kit must be dispensed.
The investigator and/or the sponsor can withdraw a patient from further study treatment in the 
event of serious and persistent non-compliance which jeopardizes the patient’s safety or 
render study results for this patient unacceptable.
Pembrolizumab will be administered at the trial site under the supervision of the investigator. 
In the event that the patient does not receive the full dose of pembrolizumab this should be 
documented and a reason given.
Drug holidays, if previously agreed with the investigator and sponsor, e.g. vacation, will not 
be considered non-compliance.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
Tumour imaging
With the early termination of the study, tumour assessment is per local standard and the 
timing and methods of imaging should follow local practice until PD, start of subsequent 
anti-cancer treatment or withdrawal from study treatment.
Imaging will be performed as indicated in the Flowchart and Appendix 10.3. The process for 
image collection and storage can be found in the Imaging Manual in case of a retrospective 
independent review. Tumour imaging should be performed by computed tomography (CT) 
(preferred). Magnetic resonance imaging (MRI) should only be used when CT is 
contraindicated or for imaging in the brain, but the same imaging technique should be used in 
a patient throughout the trial. CT scan is the more commonly used modality and is preferred 
for the majority of patients. Imaging should include the chest, abdomen, and pelvis, and, if 
clinically indicated, imaging of any other known or suspected sites of disease using an 
appropriate method according to clinical practice at the site. Local site study team reading 
(investigator assessment with site radiology reading) based on RECIST 1.1 will be used to 
determine patient eligibility.
Copies of tumour images used for the assessment of the primary endpoint should be stored at 
each investigational site. including images performed to evaluate potential ILD. If a 
retrospective independent review is required then a copy of the tumour images will be 
submitted to the central image vendor. In case of a retrospective independent review, the 
process for image collection and storage will be described in the Imaging Manual.
Baseline imaging
All baseline evaluations must be performed as close as possible and within 28 days before 
first drug intake. In patients who only have one target lesion and a biopsy of the lesion is 
required; the baseline imaging must be performed at least two weeks after the biopsy. Pre-
trial imaging, performed as part of routine clinical practice, can be used as the baseline 
imaging given that the imaging results are of diagnostic quality and within the allowed time 
window. Otherwise, the scan must be repeated at screening. In case there are multiple 
screening scans, the latest evaluable scan should be used for the trial. The site study team 
must review screening images to confirm the patient has measurable disease per RECIST 1.1.
Imaging during trial
The examinations should be performed every 9 weeks (63 ± 7 days) until confirmed PD or 
start of subsequent anti-cancer therapy. In case of a delay, interruption, or discontinuation of 
study medication or visits, imaging must continue to follow the original schedule. After PD 
or response per RECIST, repeat imaging for confirmation is required.Confirmatory imaging
is repeated at ≥ 4 weeks later to confirm PD; for SD, PR, or CR the regularly scheduled 
imaging is assessed (or as early as 4 weeks later).
Continue to perform imaging until whichever of the following occurs first:

Initial site-assessed PD is verified by repeat imaging

Start of subsequent anti-cancer treatment

Withdrawal of consent


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
Death

The end of the study
5.1.2
Imaging review
With the early termination of the study, tumour response and progression are per local 
practice and guidelines and do not have to follow RECIST. 
Response and progression will be evaluated primarily according to Response Evaluation 
Criteria in Solid Tumours (RECIST) guideline version 1.1 (R09-0262). In case of PD or 
response, tumour assessment should be repeated as per irRECIST (R15-2005). For details on 
lesion measurements and response assessment, see Appendix 10.3 RECIST 1.1 Criteria and 
Appendix 10.4 irRECIST.
Tumour response will be assessed by investigator review throughout the study and clinical 
decisions will be based on investigator assessment. Clinical lesions will only be considered 
measurable when they are superficial (e.g. skin nodules, palpable lymph nodes). In case of 
cutaneous metastases, these should be documented by colour photography including a ruler to 
estimate the size of the lesion.
RECIST Assessment of Disease
RECIST 1.1 will be applied as the primary measure for assessment of tumour response, date 
of disease progression, and as a basis for all protocol guidelines related to disease status.
irRECIST Assessment of Disease
After the first documentation of PD and if the patient is clinically stable, the investigator may 
decide that the patient may continue study treatment until confirmed PD. Imaging is repeated 
for confirmation ≥ 4 weeks later. The investigator or delegate will determine if the follow-up 
tumour imaging confirms PD (see Appendix 10.4).
irRECIST is based on RECIST 1.1, but adapted to account for the unique tumour response seen 
with immunotherapeutic drugs. irRECIST will be used by site investigator/local radiology 
review to assess tumour response and progression, and make treatment decisions. 
These data will be collected in the eCRF. If radiologic progression is confirmed by 
subsequent scan, the patient will be discontinued from trial treatment. If radiologic 
progression is not confirmed by irRECIST per the site, then the patients should continue on
trial treatment and follow the regular imaging schedule intervals until progression is 
confirmed at a later time point by the site.
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinical significant disease progression

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, radiation, 
or other palliative care
Any patient deemed clinically unstable should be discontinued from trial treatment at first
radiologic evidence of PD and is not required to have repeat tumour imaging for confirmation
of PD by irRECIST. For patients who discontinue study therapy without documented PD, 
every effort should be made to continue monitoring their disease status by tumour imaging
using the same imaging schedule used while on treatment, until the start of subsequent anti-


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cancer treatment, disease progression, death, withdrawal of consent, or the end of the study, 
whichever occurs first.
A summary of imaging and treatment requirements after first radiologic evidence of 
progression is provided in Table 5.1.2: 1.
Table 5.1.2: 1 Imaging and treatment after first radiologic evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1
Repeat imaging 
at ≥ 4 weeks to 
confirm PD
May continue study 
treatment at the 
investigator’s 
discretion while 
awaiting 
confirmatory tumour 
imaging by site by 
irRECIST
Repeat imaging at  
≥ 4 weeks to 
confirm PD per 
investigator’s 
discretion only
Discontinue 
treatment
Repeat tumour 
imaging confirms 
PD by irRECIST 
at the local site
No additional 
imaging 
required
Discontinue 
treatment (exception 
is possible upon 
consultation with 
sponsor)
No additional 
imaging required
Not applicable
Repeat tumour
imaging shows 
unconfirmed PD 
by irRECIST per 
Investigator 
assessment
Repeat imaging 
at 4 to 8 weeks 
to confirm PD.  
May occur at 
next regularly 
scheduled 
imaging visit.
Continue study 
treatment at the 
Investigator’s 
discretion.
Repeat imaging at 4 
to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only.
Discontinue 
treatment
Repeat tumour 
imaging shows 
SD, PR, or CR by 
irRECIST per 
investigator 
asessment
Continue 
regularly 
scheduled 
imaging 
assessments*
Continue study 
treatment at the local 
site investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable per 
investigator’s 
discretion. Next 
tumour imaging 
should occur 
according to the 
regular imaging 
schedule
* In case of SD/PR/CR, patients do not need to undergo the next scheduled tumour imaging if 
it is less than 2 weeks later; tumour imaging may resume at the subsequent scheduled 
imaging time point.
5.2
ASSESSMENT OF SAFETY
The safety of afatinib in combination with pembrolizumab will be assessed by a descriptive 
analysis of incidence and severity of adverse events graded according to CTCAE version 
4.03.


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Safety run in
After the first 12 patients have been treated for at least one full cycle, the SMC (see Sections
3.1 and 8.7) will assess the overall safety profile and confirm the RP2D (refer to Section 4.1.2
and Figure 3.1: 2). In case 40 mg afatinib in combination with pembrolizumab is considered 
too toxic, ongoing patients on afatinib 40 mg will have their dose reduced to 30 mg and 12 
more patients will be included in the safety run in with a starting dose of afatinib 30 mg once 
daily. After they have been treated for at least one full cycle, the SMC will assess the data 
and confirm the RP2D. In case the RP2D is confirmed as 30 mg, the patients will continue on 
this dose. In case 30 mg is considered too toxic, the trial will be stopped.
Main part
Once the RP2D of afatinib in combination with pembrolizumab has been established, this 
will be the starting dose of afatinib for any future patients entered to the trial (i.e. the main 
part). In total, 38 patients will be included in the main part.
5.2.1
Physical examination
A physical examination will be performed at the time points specified in the Flowchart.
A full physical examination serves as a clinical tumour assessment and should include a 
cardiopulmonary examination, examination of the regional lymph nodes, the abdomen and an 
assessment of the mental and neurological status. Additional symptoms which have not been 
reported during a previous examination should be clarified. Wherever possible the same 
investigator should perform this examination.
A limited physical examination should include a cardiopulmonary examination, a clinical 
tumour assessment, an examination of the regional lymph nodes, and an examination of the 
abdomen.
Measurement of height (in cm), body weight (in kg), and the evaluation of the ECOG 
performance status (see Appendix 10.7) will be performed at the time points specified in the 
Flowchart.
The results must be included in the source documents available at the site.
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flowchart.
This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest.
5.2.3
Safety laboratory parameters
Safety laboratory samples will be analysed at a local laboratory and the data will be manually 
entered in the eCRF. Safety laboratory examinations to be assessed are listed in Table 5.2.3:1. 
For the sampling time points please see the Flowchart.
Thyroid function testing is to be performed as indicated in the flowchart while on treatment 
with pembrolizumab. Thyroid panel should include:

Triiodothyronine (T3) or Free Triiodothyronine (FT3)

Free thyroxine (FT4)


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
Thyroid stimulating hormone (TSH)
Additional samples can be collected if clinically required at the discretion of the investigator. 
The date of assessment and results will be recorded on the patient’s eCRF.
Table 5.2.3: 1 
Safety laboratory tests
Category
Parameters
Hematology
Red blood cell count (RBC), haemoglobin,
haematocrit, platelet count, reticulocytes, white 
blood cell count (WBC) with differential 
(neutrophils, bands, lymphocytes, monocytes, 
eosinophils, basophils)
Coagulation
International Normalised Ratio (INR), activated 
Partial Thromboplastin Time (aPTT)
Electrolytes
Sodium, potassium, calcium, magnesium, 
chloride, bicarbonate (HCO3)
Liver function tests
Alkaline phosphatase, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), γ-
glutamyltransferase (GGT), total bilirubin
Renal function parameters
Blood urea (preferred) or blood urea nitrogen 
(BUN), creatinine; creatinine clearance at 
screening if applicable*
Pancreatic function 
parameters
Amylase, Lipase
Other
Glucose, albumin, cholesterol, triglycerides, 
phosphorus, lactate dehydrogenase (LDH), total 
protein, uric acid, creatine phosphokinase (CPK)
Urinalysis
pH, protein, glucose, blood, leucocytes, nitrite; in 
case of pathological finding further evaluation 
should be performed and results documented
Pregnancy test
β-HCG testing in urine or serum in women of 
childbearing potential (WOCBP)
Thyroid function testing
Triiodothyronine (T3) or Free Triiodothyronine 
(FT3), Free thyroxine (FT4), Thyroid stimulating 
hormone (TSH)
* Creatinine clearance should be calculated per institutional standard. See also Appendix 
10.6.
The investigator should complete additional evaluations of laboratory tests as clinically 
indicated. Any abnormal and clinically relevant findings from these investigations need to be 
reported as an adverse event (please refer to Section 5.2.6.2).
Patients do not have to be fasted for the blood or urine sampling for the safety laboratory.


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In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Sections 5.2.6.1 and 10.5 and the DILI Checklist provided in the ISF). 
The amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
5.2.4
Electrocardiogram
The 12-lead ECGs will be recorded as scheduled in the Flowchart. The investigator or a 
designee will evaluate whether the ECG is normal or abnormal and whether it is clinically 
relevant, if abnormal. ECGs may be repeated for quality reasons and the repeated recording 
used for analysis.
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as adverse events and will be followed up 
and/or treated as medically appropriate.
5.2.5
Other safety parameters
5.2.5.1
Dose limiting toxicities
The occurrence of any of the below mentioned toxicities will be considered a DLT, if judged 
by the investigator to be related to study drug administration. DLTs occurring during the first 
21-day period (Cycle 1) in the safety run in will be considered protocol specified AESI (see 
Section 5.2.6.1).
Table 5.2.5.1: 1 Dose Limiting Toxicities
Related toxicity 
category
Criteria defining a DLT*
Hematologic

CTCAE Grade 4 neutropenia lasting ≥ 7 days.

CTCAE Grade ≥ 3 documented infection with neutropenia.

CTCAE Grade ≥ 3 febrile neutropenia (ANC<1000/mm3 complicated by fever 
≥38.5°C or a sustained temperature of ≥38.0°C for more than 1 hour).

CTCAE Grade 3 thrombocytopenia associated with bleeding requiring 
transfusion.

CTCAE Grade 4 (<25,000/m3) thrombocytopenia.

CTCAE Grade 4 anaemia.
Non-hematologic

Any Grade ≥ 3 non-hematologic (not laboratory) toxicities lasting >3 days 
despite the use of adequate/maximal medical interventions and/or prophylaxis as 
dictated by local institutional clinical practices or the judgment of the 
investigator.

Any Grade 3 or Grade 4 non-hematologic laboratory value if:
-
Medical intervention is required to treat the patient, or
-
The abnormality leads to hospitalization, or
-
The abnormality persists for >1 week.
-
Exceptions: Clinically non-significant, treatable, and reversible 
laboratory abnormalities including liver function tests, uric acid, etc.

Grade ≥ 2 ILD.

Grade ≥ 2 colitis.

Grade ≥ 2 renal failure or nephritis.


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
Any grade 5 event.

An elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.

An elevated AST or ALT lab value that is greater than or equal to 5X the upper 
limit of normal and an elevated total bilirubin lab value greater than or equal to 
2X upper limit of normal measured in the same blood draw sample, with the 
exclusion of causes due to underlying diseases (for patients with elevated liver 
enzymes at baseline).
Re-Treatment Delay

Any related toxicities that result in a > 14 days delay in initiating Cycle 2 Day 1 
dosing with afatinib and/or pembrolizumab.

Patients who miss more than 5 days of therapy for treatment related toxicity at 
first cycle.
*It is the responsibility of the investigator to follow-up on these in a timely manner.
The RP2D confirmation will be based on DLTs observed during the first cycle of the safety 
run in from the patients treated with a starting dose of 40 mg afatinib or 30 mg afatinib (in 
case the 40 mg is considered too toxic) (see Appendix 10.9.3). However, all DLT observed in 
all treatment cycles will be considered for re-estimation of the RP2D based on the BLRM as 
a sensitivity analysis. To obtain this, the model might be re-run including the DLT 
information from all cycles. Based on both RP2D estimates, the recommended dose for 
further development will be selected. In regular intervals, all available safety data including 
adverse events qualifying for DLT will be submitted to the SMC.
5.2.5.2
Performance status
With the early termination of the study, the evaluation of the ECOG performance status is no 
longer performed.
Evaluation of the ECOG performance status will be performed at the time points specified in 
the Flowchart. The ECOG performance status (also called the WHO or Zubrod score) is 
found in Appendix 10.7.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.


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Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which 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.
-
requires inpatient hospitalisation; or 
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity; or
-
is a congenital anomaly / birth defect; or
-
is deemed serious for any other reason if it is an important medical event when based 
on 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.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse.
AEs considered “Always Serious”
Every new occurrence of cancer of new histology must be classified as a serious event 
regardless of the time since discontinuation of the trial medication and must be reported as 
described in Section 5.2.6.2, subsections “AE Collection” and AE reporting to sponsor and 
timelines”. Note: PD of the underlying malignancy and without a causal relationship between 
the study drug and the PD are reported as a study endpoint and as such is exempted from 
reporting as an (S)AE (see later in Section 5.2.6).
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” will be made available to the investigators. These 
events should always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified as being of particular 
concern for prospective safety monitoring and safety assessment within this trial, e.g. the 
potential for AEs based on knowledge from other compounds in the same class. AESIs will 
be reported on the eCRF/SAE reporting forms, as per the SAE reporting instructions detailed 
in the ‘Adverse Event Reporting’ Section of the ISF. AESI are to be reported in an expedited 
manner similar to Serious Adverse Events, even if they do not meet any of the seriousness 
criteria.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 


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For patients with normal liver function (ALT, AST, bilirubin within normal limits) at 
baseline:

An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing*.
For patients with abnormal liver function at baseline (AST and/or ALT>ULN)):

An elevated AST or ALT lab value that is greater than or equal to 5X the upper limit of 
normal and an elevated total bilirubin lab value greater than or equal to 2X upper limit of 
normal measured in the same blood draw sample, with the exclusion of causes due to 
underlying diseases.
*Note: These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The trial site guidance for assessment and 
follow up of these criteria can be made available. It may also be appropriate to conduct 
additional evaluation for an underlying etiology in the setting of abnormalities of liver blood 
tests including AST, ALT, bilirubin, and alkaline phosphatase that do not meet the criteria 
noted above. In these cases, the decision to proceed with additional evaluation will be made 
through consultation between the study investigators and the sponsor representative. 
However, abnormalities of liver blood tests that do not meet the criteria noted above are not 
AESIs for this trial.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Dose Limiting Toxicities
Dose Limiting Toxicities (DLT) occurring during the first cycle in patients included in the 
safety run in will be considered protocol specified AESI. See Table 5.2.5.1: 1 for DLT 
definitions.
Overdose
For this trial, an overdose will be defined as any dose of 1000 mg or ≥5 times the indicated 
dose of pembrolizumab.
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the patient should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated.
An overdose, that is not associated with clinical symptoms or abnormal laboratory results,
also needs to be reported.


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Intensity (severity) of AEs
The intensity (severity) of adverse events should be classified and recorded in the eCRF
according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies 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 dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
With the early termination of the study, AESIs, AEs and SAEs are not collected and 
documented in the eCRF after the end of the REP for pembrolizumab and afatinib. 


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Investigators will report all deaths/fatal AEs regardless of relationship, until the end of the 
REP only. After the REP, investigators only report SAEs and AESIs related to afatinib that 
the investigator becomes aware of.
The following must be collected, documented on the appropriate eCRF(s) by the investigator:
For pembrolizumab:

From signing the informed consent onwards until the end of treatment, which includes 
the REP: 
- All AEs (non-serious and serious) and all AESIs.

After the end of the REP until the individual subject’s end of trial, 90 days after last 
dose of pembrolizumab or 30 days following cessation of trial treatment if the subject 
initiates new anticancer therapy, whichever is earlier:
- All SAEs.
For afatinib

From signing the informed consent onwards until the end of treatment, which includes 
the REP: 
- All AEs (non-serious and serious) and all AESIs.

After the end of the REP until the individual subject’s end of trial or 30 days 
following cessation of trial treatment if the subject initiates new anticancer therapy, 
whichever is earlier:
- All AESIs related to afatinib and all SAEs.

After the subject initiates new anticancer therapy (if applicable) and until the 
individual subject’s end of trial:
- All AESIs and SAEs related to afatinib.

After the individual patient’s end of the trial:
- The investigator does not need to actively monitor the patient for AEs but should 
report SAEs and AESIs related to afatinib of which the investigator may become 
aware of by any means of communication, e.g. phone call. Those AEs should 
however, not be reported in the eCRF.
See also Figure 5.2.6.2: 1 and 5.2.6.2: 2.
The rules for Adverse Event Reporting exemptions still apply.
Figure 5.2.6.2: 1
AE reporting process for pembrolizumab


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Figure 5.2.6.2: 2
AE reporting process for afatinib
Patients, who discontinue trial medication prematurely and agree to be contacted further,
should be followed up as described in Section 3.3.4.1. From then on until the individual 
patient’s end of the trial the investigator must report all deaths/fatal AEs regardless of 
relationship, in addition to requirements outlined in Figure 5.2.6.2:1.
The Residual Effect Period (REP) is defined as 30 days for both afatinib and pembrolizumab.
All AEs which occurred through the treatment phase and throughout the REP will be 
considered as on treatment; please see Section 7.3.4.
Events which occur after the REP will be considered as post treatment events.
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, if applicable. The investigator should determine the causal 
relationship to the trial medication.
The following should also be recorded as an (S)AE in the eCRF and BI SAE form (if 
applicable):
Worsening pre-existing conditions other than underlying disease.
Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected as such in the eCRF only. All (S)AEs, including 
those persisting after individual patient’s end of trial must be followed up until they have 
resolved, have been assessed as “chronic” or “stable”, or no further information can be 
obtained.


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Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a written consent of the pregnant partner.
Information about pregnancy of female patients of childbearing potential and female partners 
of male trial participants that occur from the time of treatment allocation through 120 days 
following the last dose of pembrolizumab, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, must be reported. This reporting 
period is 2 weeks after last afatinib treatment in case of monotherapy treatment with afatinib.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
Exemptions to SAE reporting
Protocol specified outcome events should be collected on the appropriate eCRF page only.
Disease Progression is a study endpoint for analysis of efficacy, and as such is exempted 
from reporting as an (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 and will 
not be reported on the (S)AE form. Death due to disease progression is also to be recorded on 
the appropriate (e)CRF page and not on a SAE form. It will therefore not be entered in the 
safety database.
However, when there is evidence suggesting a causal relationship between the study drug and 
the progression of the underlying malignancy, the event must be reported as (S)AE on the 
eCRF and on the SAE form.
Examples of exempted events of PD are:

Progression of underlying malignancy (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.


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Exempted events are monitored at appropriate intervals during Medical and Quality Review 
Meetings (MQRMs).
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Blood samples will be collected from all patients on the days of 2nd (C2_V) and 3rd (C3_V)
infusion of pembrolizumab, at the time points described in Appendix 10.1 (Table 10.1.2: 1) in 
order to assess the pharmacokinetics of afatinib and pembrolizumab.
The objective of afatinib PK assessment is to characterize the impact of pembrolizumab 
comedication on steady state parameters of afatinib as determined by steady state pre-dose 
plasma concentrations (Cpre, ss) on day 22 and 43 of treatment, respectively.
5.3.2
Methods of sample collection
PK blood sampling will be performed as described in Appendix 10.1. For quantification of
drug concentrations of afatinib 1 x 2 mL of venous blood will be collected at each PK blood
draw. For quantification of drug concentrations of pembrolizumab 1 x 3.5 mL of venous 
blood will be collected at each PK blood draw.
Date and clock time of drug administration, as well as blood collection times at all visits 
where PK sampling is performed must be recorded in the eCRF.
Correct, complete, and legible documentation of drug administration and blood sampling
times as well as adequate handling and identification of PK samples (the labels of the PK
tubes have to contain at minimum: study number, visit number, patient number, and planned
time) is mandatory to obtain data of adequate quality for the pharmacokinetic analysis. In
order to prevent instabilities of PK samples special precautions have to be taken during
collection, handling, storage, and shipment of PK samples. A freezer temperature log must be
maintained if samples are being stored at any time until shipment. Detailed instructions are
provided in the lab manual.
5.3.3
Analytical determinations
Afatinib drug concentrations will be determined by a validated high performance liquid
chromatography-tandem mass spectrometry (HPLC-MS/MS) assay. The procedure and
specification of the analytical method are available at the analytical laboratory 
PK blood samples for pembrolizumab will be stored and pembrolizumab drug concentrations 
will be determined by 
 upon request.
5.3.4
Pharmacokinetic – pharmacodynamic relationship
No pharmacokinetic-pharmacodynamic relationship investigation is planned.


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5.4
ASSESSMENT OF BIOMARKER(S)
This section refers to exploratory biomarkers. The provision of a tumour sample for central 
PD-L1 assessment and correlative studies is also described in Section 3.3.2.
Handling of Samples and Biomarker Results
Detailed instructions for handling, storage, and shipment of the biomarker samples will be 
provided in the laboratory manual included in the ISF. All required materials and labels will 
be provided. For the mandatory sample obtained at screening, a fresh biopsy is preferred and 
freshly cut slides should be immediately submitted to the testing laboratory.
A brief description of the biomarker analyses to be performed is provided here. The results of 
the analyses will not be directly reported to investigators.
5.4.1
Tumour tissue samples
All tumour samples will be obtained at the time points as defined in the Flowchart and 
Appendix 10.2.
Tumour Tissue Sample at Screening Visit (Mandatory):
As described in Section 3.3.2, patients cannot be enrolled in the study if they are unable to 
provide a sample of their tumour. A sample of a fresh biopsy is preferred but archival tumour 
tissue can also be used. Tumour samples should be provided in the form of a formalin-fixed 
paraffin embedded (FFPE) block (preferred) or less preferably in the form of a mandatory 
minimum of 10 slides of unstained 4-5-micron sections from the FFPE tumour block.
The tumour tissue sample will be used to (i) measure the expression of the protein PD-L1 by 
means of an immuno-histochemical (IHC) assay and (ii) to measure the mRNA expression of 
genes involved in the immune system.
Tumour Biopsy for Exploratory Analysis at screening (Optional):
For patients who agreed to exploratory biomarker testing and if local regulations allow, 
excess tissue obtained at screening may be used to further address scientific questions as new 
information in regard to the disease or the study drug becomes available. These analyses 
might comprise but are not limited to the further evaluation of the patient’s immune status by 
determination of tumour infiltrating cells (e.g. CD8+ cells) or TH1-type cytokines.
Any leftover samples from the study will be stored at Boehringer Ingelheim or contract 
research organization for up to 3 years after final study report.
5.4.2
Blood samples for biomarker analyses
With the early termination of the study, there will be no exploratory retrospective assessment of 
biomarkers in blood samples.
Participation in blood sampling for biomarkers is voluntary and not a prerequisite for 
participation in the trial but is highly encouraged. Blood samples for biomarkers will be taken 
only after a separate informed consent has been given in accordance with local ethical and 
regulatory requirements. Blood samples (~19 mL) for biomarker analysis should be taken as 
specified in the Flowchart.


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The blood samples may be utilised for the measurement of the levels of proteins in the blood, 
or on the surface of blood cells, which may be of prognostic or predictive relevance to the 
patients’ response to the study medications. For example, the measurements of cytokine 
levels in the blood may be informative of the patient’s immune response following the 
administration of medication or the measurement of plasma protein levels using the 
immunostrat (Biodesix) technology may be informative in identifying patients likely to 
receive maximum benefit from the treatment.
Blood samples for biomarker analyses will be stored at Boehringer Ingelheim or contract 
research organization for up to 3 years after final study report.
Methods and timing of sample collection:
Sampling will be performed at the time points specified in the Flowchart.
Plasma
Approximately 10 mL blood will be drawn into an EDTA blood collection tube.
Serum
Approximately 8.5 mL blood will be drawn into a serum separation tube.
For all biological samples collected, detailed instructions on sampling, preparation, 
processing, shipment, and storage are provided in the laboratory manual.
5.5
OTHER ASSESSMENTS
Not applicable.
5.6
APPROPRIATENESS OF MEASUREMENTS
All clinical assessments are standard measurements commonly used in studies of advanced 
solid tumours. RECIST version 1.1 (R09-0262) and irRECIST (R15-2005) are used for 
assessment of the change in tumour burden. These criteria are well established and well 
received by the regulatory authorities and scientific community.
The US National Cancer Institute (NCI) CTCAE is used in the assessment of adverse events 
in cancer patients. In the present trial CTCAE version 4.03 will be used.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
With the early termination of the study, patients are no longer followed for progression or 
survival after study treatment completion. A patient is considered to have completed the trial 
after the REP visit.
Written informed consent must be obtained before any protocol specific screening 
assessments are performed. Informed consent may be signed by the patient prior to the 
screening visit. A separate written informed consent must be obtained before the collection of 
blood samples for biomarkers and before shipment of tumour tissue for biomarker testing.
Eligible patients will receive the study treatment for up to 35 cycles (about 2 years) or until 
any of the criteria for stopping medication are met (see Section 3.3.4.1). During the treatment 
phase, visits should be performed on week one, week three, and then every three weeks, but 
within three days of the scheduled date. The scheduled time interval for each visit is relative 
to the initiation of trial medication. Following discontinuation of both trial medications, 
patients will be followed at EOT visit at the end of the residual effect period. Then the patient 
will enter the follow-up period until trial completion. Please see the Flowchart for the visit 
schedule.
Unscheduled visits can be performed as necessary and assessments will be performed as 
required at the discretion of the investigator. In case a patient missed a visit and the patient 
reports to the investigator between the missed visit and the next scheduled visit, the date of 
the report and the reason for the delayed visit should be noted in the patient's chart. The next 
visit, however, should take place at the scheduled time. In the event of any interruption/delay 
of treatment, the imaging schedule should not be changed.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The assessments to be performed at the respective visits are outlined in the Flowchart and the 
procedures for each assessment are described in detail in Section 5.
6.2.1
Screening and run-in period(s)
Screening Period
The screening visit should be performed within 28 days before the first administration of 
treatment.
Before or during the screening visit, prior to any study procedures, all patients will need to 
sign the Informed Consent Form (ICF) for trial participation.
Examinations and assessments will be conducted as depicted in the Flowchart. Patients’ 
medical history and demographic information will be collected and in- and exclusion criteria 
must be assessed. Details are given below.
A tumour tissue biopsy will be submitted to the central laboratory. This is a mandatory 
requirement for study enrolment.
Demographics to be collected during the screening visit are:

Gender;


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
Date or year of birth (in accordance with local laws and regulations);

Race (in accordance with local laws and regulations);

Alcohol history;

Histological subtype.
The smoking history will be documented as smoking status defined as:

Never smoker with <100 cigarettes/lifetime;

Current-smoker;

Former smoker.
Baseline Conditions
Baseline conditions and concomitant therapies present during screening will be recorded in 
the eCRF.
Medical History:
Medical history of NSCLC will be obtained during screening and reported in the eCRF:

The date of first histological diagnosis;

The primary tumour site;

The number and location of metastatic sites at screening (bone, brain, liver, pleural 
effusion, other);

Previous treatment for NSCLC, including any surgery, radiotherapy, and or systemic 
therapy, including start and end dates and the outcome.
Baseline imaging
If images are available from before the obtainment of the informed consent and the images 
are within 28 days of start of treatment and performed as part of routine clinical practice, 
imaging does not need to be repeated at the screening visit, provided it is clear from source 
documents that the imaging was not performed for the purpose of the present trial.
6.2.2
Treatment period(s)
Eligible patients will be administered study medication in 21 day treatment cycles until 
criteria for treatment discontinuation are met (see Section 3.3.4). The EOT visit should be 
performed for all patients after permanent discontinuation of both trial treatments (see the 
Flowchart for time window).
Treatment visits are specified in the Flowchart and must be conducted as scheduled and 
outlined there.
PK blood samples are drawn just before administration of afatinib and infusion of 
pembrolizumab at C2_V and C3_V as specified in Section 10.1. 
6.2.3
Follow-up period and trial completion
With the early termination of the study, patients are no longer followed for progression or 
survival after study treatment completion. A patient is considered to have completed the trial 
after the REP visit. 
After the end of study treatment (EOT), all patients are required to attend the end of the 
residual effect period (EOR) visit to evaluate safety. The Residual Effect Period (REP) is
defined as 30 days for both afatinib and pembrolizumab. During the REP one visit is 


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conducted as indicated in the Flowchart. In case only one of the trial medications is 
discontinued, the patient is considered as still being in the treatment period; however, the 
individual termination of trial medication eCRF page must be completed when either is 
discontinued. The purpose of this follow-up visit is primarily to collect all new AEs that 
occurred after EOT and a follow-up of adverse events ongoing at EOT. For the majority of 
patients, disease progression will already be documented at this point. However the REP 
follow-up visit should occur for all patients, including those patients with disease progression 
and/or start of subsequent anti-cancer treatment.
For AE reporting after EOT, see Section 5.2.6.2.
After study treatment completion, further therapy will be decided by the investigator 
including continuation of afatinib (using commercial products), alternative therapy, or best 
supportive care.
Follow-up for progression
If a patient does not have documented disease progression or did not start subsequent anti-
cancer treatment during the trial treatment or REP, he/she will continue to have regular 
follow-up visits (FU-PD) and tumour assessments according to the Flowchart. The end of 
FU-PD will occur at the time point of disease progression or start of subsequent anti-cancer 
treatment, whichever occurs first.
Follow-up for survival
After disease progression and/or start of subsequent anti-cancer treatment, the patient will 
enter the Follow-up for survival (FU-OS) period. No visits will be performed for the purposes 
of the trial, but data on further treatment and survival will be collected from medical records 
or via telephone.
Data will be collected as detailed in the Flowchart and may also be collected at additional 
time points when a snapshot of data is required (e.g. at the time of the primary analysis). Data 
collection will continue until death, lost-to follow-up, patient refusal, withdrawal of consent 
for collection of overall survival data, or completion of the whole trial (as specified in Section 
8.6) whatever occurs earlier.
If a patient cannot be contacted for vital status, information may also be obtained by other 
means in accordance with local regulations, e.g. contact with patients’ health care providers, 
public sources, e.g. death registry, obituary listing, etc. when it is available and verifiable.
6.2.4
Trial completion for an individual patient
A patient is considered to have completed the trial in case any of the following applies:

Lost to follow-up.

Refuse further follow-up.

Withdrawal of consent.

Death.

The trial is ended as described in Section 8.6.
In that case, the Final Visit (FV) is completed in the eCRF; however, the patient does not 
necessarily need to attend a visit at the site. Refer to Section 3.3.4.1 for instructions on when 
to withdraw an individual patient from trial treatment.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is an exploratory, open label, non-randomised, phase II trial of afatinib in combination 
with pembrolizumab in patients with squamous NSCLC, who progressed during or after first 
line platinum-based standard therapy and have received no prior treatment with a checkpoint 
inhibitor or EGFR targeted therapy.
The primary objective of the trial is to assess the efficacy of afatinib in combination with 
pembrolizumab, as measured by objective response OR.
Based upon these design considerations, descriptive summaries of efficacy endpoints will be 
produced. If the starting dose is reduced from 40 mg to 30 mg, the main efficacy summaries 
will be produced on the patients with a starting dose of 30 mg.
The dose confirmation will be guided by a Bayesian 5-parameter logistic regression model with 
overdose control (R13-4806, R13-4803). Further details about this model can be found in 
Appendix 10.9.
This model will be used to evaluate the adverse events occurring during the first treatment 
cycle and will serve as guidance for the SMC when deciding on the dose to be used in the 
remaining patients that are to participate in the trial. Please also see Section 5.2.5.1 for details 
on DLTs and information on which ones will be used for the BLRM evaluations. Other 
criteria evaluated by the SMC are described in Section 3.1.
7.2
NULL AND ALTERNATIVE HYPOTHESES
As an exploratory Phase II trial, inferences about the efficacy of afatinib when given in 
combination with pembrolizumab will be based on the magnitude of the observed OR and 
other efficacy endpoints (e.g. PFS, DoR), rather than formal hypothesis testing.
7.3
PLANNED ANALYSES
In order to expedite the reporting of the primary efficacy endpoint of OR, two analysis time 
points are defined, and all efficacy and safety endpoints will be analysed at each time point. 
The first analysis will be performed when all treated patients have either reached the fourth 
imaging time point (week 36) or have been withdrawn from the trial, whichever occurs 
earlier.
A second and final analysis time point will take place when the trial has reached its 
completion. See Section 8.6 for the definition of the end of the trial.
The primary analyses of efficacy and safety will be performed on the patients treated with the 
RP2D as starting dose. This will consist of all patients receiving at least one dose of afatinib 
(at the starting RP2D) and/or pembrolizumab. All data collected by the primary analysis time 
point, will be included.
No per protocol set will be used for the analyses. However, important protocol violations will 
be summarised, these will be specified in the trial statistical analysis plan (TSAP).


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All imaging related endpoints will be investigator assessed primarily according to RECIST 
1.1. Supportive summaries will also be produced without the supplemented irRECIST 
criteria.
7.3.1
Primary endpoint analyses
In this exploratory study objective response (OR) is defined as the primary endpoint of 
interest. The analysis will be based on treated patients, based upon the starting dose they have 
been taking.
For OR status tumour imaging will be performed until the earliest of disease progression, 
death, or last evaluable tumour assessment before the start of subsequent anti-cancer therapy, 
lost to follow-up, or withdrawal of consent. OR will be analysed in terms of OR rate (ORR), 
defined as the proportion of patients with best overall response of CR or PR as determined by 
RECIST 1.1. The ORR will be calculated and presented with 95% two-sided confidence 
intervals using the exact Clopper-Pearson method. In addition, frequencies and percentages 
are also shown. As per RECIST 1.1 (R09-0262) guidance confirmation of OR is a 
requirement for this trial.
The analysis of the primary endpoint will be repeated in the following subgroups:

PD-L1 status (<1%, 1-49%, ≥50%)

Subgroups defined by the biomarkers related to immune status

Other sub groups may be defined in the TSAP
7.3.2
Secondary endpoint analyses
All secondary endpoints will be evaluated.
Disease control (DC)
DC will be analysed in terms of DC rate (DCR), defined as the proportion of patients with 
best overall response of CR, PR, or SD according to RECIST 1.1. Proportions will be 
presented with 95% two-sided confidence intervals using the exact Clopper-Pearson method. 
In addition, frequencies and percentages are also shown.
Duration of objective response (DoR)
For all patients with an OR the duration of OR will be calculated as follows:
For patients with disease progression or death:

Duration of OR [days] = date of outcome – date of first assessment indicating OR + 1
For patients without disease progression or death:

Duration of OR (censored) [days] = date of outcome – date of first assessment 
indicating OR + 1
The censoring rules for OR (i.e. outcome and date of outcome) will be described in the 
TSAP. The outcome will be assessed according to RECIST 1.1.
Kaplan-Meier estimates will be used to display the distribution of DoR with 95% confidence 
intervals, using Greenwood’s variance estimate. Kaplan-Meier estimates will be used to 
calculate median duration of OR.


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Progression-free survival (PFS)
PFS is defined as time from first drug intake until disease progression or death from any 
cause, whichever occurs earlier. The date of progression will be based on the investigator 
assessment according to the RECIST 1.1.
For patients with ‘event’ as an outcome for PFS:

PFS [days] = date of outcome – date of start of treatment + 1
For patients with ‘censored’ as an outcome for PFS:

PFS (censored) [days] = date of outcome – date of start of treatment + 1
The censoring rules for PFS (i.e. outcome and date of outcome) will be described in the 
TSAP.
Kaplan-Meier estimates will be used to display the distribution of PFS with 95% confidence 
intervals, using Greenwood’s variance estimate.
Overall survival
For patients with known date of death (any reason):

Overall survival [days] = date of death – date of start of treatment + 1
For patients known to be alive by the end of trial or follow-up period:

Overall survival (censored) [days] = date of last visit when patient is known to be 
alive – date of start of treatment + 1
Patients with unknown OS status or date will be handled as described in the TSAP.
Kaplan-Meier estimates will be used to display the distribution of OS with 95% confidence 
intervals, using Greenwood’s variance estimate.
Tumour shrinkage
Tumour shrinkage measured as the difference between the minimum post-baseline sum of 
diameters of target lesions (longest for non-nodal lesions, short axis for nodal lesions) and the 
baseline sum of longest diameters of the same set of target lesions will be analysed using 
mean and standard deviation. Maximum percentage decreases will also be summarised, 
including waterfall plots.
All secondary endpoint analyses related to efficacy will be repeated in the following 
subgroups:

PD-L1 status (<1%, 1-49%, ≥50%)

Subgroups defined by the biomarkers related to immune status
Recommended Phase II Dose
The dose confirmed by the SMC based on the process and parameters described in Section 
1.4, Section 3.1, and Section 5.2.


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7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Frequency, severity, and causal relationship of adverse events will be tabulated 
by system organ class and preferred term. Standard BI summary tables and listings will be 
produced. All adverse events with an onset between start of treatment and end of the residual 
effect period (REP), a period of 30 days after end of last trial drug administration, will be 
assigned to the on-treatment period for evaluation.
All treated patients will be included in the safety analysis, based upon the starting dose they 
have been taking. In general, safety analyses will be descriptive in nature and will be based 
on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
residual effect period. Adverse events that start before first drug intake and deteriorate under 
treatment will also be considered as ‘treatment-emergent’.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges as well as by evaluations 
based on CTCAE grading. Values outside the reference range as well as values defined as 
clinically relevant will be summarised. Treatment groups will be compared descriptively with 
regard to distribution parameters as well as with regard to frequency and percentage of 
patients with abnormal values or clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
Adverse events as well as laboratory parameters will be graded according to CTCAE, version 
4.03 (R15-5988).
Standard tabulations arranged by MedDRA SOC and PT will include:

The overall incidence and severity of adverse events,

AE judged to have been related to study drug

AE leading to dosage reduction

AE leading to permanent treatment discontinuation


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
SAE

Fatal outcome
Additional more in-depth analyses of AEs and laboratory data will be performed as needed 
and detailed in the TSAP.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
Please refer to Section 7.3.3 for the description of the planned PK analysis.
7.3.6
Biomarker and pharmacogenetic analyses
Primary and secondary measures of clinical efficacy will be assessed by PD-L1 status, see 
Section 2.2.1.
The mRNA expression of genes involved in the immune system will be investigated 
descriptively and its association to measures of clinical efficacy will be explored.
Additional exploratory biomarker analyses, e.g. of mutations related to the emergence of 
resistance, will be defined in a statistical analysis plan, if deemed necessary.
7.4
INTERIM ANALYSES
No interim analysis is planned, however after 12 patients have been entered into the study, 
have received 40 mg afatinib + 200 mg pembrolizumab, and have completed at least their 
first cycle of treatment, the SMC will evaluate and confirm whether 40 mg of afatinib in this 
combination trial is an adequate RP2D, or whether 30 mg afatinib should be the starting dose 
for any patient treated with this combination. In case the RP2D is not confirmed as 40 mg 
afatinib in combination with pembrolizumab, there will be a second safety run in and the
SMC will evaluate and confirm the RP2D after 12 patients in the second safety run in have 
completed at least their first cycle of treatment at 30 mg dose level.
A clinical safety summary will be created on the basis of the safety run in.
This decision will be taken using the safety criteria defined in Section 5.2.5.1 and analysed 
with a BLRM (see Section 3.1 and Appendix 10.9 for details), efficacy criteria (see Section 
2.1 for more details), and the totality of the patients’ data. The evaluation of the safety criteria 
has to be taken in a non-binding sense and will serve as guidance for the decision making 
process of the SMC.
7.5
HANDLING OF MISSING DATA
In general, missing data will not be imputed.
For PFS and OS, every effort will be made to obtain date of progression or death for patients 
known to have progressed or died. Detailed censoring rules will be specified in the TSAP.
For partial or missing AE onset and/or end dates, BI internal rules will be followed for 
imputation (see Reference Document 001-MCG-156_RD01 “Handling of missing and 
incomplete AE dates”).


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Pharmacokinetics:
Pharmacokinetic parameters: In the non-compartmental analysis, concentration data
identified with NOS, NOR, and NOA will not be considered. BLQ and NOP values in the lag
phase will be set to zero. The lag phase is defined as the period between time 0 and the first
time point with a concentration above the quantification limit. All other BLQ and NOP
values of the profile will be ignored. Descriptive statistics of parameters will be calculated
only when at least 2/3 of the individual parameter estimates of a certain parameter are
available. Pharmacokinetic parameters which cannot be determined will be identified by "not
calculated" (NC).
7.6
RANDOMISATION
This is an open label, non-randomised, single-arm trial of afatinib in combination with 
pembrolizumab.
7.7
DETERMINATION OF SAMPLE SIZE
The expected ORR with single agent afatinib is approximately 6% (P15-06906) and with 
single agent pembrolizumab approximately 18% (R15-6023). It is anticipated that the 
combination of the two agents will have an ORR of approximately 30-40%. With 50 
evaluable patients an ORR of 30% or more would be observed with a probability of about 
81% assuming a true response rate of 35%. The probability to observe a false positive signal, 
e.g. to observe at least an ORR of 30% if the underlying true ORR is 18%, is around 3%. 
Table 7.7: 1 summarises the probabilities of observing certain ORRs based on different 
assumptions of the underlying ORR.
As such it is planned to treat 50 patients at the RP2D. If 40 mg is chosen as the starting RP2D 
then only 50 treated patients will be required, however if 30 mg is chosen as the starting 
RP2D then up to 62 treated patients may be required (12 at 40 mg and 50 at 30 mg). In case 
the 30 mg is considered too toxic, the trial will be stopped and in that case 24 patients will be 
required.
Table 7.7: 1 Probabilities of observing certain objective response rates
True 
underlying 
OR rate
Patients
Probability to observe at least
ORR≥25%
(≥13 ORs)
40%
50
98.7%
40%
50
35%
50
93.4%
35%
50
30%
50
77.7%
30%
50
18%
50
10.2%
18%
50
Note: Exact binomial probabilities calculated in SAS v9


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. 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 rule, no trial results should be published prior to finalization of the Clinical Trial Report
(CTR).
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, 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.
A separate informed consent to allow exploratory biomarker analyses on blood samples as 
well as tumour biopsies must be given in accordance with local ethical and regulatory 
requirements.
The patient must be given sufficient time to consider participation in the trial. The 
investigator obtains written consent of the patient’s own free will with the informed consent 
form after confirming that the patient understands the contents. The investigator must sign (or 
place a seal on) and date the informed consent form if required as per local IRB/IEC. If a trial
collaborator has given a supplementary explanation, the trial collaborator also signs (or 
places a seal on) and dates the informed consent.


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Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance 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
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
During the site visit the sponsor’s CRA or auditor must be granted access to the original 
patient file (please see Section 8.3.2). The investigator must ensure that all patient identifiers 
(e.g. patient’s name, initials, address, phone number, social security number) have properly 
been removed or redacted from any copy of the patients’ source documents before sending 
them to the sponsor.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations).

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed).

Dates of patient’s visits, including dispensing of trial medication.

Medical history (including trial indication and concomitant diseases, if applicable).


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
Medication history.

Adverse events and outcome events (onset date (mandatory) and end date (if available))

Serious adverse events (onset date (mandatory) and end date (if available)).

Concomitant therapy (start date, changes).

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available).

Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of site monitoring will be determined by assessing 
all characteristics of the trial, including its nature, objective, methodology and the degree of 
any deviations of the intervention from normal clinical practice.
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review,
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector (e.g.
FDA). They may review all CRFs and informed consents. The accuracy of the data will be 
verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
Exemptions from expedited reporting are described in Section 5.2.6.2, if applicable.


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8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
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.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, storage, and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular

A Quality Management System has been implemented to ensure the adherence with 
the Principles of Good Clinical Practice as outlined in 'Note For Guidance On Good 
Clinical Practice' (CPMP/ICH/13 5/95).

The BI-internal facilities storing and analysing biological samples and data from 
clinical trial participants as well as the laboratories' activities for clinical trials 
sponsored by Boehringer Ingelheim are regularly audited. The analytical groups are 
therefore assessed to be qualified for the storage and use of biological samples and 
data collected in clinical trials.

Samples and data are used only if an appropriate informed consent is available.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
Last Patient Last Visit Primary Endpoint (LPLV PE): The primary analysis will take 
place four imaging cycles after the last patient entered the trial.
The end of the trial is defined as the date of the last visit (Final Visit) of the last patient in 
the trial (“Last Patient Out”). All patients must have completed (or been prematurely 
withdrawn from) study treatment and attended end of the residual effect period visit. All 
patients must also have had a minimum of 24 months vital status collection from study entry
(unless prematurely withdrawn from study). The trial will be completed about 27 months 
after last patient entered the trial. With the early termination of the study patients will not 
need 24 months of vital status collection. The end of the trial is defined as the date of the REP 
visit for the last patient.


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The “Last Patient Drug Discontinuation” (LPDD) date is defined as the date on which the 
last patient at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual investigators will be notified of SUSARs occurring with the trial
medication until 30 days after LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The study will be performed by investigators specialised in the treatment of lung cancer. The 
trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract.
A Safety Monitoring committee (SMC) composed of sponsor representatives, coordinating 
investigator, and two to three other investigators will be established to review individual and 
aggregated safety and efficacy data at regular intervals to determine the safety profile and 
benefit/risk ratio and recommend the RP2D. The SMC may also provide recommendations to 
further enhance safety, e.g. regarding patient selection/ recruitment/dose adjustments, or 
request additional safety analysis. External experts may be appointed as needed. The sponsor 
will review the recommendations of the SMC and make the final decision. Details of the 
SMC responsibilities and procedures are described in the SMC charter.
Relevant documentation on the participating (Principal) investigators (e.g. their curricula 
vitae) will be filed in the Investigator Site File (ISF). The investigators will have access to the 
BI clinical trial portal (Clinergize) to facilitate document exchange and maintain electronic 
ISF.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to

Manage the trial in accordance with applicable regulations and internal SOPs,

Direct the clinical trial team in the preparation, conduct, and reporting of the trial,


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
Ensure appropriate training and information of Local Clinical Monitors (CML), 
Clinical Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service for the analysis of biomarkers, logistics of such tissue/blood 
samples, and an IRT vendor will be used in this trial. Details will be provided in the IRT 
Manual and Central Laboratory Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P15-06906
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 16 (8), 897-907 (2015)
R01-0787
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, 
Carbone PPToxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5, 649 - 655 (1982)
R07-4845
Frey U, Stocks J, Coates A, Sly P, Bates J, ERS/ATS Task Force on Standards 
for Infant Respiratory Function Testing. Specifications for equipment used for 
infant pulmonary function testing. Eur Respir J 16, 731 - 740 (2000)
R09-0262
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, 
Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd 
L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45, 228 - 247 
(2009)
R11-0826
Potthoff K, Hofheinz R, Hassel JC, Volkenandt M, Lordick F, Hartmann JT, 
Karthaus M, Riess H, Lipp HP, Hauschild A, Trarbach T, Wollenberg A. 
Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a 
German expert opinion. Ann Oncol 22 (3), 524 - 535 (2011)
R13-4802
Jaki T, Clive S, Weir CJ. Principles of dose finding studies in cancer: a 
comparison of trial designs. Cancer Chemother Pharmacol 71, 1107 - 1114 
(2013)
R13-4803
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian 
approach to phase I cancer trials. Stat Med 27, 2420 - 2439 (2008)
R13-4806
Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose
escalation with overdose control. Stat Med 17, 1103 - 1120 (1998)
R13-4881
FDA's critical path initiative (page last updated: 12/28/2012). 
http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/ucm
07668 9.htm (access date: 8 November 2013
R15-1555
Akbay EA et al., Activation of the PD-1 pathway contributes to immune 
escape in EGFR-driven lung tumors. Cancer Discov. 2013
R15-1556
Chen N, Fang W, Zhan J et al. Up-regulation of PD-L1 by EGFR activation 
mediates the immune escape in EGFRdriven NSCLC: Implication for optional 
immune targeted therapy for NSCLC patients with EGFR mutation. J. Thorac. 
Oncol. 10(6), 910–923 (2015)
R15-2005
Bohnsack O, Ludajic K, Hoos A. Adaptation of the immune-related response 
criteria: irRìIST. 39th Ann Cong of the European Society for Medical 
Oncology (ESMO), Madrid, 26 - 30 Sep 2014 (Poster)


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R15-2034
Lopez-Malpartida AV, Ludena MD, Varela G, Garcia Pichel J. Differential 
ErbB receptor expression and intracellular signaling activity in lung 
adenocarcinomas and squamous cell carcinomas. Lung Cancer (Neth) 65 (1), 
25 - 33 (2009)
R15-2035
Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and 
coincidence in non small-cell lung cancer: meta-analyses by ethnicity and 
histology (mutMap). Ann Oncol 2013; 24: 2371–76
R15-5988
Common terminology criteria for adverse events (CTCAE): version 4.0 (NIH 
publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 2010), 
revised June 2010, reprinted June 2010, 5x7, 196 pages). 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf (access date: 30 November 2015) (2010)
R15-6023
Garon EB, et al., Pembrolizumab for the treatment of non-small-cell lung 
cancer. N Engl J Med. 372 (21), 2018-2028 (2015)
R15-6033
Karim R, Jordanova ES, Piersma SJ, Kenter GG, Chen L, Boer JM, Melief CJ, 
Burg SH van der. Tumour-expressed B7-H1 and B7-DC in relation to PD-1+ 
T-cell infiltration and survival of patients with cervical carcinoma. Clin Cancer 
Res 15 (20), 6341 - 6347 (2009)
R15-6037
Sanmamed MF, Chen L. Inducible expression of B7-H1 (PD-L1) and its 
selective role in tumour site immune modulation. Cancer J (Sudbury) 20 (4), 
256 - 261 (2014)
R15-6038
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, 
Klein AP, Pardoll DM, Topalian SL, Chen L. Colocalization of inflammatory 
response with B7-H1 expression in human melanocytic lesions supports an 
adaptive resistance mechanism of immune escape. Sci Transl Med 4 (127), 
127ra37 (2012)
R16-0317
Rizvi NA, Chow LQM, Borghaei H et al. Safety and response with nivolumab 
plus erlotinib in patients with epidermal growth factor receptor mutant (EGFR 
MT) advanced NSCLC. ASCO Meeting Abstracts 32(Suppl. 15), 8022 (2014)
R16-0876
Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, 
Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, Castro G de, Garrido M, 
Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab 
versus docetaxel for previously treated, PD-L1-positive, advanced non-small-
cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet, 
(2015
R16-4467
Ahn MJ, Yang J, Yu H, Saka H, Ramalingam S, Goto K, et al. Osimertinib 
combined with durvalumab in EGFR-mutant non-small cell lung cancer: 
results from the TATTON phase lb trial. 6th Eur Lung Cancer Conf (ELCC), 
Geneva, 13 - 16 Apr 2016. J Thorac Oncol 11 (4) (Suppl), S115, Abstr 1360 
(2016)
R16-4803
Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al, 
KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-


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L1-positive non-small-cell lung cancer. N Engl J Med 375 (19), 1823 - 1833 
(2016)
R16-5263
Pilotto S, Carbognin L, Karachaliou N, Garassino M, Cuppone F, Petraglia S, 
et al. Moving towards a customized approach for drug development: lessons 
from clinical trials with immune checkpoint inhibitors in lung cancer. Transl 
Lung Cancer Res 4 (6), 704 - 712 (2015)
R16-5545
Hellmann MD, Gettinger SN, Goldman JW, Brahmer JR, Borghaei H, Chow 
LQ, et al. CheckMate012: safety and efficacy of first-line (1L) nivolumab 
(nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. 52nd Ann Mtg of 
the American Society of Clinical Oncology (ASCO), Chicago, 3 - 7 Jun 2016. 
J Clin Oncol 34 (Suppl), Abstr 3001 (2016)
R16-5728
Hirsch FR, Varella-Garcia M, Bunn PA, Maria MV di, Veve R, Bremnes RM, 
et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: 
correlation between gene copy number and protein expression and impact on 
prognosis. J Clin Oncol 21 (20), 3798 - 3807 (2003)
R17-0546
Rudin C, Cervantes A, Dowlati A, Besse B, Ma B, Costa D, et al: Safety, 
clinical activity and biomarker results from a phase lb study of erlotinib plus 
atezolizumab in advanced NSCLC. 17th World Conf on Lung Cancer 
(WCLC), Vienna, 4 - 7 Dec 2016. J Thorac Oncol 12 (Suppl 1), S1303, Abstr 
P3.02c-046 (2017)
9.2
UNPUBLISHED REFERENCES
c01617169-04Investigator’s brochure. Afatinib (BIBW 2992). Current Version
c16013985
., Investigator’s brochure. MK-3475. Current 
version.
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. 30 March 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 tumours. Trial 1200.3. 30 January 2008. Revised 25 February 
2010


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10.
APPENDICES
10.1
PHARMACOKINETIC ANALYSES
To evaluate the effect of pembrolizumab on afatinib pharmacokinetic (PK) properties, pre-
dose PK samples will be taken of all patients.
PK sampling afatinib:

C2_V and C3_V day 1 pre-dose, shortly before administration of afatinib & 
pembrolizumab (e.g. -0:05)
Additional PKsamples for pembrolizumab will be taken, which may be analysed upon 
request.
PK sampling pembrolizumab:

C2_V and C3_V day 1 pre-dose, shortly before administration of afatinib & 
pembrolizumab (e.g. -0:05)
Endpoints and Analyses (afatinib)

Listings of Cpre,ss values at day 22 and 43 of treatment, respectively

Historical comparison
10.1.1
Handling procedure of blood samples for plasma concentration-time 
measurements
Drug concentration-time profiles: Concentration data identified with NOS (no sample), NOR
(no valid result), NOA (not analysed), BLQ (below the limit of quantification) and NOP (no
peak detectable) will be ignored and not replaced by zero at any time point (including the lag
phase). Descriptive statistics of concentrations at specific time points will be calculated only
when at least 2/3 of the individuals have concentrations within the validated concentration
range.
Pharmacokinetic parameters: In the non-compartmental analysis, concentration data
identified with NOS, NOR and NOA will not be considered. BLQ and NOP values in the lag
phase will be set to zero. The lag phase is defined as the period between time 0 and the first
time point with a concentration above the quantification limit. All other BLQ and NOP
values of the profile will be ignored. Descriptive statistics of parameters will be calculated
only when at least 2/3 of the individual parameter estimates of a certain parameter are
available. Pharmacokinetic parameters which cannot be determined will be identified by "not
calculated" (NC).


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10.1.2
Time schedule for pharmacokinetic blood sampling
Table 10.1.2: 1
Time schedule for PK blood sampling
Treatment 
Period
Visit
Time Point 
PlannedTime
[hh:min]
Event Afatinib Pembrolizumab
Cycle 2
C2_V
Shortly before 
drug 
administration
-0:05
PK 
Blood
X
X
Cycle 3
C3_V
Shortly before 
drug 
administration
-0:05
PK 
Blood
X
X


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10.2
TRIAL BIOMARKER PLAN
The details of the biomarker aspects are described in Section 5.4. The analyses of biomarkers 
are described in Section 7.3.6. The optional biomarker sampling is strongly recommended.
With the early termination of the study, the optional blood sample at the time of PD will not 
be collected.
Table 10.2: 1
Time schedule for biomarker sampling
Type of 
sample
Visit
Time point
Planned Time
[hh:min]
Planned analyses
Mandatory or 
Optional
Tumour 
tissue
SV
Screening
NA

PD-L1

mRNA expression of 
genes involved in the 
immune system
Mandatory
SV
Screening
(excess tissue)
NA

Exploratory analyses
Optional
Blood 
(plasma 
and 
serum)
C1_V1
C1_V1 prior to 
first drug 
administration
-0:05

Exploratory analyses
Optional
C4_V
C4_V
NA

Exploratory analyses
Optional
EOT 
or FU-
PD
At time of PD
NA

Exploratory analyses
Optional


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10.3
RECIST 1.1 CRITERIA
The criteria below are based on RECIST 1.1 (R09-0262).
Tumour assessments should include CT scans of the chest and abdomen and a brain MRI at 
screening. If clinically indicated, imaging of any other known or suspected sites of disease 
(e.g. pelvis, bone) using an appropriate method (CT scan, MRI or bone scan) should be 
performed. The same radiographic procedure must be used throughout the study. If bone 
lesions are already known or confirmed at screening, correlative imaging (X-ray, CT scan, 
MRI or bone scan) should be performed. Correlative imaging should then be repeated at each 
tumour assessment.
The preferred method of assessment is a spiral CT scan with i.v. and oral contrast, unless i.v.
and/or oral contrast are medically contraindicated. Scans of the abdomen, pelvis and other 
areas of the body, but not chest, may be done with MRI instead of CT.
Skin lesions followed as target lesions must be documented by colour digital photography 
and must include in the image a ruler with millimetre subdivisions and a label that includes 
the patient’s ID and date.
Bone scans (using 99m-technetium polyphosphonate scintigraphy) are recommended at 
baseline if the patient has any signs and symptoms consistent with bone metastasis or a 
history of bone metastasis. Bone metastasis identified at baseline must be documented and 
assessed according to RECIST 1.1 at the times of the other tumour measurements indicated in 
the Flowchart. During the study bone scans should be repeated as clinically indicated in 
patients without bone metastasis at Baseline.
For the purposes of this study, patients should be re-evaluated for response every 9 weeks (63 
± 7 days). In the event of a treatment delay, interruption or discontinuation of treatment, 
tumour assessment should continue to follow the original schedule.
Follow-up tumour assessments must utilize the same CT/MRI/photographic method and 
acquisition technique (including use or non-use of i.v. contrast) as were used for screening 
assessments to ensure comparability. A chest x-ray or skeletal x-ray which clearly 
demonstrates a new metastatic lesion may be used to document progression in lieu of 
CT/MRI/bone scan.
Only those patients who have measurable disease present at baseline, have received at least 3 
weeks of therapy, and have had their disease re-evaluated will be considered evaluable for 
response. These patients will have their response classified according to the definitions stated 
below.
Measurability of tumour at baseline
Measurable lesions
Lesions that can be accurately measured in at least one dimension with longest diameter ≥10 
mm (by CT scan, MRI, caliper measurement) or ≥20 mm (by chest X-ray). Pathological 
lymph nodes, defined as lymph nodes with a short axis >15 mm are also measurable.
Measurable disease
Measurable disease requires the presence of at least one measurable lesion. Measurable lesion 
if limited to either small (<2 cm) solitary visceral lesion or scant (<5 cm) lymph nodes only 


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metastasis should be evaluated for additional evidence of malignant nature and discussed 
with the sponsor before enrolling.
Non-measurable disease
Non-measurable lesions are all other lesions, including small lesions (longest diameter 
<10 mm with CT scan, MRI or caliper measurement or <20 mm with chest X-ray or 
pathological lymph nodes with shortest axis ≥10 and <15 mm) as well as truly non-
measurable lesions. Lesions considered truly unmeasurable include leptomeningeal disease, 
ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/ abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques.
New lesions in irradiated fields
At baseline, previously irradiated lesions should not be used as indicator lesions unless they 
have progressed since irradiation. New lesions occurring in previously irradiated fields can be 
used as indicator lesions.
Methods of measurement
All measurements must be recorded in metric notation, using a ruler or callipers. All baseline 
evaluations must be performed as close as possible to the treatment start and never more than 
28 days before the beginning of the treatment. If a lesion is considered too small to measure, 
a default measurement of 5 mm should be applied. If the lesion is not visible, a default 
measurement of 0 mm should be applied.
The same method of assessment and the same technique must be used to characterise each 
identified and reported lesion at baseline and during follow-up.
Clinical lesions will only be considered measurable when they are superficial (e.g. skin 
nodules, palpable lymph nodes). In the case of skin lesions, documentation by colour 
photography including a ruler to estimate the size of the lesion is obligatory.
CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed 
with cuts of 5 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm. This applies to the chest, abdomen and 
pelvis.
Ultrasound, endoscopy and laparoscopy should not be used to measure tumour lesions or 
evaluate tumour response. However, these techniques can be useful to supplement 
information from other techniques.
Cytology and histology can be used to differentiate between PR and CR in rare cases (for 
example, residual lesions in tumour types such as germ cell tumours where known residual 
benign tumours can remain).
Baseline Documentation of Target and Non-target Lesions
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs should be identified as target lesions and will be 
recorded, measured (longest diameter (LD) for all lesions except lymph nodes, where shortest 
diameter (ShD) is used) and numbered at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter) and their suitability for accurate 


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repetitive measurements (either by imaging techniques or clinically). Lymph nodes must be 
≥15 mm in order to be considered as target lesions.
A sum of diameters (SoD) for all target lesions will be calculated (using ShD for lymph 
nodes and LD for all other lesions) and reported as the baseline SoD. The baseline SoD will 
be used as reference to further characterise the objective tumour response of the measurable 
dimension of the disease (see Table 10.3: 1).
Table 10.3: 1
Evaluation of target lesions
Complete Response 
(CR)
Disappearance of all target lesions. Any pathological lymph nodes 
must have reduction in short axis to <10 mm.
Partial Response 
(PR)
At least a 30% decrease in the SoD of target lesions taking as 
reference the baseline SoD.
Progression (PD)
At least a 20% increase in the SoD of target lesions, taking as 
reference the smallest SoD recorded on study (including baseline), 
together with an absolute increase in the SoD of at least 5 mm.
OR
The appearance of one or more new lesions.
Stable Disease 
(SD)
Neither sufficient shrinkage to qualify for PR, taking as reference 
the baseline SoD, nor sufficient increase to qualify for PD taking as 
reference the smallest SoD recorded on study (including baseline).
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements are not required and these lesions should be 
followed as “present” or “absent” (see Table 10.3: 2).
Table 10.3: 2
Evaluation of non-target lesions and new lesions
Complete 
Response (CR)
Disappearance of all non-target lesions and normalisation of tumour 
marker level. All lymph nodes must be non-pathological in size 
(<10 mm short axis).
Non-CR/Non-PD 
Persistence of one or more non-target lesions or/and maintenance of 
tumour marker level above normal limits.
Progression (PD) 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.
Although a clear progression of non-target lesions only is 
exceptional, in such circumstances, the opinion of the treating 
physician should prevail and the progression status should be 
confirmed later by the review panel (or study chair).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status.


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Confirmation
In case of PD, confirmation will be performed with a repeat assessment ≥ 4 weeks after the 
RECIST criteria for response have been met. 
In case of tumour response (CR or PR) confirmation will be performed with a repeat 
assessment at the next imaging time point (or ≥4 weeks later). An additional assessment in 
addition to the scheduled assessments is not expected. In the case of SD, measurement must 
have met the SD criteria at least once after study entry at an interval of not less than 6 weeks.
Evaluation of best response to study treatment
The best response to study treatment (Table 10.3: 3) is the best response recorded from the 
start of treatment until disease progression and/or start of subsequent anti-cancer treatment 
(taking as reference for progressive disease the smallest SoD recorded on study). In general, 
the patient’s best response assignment will depend on the achievement of both measurements 
and confirmation criteria (Table 10.3: 3).
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment.
Table 10.3: 3
Algorithm for evaluation of overall response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/ Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not 
evaluated
No
PR
SD
Non-PD or not 
evaluated
No
SD
Not evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD


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10.4
IMMUNE RELATED RECIST (IRRECIST)
RECIST 1.1 will be adapted to account for the unique tumour response characteristics seen 
with treatment of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may 
produce anti-tumour effects by potentiating endogenous cancer-specific immune responses. 
The response patterns seen with such an approach may extend beyond the typical time course 
of responses seen with cytotoxic agents, and can manifest a clinical response after an initial 
increase in tumour burden or even the appearance of new lesions. Standard RECIST may not 
provide an accurate response assessment of immunotherapeutic agents such as 
pembrolizumab. Therefore, RECIST 1.1 will be used with the following adaptations:
After first documentation of PD or response and if the patient is clinically stable, the patient 
may continue study treatment until confirmed PD. Confirmatory imaging may be performed 
≥ 4 weeks later. Please also see Table 5.1.2: 1.
If repeat imaging shows < 20% tumour burden compared to nadir, stable or improved 
previous new lesion (if identified as cause for initial PD), and stable/improved non-target 
disease (if identified as cause for initial PD), treatment may be continued / resumed.
If repeat imaging confirms PD due to any of the scenarios listed below, patients will be 
discontinued from study therapy.
In determining whether or not the tumour burden has increased or decreased, site study team 
should consider all target lesions as well as non-target lesions.
Scenarios where PD is confirmed at repeat imaging:

Tumour burden remains ≥ 20% and at least 5 mm absolute increase compared to 
nadir.

Non-target disease resulting in initial PD is worse (qualitative).

New lesion resulting in initial PD is worse (qualitative).

Additional new lesion(s) since last evaluation.
For patients who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a patient on study treatment 
until repeat imaging is obtained (see Table 5.1.2: 1). This decision by the investigator should 
be based on the patient’s overall clinical condition
Clinical stability is defined as following:

Absence of signs and symptoms indicating disease progression.

No decline in ECOG performance status.

No requirements for intensified management, including increased analgesia, radiation, 
or other palliative care.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per irRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression as defined above, but the 
participant is achieving a clinically meaningful benefit, an exception to continue study 


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treatment may be considered following consultation with the sponsor. In this case, if study 
treatment is continued, tumour imaging should continue to be performed following the 
intervals as outlined in Flowchart and Appendix 10.3.
When feasible, patients should not be discontinued until progression is confirmed. This 
allowance to continue treatment despite initial radiologic progression takes into account the 
observation that some patients can have a transient tumour flare in the first few months after 
the start of immunotherapy, but with subsequent disease response. Patients that are deemed 
clinically unstable are not required to have repeat imaging for confirmation of progressive 
disease (R15-2005).
10.5
CLINICAL EVALUATION OF LIVER INJURY
10.5.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.6.1 (Adverse Events of 
Special Interest), are to be further evaluated using the following procedures:
10.5.2
Procedures
Any elevation of ALT/AST and bilirubin qualifying as laboratory alert should be confirmed 
using the initial sample if possible.
If the alert is confirmed on initial sample or it is not possible to repeat testing using initial 
sample, the data in the DILI checklist is collected and followed up simultaneously to meet the 
following timelines (or as quickly as possible, if the timelines cannot be met):

Reflex testing from initial blood sample within 24 hours upon laboratory hepatic 
injury alert / notification, including (if appropriate specimen is available):
o
Repeat of AST, ALT, bilirubin (with fractionation to total and direct)
o
Creatinine kinase
o
Acetaminophen level
o
Lactate dehydrogenase
o
Haptoglobin
o
Complete blood count and cell morphology
o
Reticulocyte count
o
Alkaline Phosphatase

DILI Kit assessment (new blood sample) within 48 hours upon laboratory hepatic 
injury alert / notification

Abdominal ultrasound: within 48 hours upon laboratory hepatic injury alert / 
notification

The following part of the DILI checklist is collected within 48 hours upon receipt of 
the laboratory hepatic injury alert / notification:
o
Alcohol consumption
o
Medical history / concomitant diagnoses
o
Complete physical examination
o
Concomitant therapy/supplements


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
Complete the following laboratory tests as detailed in the DILI checklist provided in 
the ISF:
o
Clinical chemistry
alkaline phosphatase, cholinesterase (serum)*, albumin, PT or INR, CK, CK-
MB, coeruloplasmin*, α-1 antitrypsin*, transferrin*, amylase, lipase, fasting 
glucose, cholesterol, triglycerides;
o
Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), 
Hepatitis C (Anti-HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, 
Anti-IgG), Hepatitis E (Anti-HEV, Anti-HEV IgM, RNA if Anti-HEV IgM 
positive), Anti-Smooth Muscle antibody (titer), Anti-nuclear antibody (titer), 
Anti-LKM (liver-kidney microsomes) antibody, Anti-mitochondrial antibody, 
Epstein Barr Virus (VCA IgG, VCA IgM), cytomegalovirus (IgG, IgM), 
herpes simplex virus (IgG, IgM)*, varicella (IgG, IgM)*, parvovirus (IgG, 
IgM)*;
o
Hormones, tumour marker
TSH*;
o
Haematology
Thrombocytes, eosinophils.
*If clinically indicated (e.g. immunocompromised patients)
The results of these tests must be reported to BI as soon as possible. In case the etiology of 
the abnormal liver tests results is not identified based on the imaging (e.g. biliary tract, 
pancreatic, or intrahepatic pathology), the “DILI checklist” must be completed. Details of the 
“DILI checklist” are provided in the ISF. The following assessments need to be performed in 
order to complete the “DILI checklist” and results will be reported via the eCRF:
Long term follow-up:

Initiate close observation of patients by repeat testing of ALT, AST, and bilirubin (with 
fractionation to total and direct) at least weekly until the laboratory ALT and or AST 
abnormalities stabilize or return to normal, then according to the protocol. Depending on 
further laboratory changes, additional parameters identified e.g. by reflex testing will be 
followed up based on medical judgement and GCP and reported via the eCRF.


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10.6
CREATININE CLEARANCE
Creatinine clearance should be calculated per institutional standard.
The following formula may be used for estimated creatinine clearance rate (eCCR) using 
Cockcroft-Gault formula. The calculations and results must be filed in the patient’s chart.
When serum creatinine is measured in mg/dl;







mg/dl
in 
Creatinine
Serum
72
85
.0
kilograms
in 
Mass
Age
140
eCCR





Female
if
When serum creatinine is measured in µmol/l;






µmol/l
in 
Creatinine
Serum
Constant
kilograms
in 
Mass
Age
140
eCCR




Where Constant ≈1.23 for men and 1.04 for women.


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10.7
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS*
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g. light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5
Dead
* As published in Am. J. Clin. Oncol. (R01-0787).


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10.8
P-GLYCOPROTEIN INHIBITORS AND INDUCERS
Examples of P-gp modulators that can be considered as potent inhibitors and/or potent 
inducers of the P-gp (P-gp is also known as MDR1) are listed in Table 10.8: 1.
Table 10.8: 1 List of potent inhibitors and inducers of P-glycoprotein (MDR1)
Inhibitors
Inducers
Amiodarone
Azithromycin
Captopril
Carvedilol
Clarithromycin
Conivaptan
Cyclosporine
Diltiazem
Dronedarone
Erythromycin
Felodipine
Itraconazole
Ketoconazole
Lopinavir
Nelfinavir
Ritonavir
Quinidine
Ranolazine
Saquinavir
Tacrolimus
Ticagrelor
Verapamil
Carbamazepine
Phenytoin
Rifampicin
St John's wort
Phenobarbital salt
Tipranavir
Ritonavir
As the information on potent inhibitors and inducers of P-gp may evolve, it is important for 
the investigator to assess such status on concomitant therapies and in case of questions 
contact sponsor/sponsor representative.


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10.9
BAYESIAN LOGISTIC REGRESSION MODEL WITH OVERDOSE 
CONTROL FOR DOSE CONFIRMATION
A Bayesian logistic regression model (BLRM) with overdose control that will be fitted to 
binary toxicity outcomes will be used to guide the dose confirmation part in this study. After 
12 patients completed at least one cycle of treatment, the prior distributions will be updated 
through Gibbs sampling procedures with the accumulated DLT data from the first treatment 
cycle. The estimate of parameters will be updated as data are accumulated using the BLRM. 
At the end of the dose confirmation, the toxicity probability at each dose level will be 
calculated to determine an estimate of the RP2D. Posterior probabilities for the rate of DLT 
will be summarised from BLRM. Confirmation of the RP2D by the SMC will be based on 
these probabilities as well as on the review of other safety and laboratory data.
The purpose of this statistical appendix is to present performance metrics (operating 
characteristics) that illustrate the precision of the design in estimating the RP2D under 
various dose-toxicity relationships through computer simulation. These results are 
summarised in Table 10.9.2: 2. Recommendations by the BLRM with overdose control 
principle are also provided under various hypothetical outcome scenarios to show how it 
facilitates the decision making process by the SMC (see Table 10.9.3: 1).
Please note that RStudio Version 0.99.484 and R version 3.2.2 were used for the 
computations shown in the subsequent parts of this appendix.
10.9.1
Definition of the model and description of the prior derivation
As described in Sections 1.4 and 3.1, the dose confirmation part will be guided by a Bayesian 
5-parameter logistic regression model with overdose control (R13-4806, R13-4803).
This logistic regression model is defined as follows. Let π1,d1 be the probability of having a 
DLT when giving dose d1 of afatinib as monotherapy, and π2,d2 the probability of having a 
DLT when giving dose d2 of pembrolizumab as monotherapy, respectively. A logistic 
regression is used to model the dose-toxicity relationship for each of these drugs individually:

Afatinib:
logit(π1,d1) =log(α1) + β1log(d1/d1*)

Pembrolizumab:
logit(π2,d2) =log(α2) + β2log(d2/d2*)
Here, the doses d1* = 40 mg and d2* = 200 mg represent the reference doses for afatinib and 
pembrolizumab, respectively.
Assuming no toxicity interaction between the two compounds, the probability of a DLT when 
giving the combination dose d1, d2 is obtained as

π012,d1,d2 = π1,d1 + π2,d2 - π1,d1π2,d2
with corresponding odds

odds(π012,d1,d2)= π012,d1,d2 /(1- π012,d1,d2).
In order to account for a potential positive (higher toxicity than expected under 
independence) or negative (lower toxicity than expected under independence) interaction 


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between afatinib and pembrolizumab, a dose-dependent interaction term -∞<η<∞ is 
introduced in the model by the following definition:

odds(π12,d1,d2) = odds(π012,d1,d2) exp(η d1/d1* d2/d2*)
and π12,d1,d2 is used in the likelihood

rd1,d2 ~ Binomial(nd1,d2,π12,d1,d2)
where rd1,d2 denotes the random variable describing the observed number of DLTs in nd1,d2
patients at the dose combination d1, d2.
Since a Bayesian approach is applied, prior distributions f for each of the parameter vectors
θ1=(log(α1),log(β1)), θ2=(log(α2),log(β2)) and for the interaction term η need to be specified.
The prior distributions for θk will be specified as a mixture of two bivariate normal 
distributions,
f(θk) = a1,k f1(θk) + a2,k f2(θk)
with
a1,k, a2,k the prior mixture weights (a1,k + a2,k = 1), k = 1,2 and
fi(θk) = MVN(µik, ∑ik) a bivariate normal distribution with mean vector µik and covariance 
matrix ∑ik where
Σ = 
	
,
	 ,	 ,


	 ,	 ,


	
,


Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust.
A weakly informative normal prior distribution will be used for η.
The estimated probability of DLT π12,d1,d2 at each dose combination d1, d2 from the model 
will be summarised using the following intervals:

Under dosing: [0.00, 0.16)

Targeted toxicity: [0.16, 0.33)

Over dosing: [0.33, 1.00]
The BLRM recommended dose combination is the combination with the highest posterior 
probability of the DLT rate falling in the target interval [0.16, 0.33) among the dose 
combinations fulfilling the overdose control. It should be unlikely (<25% posterior 
probability) that the DLT rate at the dose combination will exceed 0.33.
For the dose confirmation part, the RP2D may be considered reached if the posterior 
probability of the true DLT rate in the target interval [0.16 – 0.33) is above 0.50.


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Prior toxicity information on afatinib was taken from 1200.2, 1200.3 and 1200.4 to define the 
prior distribution of this model, using the meta-analytic predictive approach (U07-3128-02
and U08-1023-02).For pembrolizumab it was not possible to utilise information from the 
dose-finding studies as body weight dependent dosing regiments were originally investigated. 
For this part of the prior derivation process a minimally informative prior is utilised, 
combining high-tox, low-tox and expected average tox probabilities.
Prior derivation
For summaries of the data from other BI trials, see Table 10.9.1: 1 below.
Table 10.9.1: 1
Summary of data from trials 1200.2, 1200.3, and 1200.4 used for the 
prior derivation for afatinib
Dose (mg)
1200.2
1200.3
1200.4
# Patients 
treated
# DLT 
events
# Patients 
treated
# DLT 
events
# Patients 
treated
# DLT 
events
10
3
0
3
0
5
0
20
6
0
4
0
3
0
30
-----
-----
7
1
-----
-----
40
8
1
26
1
19
1
50
-----
-----
13
1
-----
-----
55
20
7
-----
-----
-----
-----
60
-----
-----
-----
-----
3
2
65
6
3
-----
-----
-----
-----
The following steps were used to derive the prior distributions for all parameters:

θ1:
o
The meta-analytic-predictive prior was derived using the information in Table 
10.9.1:1, allowing for substantial between-trial heterogeneity
o
This mixture component was assigned 90% mixture weight. A second, 
weakly-informative component was added with 10% mixture weight

θ2:
o
A weakly informative prior was derived reflecting the a priori assumption that 
the median DLT rates at the dose of 150 mg would be equal to 1% and 200 mg 
3-weekly pembrolizumab would equal to 2 %. This yields μ1 = (-3.892 , 
0.894). The standard deviations were set such that large uncertainty about the 
parameter means is reflected, and the correlation was set to 0, thus yielding 
σ1,11 = 2, σ1,22 = 2 and ρ1 = 0, respectively. The prior weight φ1 for the first 
component was chosen as 0.9.


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o
A high-toxicity weakly informative prior was derived reflecting the case that 
the compound would be much more toxic than expected. For this prior 
component, it was assumed that the median DLT rates at the dose of 150 mg 
would be equal to 5% and 200 mg would equal to 15%. These assumptions 
yield μ2 = (0.05, 0.15). The standard deviations and correlations were set 
identical to the weakly informative prior, i.e. σ2,11 = 2, σ2,22 = 2 and ρ2 = 0, 
respectively. The prior weight φ2 for the second component was chosen as 
0.05.
o
A low-toxicity weakly informative prior was derived reflecting the case that 
the compound would be much less toxic than expected. For this prior 
component, it was assumed that the median DLT rates at the starting dose of 
150 mg would be equal to 0.1% and 200 mg would equal to 0.2. These 
assumptions yield μ3 = (0.001, 0.002). The standard deviations and 
correlations were set to σ3,11 = 2, σ3,22 = 2 and ρ3 = 0, respectively. The prior 
weight φ3 for the third component was chosen as 0.05.

η:
o
Based on the a priori assumption of no interaction between the two 
compounds, a normal distribution with mean 0 and standard deviation 0.707 
was chosen. At the starting dose combination, the corresponding 95% prior 
interval covers an up to 4-fold increase (or decrease) in the odds of a DLT 
over no interaction.
The corresponding prior distribution parameters can be found in Table 10.9.1: 2 probabilities 
of a DLT at different dose combinations of afatinib and pembrolizumab, and the 
corresponding probability of under-dosing, targeted dosing and overdosing based on the 
computed prior are shown in Table 10.9.1: 3. Based on the aforementiend table, a starting 
dose of 40 mg daily afatinib in combination with 200 mg of 3 weekly pembrolizumab fulfills 
the overdose criterion and is therefore a suitable starting dose.
Table 10.9.1: 2
Prior distribution parameters for the combination of afatinib and 
pembrolizumab
Parameter
Means, standard 
deviations, correlation
Mixture weight
Component 1: log(α1),log(β1)
(-2.197, 0.967), (1.201, 
0.794), -0.077
0.9
Component 2: log(α1), log(β1)
(-2.2, 1), (1.5, 1), 0
0.1
Component 1: log(α2), log(β2)
(-3.892 , 0.894), (2, 2), 0
0.9
Component 2: log(α2), log(β2)
(-1.735, 1.436), (2, 2), 0
0.05
Component 3: log(α2), log(β2)
(-6.213, 0.881), (2, 2), 0
0.05
η
0, 0.707, NA
NA


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Table 10.9.1: 3
Prior probabilities of true DLT rates with 200 mg of 3-weekly 
pembrolizumab with 20, 30 or 40 mg of daily afatinib
Afatinib 
dose 
mg
Probability of true DLT rate in
Quantiles
[0,0.16]
[0.16,0.33]
[0.33,1]
Mean
Standard 
Deviation
2.5%
50%
97.5%
20mg
0.767
0.138
0.095
0.120
0.159
0.002
0.058
0.622
30mg
0.668
0.191
0.141
0.160
0.177
0.006
0.094
0.686
40mg
0.499
0.256
0.245
0.229
0.206
0.014
0.160
0.779
Study 1200.237, an investigator initiated study, is already investigating the dose combination 
of 40 mg daily afatinib and 200 mg of 3-weekly pembrolizumab, and it was seen as valuable 
to incorporate the prior information based on the previously described prior derivation with 
real data of the combination of these two compounds. The relevant information from 
1200.237 can be found in Table 10.9.1: 4. The aforementioned prior was combined with the 
data from 1200.237 and the predicted prior probabilities of DLTs occurring within this study 
were re-computed. The results are shown in Table 10.9.1: 5.
Table 10.9.1: 4
Summary of data from trial 1200.237
Dose (mg)
1200.237
# Patients 
treated
# DLT 
events
40 mg daily afatinib +
200 mg 3-weekly pembrolizumab
4
0
Table 10.9.1: 5
Prior probabilities of true DLT rates with 200 mg of 3-weekly 
pembrolizumab with 20, 30 or 40 mg of daily afatinib after the 
incorporation of data from 1200.237
Afatinib 
dose mg
Probability of true DLT rate in
Quantiles
[0,0.16]
[0.16,0.33]
[0.33,1]
Mean
Standard 
Deviation
2.5%
50%
97.5%
20mg
0.936
0.056
0.008
0.053
0.064
0.002
0.031
0.236
30mg
0.895
0.093
0.012
0.071
0.072
0.004
0.048
0.269
40mg
0.776
0.186
0.038
0.110
0.096
0.010
0.082
0.369
Based on the above table, a starting dose of 40 mg daily afatinib in combination with 200 mg 
of 3 weekly pembrolizumab can be seen as adequately safe to treat patients in this study.


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Current available information obtained from the study 1200.237 at the time of dose escalation 
will be incorporated in the calculation of the posterior.
10.9.2
Operating characteristics
Operating characteristics are a way to assess the long-run behaviour of a model. Under an 
assumed true dose-toxicity curve, metrics such as the probability of recommending a dose 
with true DLT rate in the target interval can be approximated via simulation. Table 10.9.2: 1
describes 4 assumed true dose-toxicity scenarios which were used to assess the operating 
characteristics of the model. These scenarios reflect a wide range of possible cases as 
follows:

Scenario 1: aligned with prior means

Scenario 2: high-toxicity scenario

Scenario 3: low-toxicity scenario

Scenario 4: low-toxicity followed by high-toxicity
Table 10.9.2: 1 
Assumed true dose-toxicity scenarios
Scenario
Dose combination (afatinib/pembrolizumab)
20/200
30/200
40/200
Scenario 1
P(DLT)
0.051
0.068
0.103
Scenario 2
0.10
0.15
0.24
Scenario 3
0.03
0.05
0.07
Scenario 4
0.03
0.10
0.26
For each of these scenarios, 1000 trials were simulated. Each cohort consisted of 12 patients. 
It was then assessed how often a dose was declared as RP2D with true DLT rate in the under-
, targeted, or over-dose range. Furthermore, the average, minimum and maximum number of 
patients per trial and the average number of DLTs per trial are reported. Results are shown in 
Table 10.9.2: 2 below.


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Table 10.9.2: 2 
Simulated operating characteristics
Scenario
% of trials confirming RP2D with true DLT rate in
# Patients
# DLTs
Underdose
Target Dose
Overdose
Stopped
Mean
(Min-Max)
Mean
(Min-Max)
1
48.2
51.3
0.0
0.5
18.69
(12-30)
2.47
(0-7)
2
10.0
85.1
2.9
0.3
17.17
(6-30)
4.13
(1-11)
3
38.8
60.5
0.0
1.2
19.45
(12-30)
2.31
(0-7)
4
12.6
83.0
2.6
0.4
17.41
(6-30)
4.28
(1-10)
In scenario 1, which reflects the case that the true dose-toxicity is aligned with prior means, 
almost all of the simulated trials have found a RP2D. Most of those trials declared the RP2D 
with true toxicity rate in the target interval; however, many declared a dose with true toxicity 
rate in the underdose interval. Very few trials stopped prematurely without an RP2D, 
indicating that by chance it may be seen that the dose combination can also be perceived as 
being too toxic.
Scenario 2 (high-toxicity scenario) illustrates that even with a doubling of the true underlying 
dose-toxicity rate it would be possible to declare an RP2D at the target dose level in over 
85% of the cases. Stopping in the underdose interval was observed in 10% of cases, and in 
the overdose interval in less than 3% of cases. A few simulated trials have been stopped 
before declaring a RP2D, but the number is still low and expected behaviour for a high-
toxicity scenario.
In scenario 3 (low-toxicity scenario) none of trials declared a RP2D with true DLT rate in the 
overdose interval. Furthermore, around 39% of trials that declared a RP2D with true DLT 
rate in the underdose interval were simulated in this scenario. Most trials that have found a 
RP2D declared this RP2D with true DLT rate in the target interval (60.5%).
Scenario 4, a mixture of the high toxicity and the low toxicity scenario, shows characteristics 
of both of these.
The mean patient numbers range from 17.17 patients (Scenario 2) to 19.45 patients (Scenario 
3) and the maximum number of patients was 30. Therefore, the patient numbers are as 
expected and increase when moving away from the high-toxicity scenario.
10.9.3
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.9.3: 1. These scenarios reflect potential 
on-study data constellations and related potential de-escalation of afatinib as suggested by the 


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model. For each scenario, the probability of overdose for the current dose, as well as the next 
potential dose and related probabilities of underdosing, target dosing and overdosing are 
shown.
Scenarios 1 to 5 represent the situation at the first pre-planned formal evaluation after 12 
patients have been treated with the starting dose combination of 40 mg daily afatinib and 
200 mg 3-weekly pembrolizumab. It can be seen that up to 4 out of 12 treated patients 
experiencing a DLT would lead to the acceptance that this starting dose is an adequate RP2D. 
With 5 or 6 patients with a DLT in the first treatment cycle the model would suggest to 
reduce the dose to 30 mg daily afatinib, as 40 mg are too toxic. With 7 patients experiencing 
a DLT in the aforementioned time interval, the model would suggest that even 30 mg afatinib 
is too toxic and any patient exposed to the combination should receive 20 mg of afatinib. 
With 8 or more DLTs, any afatinib dose is considered to be too toxic and no new patient 
should be exposed to the combination of afatinib and pembrolizumab.
Scenarios 6 to 12 show the cases where 5 DLTs were observed in the first 12 patients in the 
first treatment cycle and the second run in cohort on 30 mg is introduced. If 0 or 1 DLTs are
observed in these 12 patients, then the model would suggest that the afatinib dose could 
potentially again increase; however. Observing 2 to 4 DLTs would confirm that the de-
escalation was an adequate step and could be seen as RP2D. If 5 DLTs would be recorded in 
the first treatment cycle in this group of 12 patients, then another dose reduction to 20 mg 
afatinib would be required. With 6 or more DLTs any afatinib dose in combination with 
pembrolizumab would be determined as being too toxic to expose patients to.
Scenarios 13 to 18 show the cases where 6 DLTs were observed in the first 12 patients in the 
first treatment cycle and the second run in cohort on 30 mg is introduced. If 0 to 4 DLTs are 
observed in these 12 patients, then the model would suggest that the selected afatinib dose is 
adequate and could be seen as RP2D. If 4 DLTs would be recorded in the first treatment 
cycle in this group of 12 patients, then another dose reduction to 20 mg afatinib would be 
required. With 5 or more DLTs any afatinib dose in combination with pembrolizumab would 
be determined as being too toxic to expose patients to.
Table 10.9.3: 1 
Hypothetical Data Scenarios
Scenario
Current 
Dose
Combination
(mg/mg)
#
Patients
#
DLT
Current 
Dose
Combination
P(OD)1
Next 
Recommended
Dose 
Combination
(mg/mg)
Next Dose Combination
P(UD)2
P(TD)3
P(OD)1
1
40/200
12
4
0.160
40/200
0.229
0.661
0.160
2
40/200
12
5
0.321
30/200
0.428
0.473
0.099
3
40/200
12
6
0.516
30/200
0.315
0.499
0.186
4
40/200
12
7
0.715
20/200
0.464
0.356
0.181
5
40/200
12
8
0.849
-----
-----
-----
-----
6
40/200
30/200
12
12
5
0
0.002
40/200
0.225
0.644
0.130


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Scenario
Current 
Dose 
Combination 
(mg/mg)
# 
Patients
# 
DLT
Current 
Dose 
Combination 
P(OD)1
Next 
Recommended 
Dose 
Combination 
(mg/mg)
Next Dose Combination
P(UD)2
P(TD)3
P(OD)1
7
40/200
30/200
12
12
5
1
0.010
40/200
0.142
0.677
0.180
8
40/200
30/200
12
12
5
2
0.039
30/200
0.425
0.536
0.039
9
40/200
30/200
12
12
5
3
0.087
30/200
0.244
0.669
0.087
10
40/200
30/200
12
12
5
4
0.191
30/200
0.115
0.694
0.191
11
40/200
30/200
12
12
5
5
0.322
20/200
0.249
0.545
0.206
12
40/200
30/200
12
12
5
6
0.489
-----
-----
-----
-----
13
40/200
30/200
12
12
6
0
0.005
30/200
0.799
0.197
0.005
14
40/200
30/200
12
12
6
1
0.025
30/200
0.560
0.415
0.025
15
40/200
30/200
12
12
6
2
0.067
30/200
0.326
0.607
0.067
16
40/200
30/200
12
12
6
3
0.152
30/200
0.170
0.678
0.152
17
40/200
30/200
12
12
6
4
0.280
20/200
0.345
0.505
0.151
18
40/200
30/200
12
12
6
5
0.451
-----
-----
-----
-----
1
Probability of Overdosing
2
Probability of Underdosing
3
Probability of Target Dosing


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
12 Mar 2019
EudraCT number
EU number
2016-005042-37
BI Trial number
1200.283
BI Investigational Product(s)
Afatinib + pembrolizumab
Title of protocol
LUX-Lung IO: A phase II, open label, non-
randomised study of afatinib in combination with 
pembrolizumab in patients with locally advanced 
or metastatic squamous cell carcinoma of the lung
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
Description of change
Administrative changes for TCM, version and 
date
Rationale for change
To reflect  the change in TCM for the study, 
version number and date of new version
Section to be changed
Flowchart
Description of change
Timeline for Screening Period; remove FUPfor 
PD and OS; thyroid testing; AE reporting period 
for pembrolizumab;
Rationale for change
Allow patients to be randomised at the screening 
visit if all procedures are completed to avoid 
unnecessary visit.  To clarify that thyroid testing 
after discontinuation pembrolizumab is only 
needed if clinically indicated. To clarify that AEs 
are to be collected up to 90 days after the last dose 
of pembrolizumab. 
With the early termination of the study patients 
are no longer followed for PD and OS and blood 
samples for biomarkers are no longer needed at 
time pf PD. 
With the early termination of the study tumour 
assessment is done per standard of care.
Section to be changed
Section 2.2.1


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Description of change
There will be no assessment of biomarkers in 
blood samples. 
Rationale for change
Because of the early termination of the study this 
assessment is no longer needed.  
Section to be changed
Section 3.1
Description of change
SMC recommendation to stop the trial and not 
open the Main part of the study
Rationale for change
SMC determined that the benefit risk of the 
combination of pembrolizumab and afatinib was 
not favourable.  
Section to be changed
Section 3.3.4 and 3.3.4.1
Description of change
Add that patients will be discontinued from the 
trial treatment after completing 35 cycles with 
pembrolizumab and/or afatinib.
Patients will not be followed up for disease 
progression or overall survival after 
discontinuation from trial treatment.
Rationale for change
For clarity and consistency with other sections of 
the protocol.
Cancellation of patient follow-up for PD and OS.
Section to be changed
Table 4.1.4.2.1:1
Description of change
Guidance on dose modification in patients with

Liver metastasis at baseline who 
experience AST or ALT elevation

Myocarditis

Other immune-related AEs of grade 3 
Rationale for change
To be consistent with dose modification described 
in the SmPc for pembrolizumab 
Section to be changed
Section  4.1.4.2.2
Description of change
New section
Rationale for change
To provide guidance on dose interruption for 
pembrolizumab for reasons other than treatment 
related AE 
Section to be changed
Section 4.2.1
Description of change
Clarification and guidance on supportive care 
measure for treatment with pembrolizumab 
Rationale for change
It was missing for pembrolizumab. 
Section to be changed
Section 4.2.2.1
Description of change

Delete “oral” in “typhoid oral vaccine

Add that systemic glucocorticoids can be 
used to treat adverse reactions to afatinib 
Rationale for change

To clarify that any type of typhoid 
vaccines are excluded

To clarify that glucocorticoids can be used 
to treat adverse reactions for afatinib
Section to be changed
Table 4.2.3.3:1


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Description of change
Add that treatment with afatinib should be 
interrupted for Grade 2 diarrhea if it is intolerable 
for patients
Rationale for change
To clarify that treatment interruption of grade 2 
diarrhea is also based on patient decision
Section to be changed
Section 4.2.3.10
Description of change
Add that pembrolizumab may cause severe or life 
threatening infusion reactions with reference to 
the guidelines in the protocol. 
Rationale for change
Clarification on management of infusion reaction 
with pembrolizumab
Section to be changed
Table 4.2.3.10:1
Description of change

Editorial changes 

Clarification  on when to use epinephrine

Reference to CTCAE guidelines
Rationale for change
Clarification on management of infusion reaction 
with pembrolizumab
Section to be changed
Sections 5.1.1 and 5.1.2
Description of change
Tumour assessment will be done per local 
standard of care and will not have to follow 
RECIST 1.1
Rationale for change
Clarification of expectation with the early 
termination of the study.
Section to be changed
Section 5.2.5.2
Description of change
ECOG evaluation is no longer required
Rationale for change
Clarification of expectation with the early 
termination of the study.


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Section to be changed
Section 5.1.1
Description of change

Add clarification as to why the same 
imaging technique should be used.

Clarify that imaging manual will be 
provided in case of retrospective review

Guidance on imaging after progressive 
disease per irRECIST
Rationale for change
Clarification on imaging during the trial
Section to be changed
Section 5.1.2
Description of change

Clarification on imaging requirement for 
patients who have PD according to 
RECIST but are clinically stable.

Definition of clinical stability in the 
context of the study
Rationale for change
Added clarification on imaging requirement for 
PD according to irRECIST
Section to be changed
Table 5.1.2:1
Description of change
Clarification on imaging and treatment after first 
radiologic evidence of PD
Rationale for change
Added clarification on imaging during the trial
Section to be changed
Section 5.2.3
Description of change
Add that thyroid function testing is done only 
while on treatment with pembrolizumab
Rationale for change
Clarification on thyroid testing during the trial
Section to be changed
Section 5.2.5.1
Description of change
Added “possibly, probably and definitely” to 
related toxicities for assessing DLTs. 
Rationale for change
To clarify the relatedness of toxicities that will be 
used to determine DLTs
Section to be changed
Table 5.2.5.1:1
Description of change
Delay in initiating dosing in Cycle 2 to include 
pembrolizumab and afatinib 
Rationale for change
To clarify that delay in dosing applies to both trial 
drugs i.e afatinib and pembrolizumab. 
Section to be changed
Section 5.2.6.1
Description of change
AESIs-hepatic injury

Guidance on assessment following 
elevation of liver enzymes 
Rationale for change
Clarification on the assessment and evaluation of 
elevated liver enzymes during the conduct of the 
trial
Section to be changed
Section 5.2.6.2
Description of change
AE reporting period for pembrolizumab and 
afatinib
AESIs, AEs and SAEs are not collected after the 
end of the REP


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Clinical Trial Protocol
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Rationale for change
Clarify that for pembrolizumab duration of 
(S)AEs collection and reporting after end of REP 
is 90 days
Section to be changed
Section 5.3.2
Description of change
Correction of the blood volume for PK 
assessment
Rationale for change
Editorial error
Section to be changed
Section 5.4.2
Description of change
There will be no assessment of biomarkers in 
blood samples. 
Rationale for change
Because of the early termination of the study, this 
assessment is no longer needed.  
Section to be changed
Section 6.2.3
Description of change
Separate EOR visit from FUP visit
Rationale for change
To clarify that FUP visit and EOR visit are 
independent
Section to be changed
Section 8.6
Description of change
Change in the definition of “The end of the trial”
Rationale for change
In line with the early termination of the study 
patients will no longer be followed for 24 months
Section to be changed
Section 10.1
Description of change
PK sampling to be done shortly before trial drug 
administration rather than fixed time of 5 min 
prior to dosing
Rationale for change
Provide flexibility in the timing of PK sampling. 
Section to be changed
Section 10.4
Description of change
Clarification on imaging after evidence of 
radiological PD.
Rationale for change
To be consistent with changes in Sections 5.1.1 
and 5.1.2. 
Section to be changed
Section 10.9.1
Description of change

Include 150 mg in prior derivation for 
afatinib

Data from 1200-237 will be incorporated 
in calculation of the posterior
Rationale for change

To include in the BLRM the 2 doses 
tested in the trial i.e 150 mg and 200 mg 

Clarify how data from 1200.237will be 
included in statistical calculation


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11.2
GLOBAL AMENDMENT 2
Date of amendment
11 Apr 2019
EudraCT number
EU number
2016-005042-37
BI Trial number
1200.283
BI Investigational Product(s)
Afatinib + pembrolizumab
Title of protocol
LUX-Lung IO: A phase II, open label, non-
randomised study of afatinib in combination with 
pembrolizumab in patients with locally advanced 
or metastatic squamous cell carcinoma of the lung
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Section 3.1
Description of change
Updated language for the SMC recommendation 
to stop the trial and not open the Main part of the 
study.
Rationale for change
Correction to add text not previously incorporated 
in Version 2 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c13055147
3.0
clinical-trial-protocol-version-03
LUX-Lung IO: A phase II, open label, non-randomised study of afatinib in
combination with pembrolizumab in patients with locally advanced or metastatic
squamous cell carcinoma of the lung
Approval-Team Member Medicine
12 Apr 2019 16:23 CEST
Approval-Clinical Trial Leader
12 Apr 2019 16:34 CEST
Approval-Biostatistics
12 Apr 2019 16:47 CEST
Approval-Therapeutic Area 
15 Apr 2019 08:57 CEST
Verification-Paper Signature
Completion
15 Apr 2019 19:57 CEST


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c13055147
3.0

SAP_000.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c27745069-01
BI Trial No.:
1200.283
Title:
LUX-Lung IO: A phase II, open label, non-randomised study of
afatinib in combination with pembrolizumab in patients with
locally advanced or metastatic squamous cell carcinoma of the lung
Including protocol amendment version 3.0 [c13055147-03]
Investigational 
Product:
Afatinib in combination with pembrolizumab
Responsible trial 
statistician(s):
Telephone: 
Fax: 
Email: 
Date of statistical 
analysis plan:
14 May 2019 SIGNED
Version:
Final
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1. TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1. 
TABLE OF CONTENTS ......................................................................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) .................................................................................9
5.2
SECONDARY ENDPOINT(S) ...........................................................................9
5.2.1
Key secondary endpoint(s) .............................................................................9
5.2.2
Other secondary endpoint(s)..........................................................................9
6.
GENERAL ANALYSIS DEFINITIONS...........................................11
6.1
TREATMENTS..................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS...................................................11
6.3
PATIENT SETS ANALYSED..........................................................................13
6.5
POOLING OF CENTRES ................................................................................13
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................13
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................13
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 ENDPOINT(S) .........................................................................16
7.5.1
Key secondary endpoint(s) ...........................................................................16
7.5.2
Other Secondary endpoint(s) .......................................................................16
7.7
EXTENT OF EXPOSURE................................................................................19
7.8
SAFETY ANALYSIS.........................................................................................19
7.8.1
Adverse events ...............................................................................................19
7.8.2
Laboratory data.............................................................................................24
7.8.3
Vital signs.......................................................................................................25
7.8.4
ECG ................................................................................................................25
8.
REFERENCES.....................................................................................26
10.
HISTORY TABLE...............................................................................27


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LIST OF TABLES
Table 6.2: 1  Important protocol deviations.............................................................................12
Table 7.4: 1  Rules to determine Best overall response...........................................................16
Table 7.5.2: 1   Rules to determine events and censoring for sensitivity analyses of PFS......18
Table 7.8.1: 1 Adverse event of special search category.........................................................21
Table 7.8.2: 1 List of laboratory tests ......................................................................................24
Table 10: 1 History table..........................................................................................................27


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
RPM
Report Planning Meeting
CR
Complete Response
CRF
Case Report Form
CTCAE
Common Terminology Criteria Adverse Events
CTP
Clinical Trial Protocol
DCR
Disease Control Rate
DOR
ECOG
EGFR
Duration of Response
Eastern Cooperative Oncology Group
Epidermal Growth Factor Receptor, also known as ERBB1
EMA
ERBB2
ERBB3
European Agency for the Evaluation of Medicinal Products
Second member of the ERBB family of proteins
Third member of the ERBB family of proteins
HLT
High Level Term
ICF
Informed Consent Form
ICH
IPD
International Conference on Harmonisation
Important Protocol Deviations
MedDRA
MQRM
Medical Dictionary for Regulatory Activities
Medical Quality Review Meeting
NCI
NE
National Cancer Institute
Not Evaluable
NN
ORR
Non-CR/Non-PD
Objective Response Rate
OS
Overall Survival
PD
Progressive Disease
PDL1
Programmed Death Ligand 1
PFS
Progression Free Survival
PK
Pharmacokinetics
PSTAT
Project Statistician
PR
Partial Response
PT
Preferred Term


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Term
Definition / description
PV
Protocol Violation
RECIST
Response Criteria for Solid Tumours
SD
Stable Disease
SMQ
Standardised MedDRA query
TOC
Table of Contents
TMW
Trial Medical Writer
TSAP
Trial Statistical Analysis Plan


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3.
INTRODUCTION
As per ICH E9, 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., 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size.
The validated SAS® version will be used that is in place on the BI system at the time of 
analyses.  Currently Version 9.4 is being used.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The phase II, single arm trial was originally designed with two parts: i) Safety run-in to 
decide the RP2D of the combination therapy for the main part and ii) main part of phase II.
At the end of safety run-in, after careful consideration of benefit-risk assessment and current
available treatment options, SMC recommended to stop the trial. Below are some of the main 
changes compared to planned analysis in study protocol version 2.0, considering that the trial 
will not go to the main part:

Analysis and decision on RP2D was not conducted as the trial will not go to the main 
part of the phase II.

Analysis of duration of response will not be done, as there are not enough number of 
responses to do this analysis.

No extensive subgroup analysis for primary endpoint will be done for PD-L1 
expression, and for subgroups defined by the biomarkers related to immune status. 

Subgroup analysis for other efficacy endpoint e.g. PFS, OS, ORR, DOR involving 
PD-L1 expression and subgroups defined by the biomarkers related to immune status
will not be done due to small number of patients.

No analysis, except a listing, will be done for irRECIST criteria.

The analysis of PK assessment, mentioned in section 7.3.3 of the protocol, will not be 
done. A listing with the information on actual time of collection of PK-sample with 
the values of plasma concentration will be reported. 


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5.
ENDPOINT(S)
This trial is an open-label, single arm phase II study assessing the tolerability and anti-tumour
activity of afatinib when given in combination with a fixed dose of pembrolizumab in
patients with squamous NSCLC, who progressed during or after first line platinum-based
standard therapy and had no prior treatment with an immune checkpoint inhibitor or EGFR
targeted therapy.
This trial consists of two parts: 
1) Safety run-in:  Maximum of 24 patients will be treated in the first part. 
a) At first 12 patients will be treated, for at least one full cycle, at the starting dose of 
40 mg of afatinib and 200 mg of pembrolizumab. Along with the results from 
Bayesian logistic model (BLRM), safety-monitoring committee (SMC) will assess 
the overall safety and tolerability of this dose. If the starting dose is tolerable and 
safe, it will be declared as RP2D. 
b) If the starting dose of afatinib (40 mg) is intolerable, 12 more patients will be 
included in the safety run-in and they will receive a starting dose of afatinib of 30 
mg along with 200 mg of pembrolizumab. After they have been treated for at least 
one full cycle, the SMC will assess the overall safety profile along with results 
from BLRM to confirm this combination as RP2D and the study will go to main 
part. 
If this reduced dose (30 mg afatinib with 200 mg of pembrolizumab) is also too 
toxic no additional patients will be enrolled and the study will be stopped and will 
not go to main part.
Note that this safety run-in is to determine the safe dose of afatinib in combination 
with standard dose of pembrolizumab.
2) Main part: Once the RP2D has been established, this will be the starting dose of 
afatinib for future patients entered to the main part of the trial. In total, 38 patients 
will be included in the main part to assess efficacy and safety of this treatment 
combination.
If the RP2D is defined as the original starting dose of afatinib (40 mg daily) in combination
with pembrolizumab, the trial will include 12 patients from the safety run in and 38 patients
from the main part, leading to 50 patients in total. However if the RP2D is defined as 30 mg
of afatinib in combination with pembrolizumab, the trial will include 62 patients in total (12
patients at 40 mg and 50 patients at 30 mg).
Decision after safety run-in: Safety monitoring committee reviewed safety and efficacy data 
of 24 patients from two cohorts of safety run-in phase. In the first cohort, 12 patients were 
treated with a starting dose of 40 mg of afatinib and 200 mg of pembrolizumab and in the 
second cohort, 12 additional patients were treated with a starting dose of 30 mg of afatinib 


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and 200 mg of pembrolizumab. After careful assessment of benefit-risk, and considering 
current available treatment options for the population, the committee advised to stop the trial. 
The analysis for this trial will include patients from the safety run-in phase.
5.1
PRIMARY ENDPOINT(S)
The primary endpoint for this study is to assess the efficacy of afatinib in combination with 
pembrolizumab as measured by Objective Response rate (ORR). ORR is defined as the 
proportion of patients with the best overall response of complete response (CR) or partial 
response (PR) from first drug intake until the earliest of disease progression, death, or last 
evaluable tumour assessment before start of any new subsequent anti-cancer therapy, lost to 
follow-up, or withdrawal of consent.
RECIST 1.1 (2) will be used to determine all response and progression endpoints.
Note: As the study will not go to the second stage, protocol mentioned “supportive analysis
with summaries” will not be done with supplemented immune-related RECIST (irREICST 
(9)) criteria; though a detailed listing will report all the assessments, following RECIST and 
irRECIST criteria, done in this study.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
The key secondary objectives are to confirm the recommended phase II dose (RP2D) of daily 
afatinib when combined with pembrolizumab given in 3-weekly cycles and assess the safety
profile of the combination treatment.
5.2.2
Other secondary endpoint(s)
Other secondary endpoints are: 

Disease control rate (best overall response of CR, PR (confirmed) or SD).

Progression-free survival (PFS), defined as the time from the treatment start date to 
the date of disease progression, or to the date of death from any cause, whichever 
occurs earlier.

Overall survival (OS), defined as the time from the date of treatment start date to the 
date of death.

Tumour shrinkage.
Note: As the trial will not go to the main part, no formal analysis will be done for protocol 
specified secondary endpoint “Duration of (confirmed) objective response” and no decision/ 
analysis on “Recommended Phase II Dose (RP2D)” will be done as well for this trial.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
All outputs will be presented by the starting dose of afatinib (30 mg or 40 mg) in combination 
with pembrolizumab, with patients grouped according to their actually assigned treatment. A
"Total" treatment column will be introduced if different afatinib starting doses should be used
within the trial.
The following definitions and study periods based on actual start and stop dates of afatinib
and pembrolizumab administration are defined:

First administration of study treatment: Date when first dose of afatinib or 
pembrolizumab, whichever occurs earlier, been administered.

Last administration of study treatment: Date when last dose of afatinib or 
pembrolizumab, whichever occurs later, been administered.

Screening: Day of informed consent to day prior to the first administration of study 
treatment.

On-treatment period: Day of first administration of study treatment to (the last 
administration of study treatment + 30 days).

Residual effect period: day after last administration of study treatment to the 30th day 
after last administration of study treatment.

Post-study: on or after the 31st day after last administration of study treatment.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Patients with potentially important protocol deviations (IPDs) will be documented.  The 
following list of potentially IPDs will be used; note that this is a working list and may not be 
finalised until the final Report Planning Meeting (BRPM) prior to database lock.


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Table 6.2: 1 Important protocol deviations
Category/code
Description
Comment
Manual/ 
Automatic
A
Entrance criteria not 
met
Automatic
A1
Diagnosis of trial
disease questionable
Refer to IN  1, 2, 3
Manual
A2
Patient not eligible
Refer to IN 4,5
Automatic 
for IN 4 and 
Manual for 
IN5
A3
Prohibited baseline
condition, diagnosis
or treatment
Refer to IN 6, 7, 8 or EX 1-24
Automatic
for IN 6, 7, 
8. Manual 
for EX24.
A4
Not reached legal age
of consent
Refer to IN 9
Automatic
A5
Pregnancy
Violation of IN 11 or EX 25
Manual
B
Informed consent
B1
Informed consent not 
available/not done
Informed consent not signed
Automatic
B2
Informed consent too
late
Informed consent date after screening visit 
date
Automatic
C
Trial medication
C1
Incorrect trial
medication taken
Treatment was not paused, dose reduced, or
discontinued according to protocol. This will 
be collected manually and reviewed at 
MQRMs.
Manual
C2
Non-compliance 
Overall Afatinib compliance rate < 80%
Manual
D
Concomitant 
medication
D1
Use of prohibited 
concomitant medications  
Review concomitant medications for 
prohibited medication use. Refer to section 
4.2.2.1
Manual
E
Trial specific
E1
Prohibited  anticancer 
interventions 
Patient received therapeutic radiation or 
another anti-cancer treatment before 
termination of study treatment
Manual


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6.3
PATIENT SETS ANALYSED
Treated set: this includes all patients who received at least one dose of afatinib or 
pembrolizumab. 
The “treated set” will be used for all efficacy and safety analyses.
Note: Safety monitoring committee reviewed safety and efficacy data for 24 patients from 
safety run-in phase. After careful assessment, of benefit-risk and considering current 
available treatment option for the population, the committee advised to stop the trial. The 
analysis for this trial will include patients treated in “safety run in” phase only.
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing efficacy data will not be imputed and all reasonable efforts will be taken during the 
study to obtain such data.  Patients with unknown vital status or time to progression will be 
censored for time to event analyses; further details are provided in Section 7.  
Missing or incomplete AE dates will be imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”). (3)
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baseline values will be the measurements taken most recently prior to first dose of study 
treatment (refer to section 6.1 for definition).
Study day will be calculated relative to the date of the first administration of study treatment.
The day, prior to first administration of study treatment, will be ‘Day -1’ and the day of first 
administration of study treatment will be ‘Day 1’; therefore ‘Day 0’ will not exist.
Time windows and visits will be calculated to determine the planned day of tumour 
measurement and response status, based on the protocol-specified tumour imaging schedule. 
Imaging data will be displayed as screening, Week 9, 18, 27… etc. First imaging is scheduled 
to be performed at week 9 (56-63 days after C1_V1) and every 9-weeks intervals (63 ± 7 
days, 126 days ± 7 days etc.) thereafter until PD/start of subsequent anti-cancer treatment. 


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After first documentation of PD, as per RECIST 1.1, repeat imaging is needed at ≥4 weeks to 
confirm PD as per irRECIST.


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7.
PLANNED ANALYSIS
In general the display format of the analysis results will follow BI guideline (7, 8) as much as 
possible.
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / Standard deviation 
(StD) / Min / Median / Max.
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to Mean, StD, Min and Max.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage. Percentages will 
be rounded to one decimal place. The category missing will be displayed only if there are 
actually missing values.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. Demographic parameters
collected and to be presented include

Gender (Male, Female)

Race and ethnicity (as defined in the eCRF)

Age [years]

Height [cm]

Weight [kg]

Body mass index [kg/m2] (defined as weight [kg]/(height [cm]/100)2)

Smoking history  (Never-smoked, Ex-smoker, Currently smokes)

Alcohol History (Non-drinker,  drinks – no interference, drinks – possible 
interference)

Country
7.2
CONCOMITANT DISEASES AND MEDICATION
Descriptive statistics using standard summary tables for all treated patients are planned for 
this section of the report.
7.3
TREATMENT COMPLIANCE
Descriptive statistics using standard summary tables for the treated set of patients are planned 
for this section of the report.  A summary of whether patients took study drugs, afatinib and 
pembrolizumab, according to the protocol and whether they missed any doses will be 


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produced for each planned visit.  In addition, a summary of overall percentage compliance 
will be produced using visit dates and the total number of doses missed during the study.
7.4
PRIMARY ENDPOINT(S)
The primary endpoint for this study is Objective Response rate (ORR), defined as the 
proportion of patients with best overall response of complete response (CR) or partial 
response (PR) from first drug intake until the earliest of disease progression, death, or last 
evaluable tumour assessment before start of subsequent anti-cancer therapy, lost to follow-up, 
or withdrawal of consent. Confirmation of the response is needed with a repeat assessment at 
the next imaging time point (or ≥4 weeks later). Table 7.4:1 describes different best overall 
responses.
Table 7.4: 1 Rules to determine Best overall response
Item
Best Overall Response
Definition
1
Complete response (CR)
At least two determinations of CR at least 4 
weeks apart before progression, death or start 
of new anticancer therapies.
2
Partial response (PR)
At least two determinations of PR at least 4 
weeks apart before progression, death or start 
of new anticancer therapies. Some examples:
1)
PR-SD-PR: BOR will be PR 
provided 4 weeks gap between two 
PR-determinations.
2)
PR-CR-PD: BOR will be PR 
provided 4 weeks gap between PR
and CR determinations.
3
Stable Disease (SD)
At least one SD assessment (or better) > 6
weeks after treatment start date and not 
qualifying for CR or PR.
4
Progressive Disease (PD)
Progression < 12 weeks and not qualifying 
for CR, PR and SD.
5
UNKNOWN (UNK)
If not satisfied above 4 items.
Note: Use “else if” conditions starting from Item 1.
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
The key secondary objectives are to confirm the recommended phase II dose (RP2D) of daily 
afatinib when combined with pembrolizumab given in 3-weekly cycles and assess the safety 
profile of the combination treatment.
7.5.2
Other Secondary endpoint(s)

Disease control rate (DCR) is defined as the proportion of patients with best overall 
response of CR, PR, or stable disease (SD) from first administration of study 


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treatment until the earliest of disease progression, death or last evaluable tumour 
assessment before start of subsequent anti-cancer therapy, lost to follow-up or 
withdrawal of consent.
A summary of disease control rate using the investigator assessment of response will 
be produced.

Progression-free survival (PFS), defined as the time (months) from the date of first 
administration of study treatment to the date of disease progression, or to the date of 
death from any cause, whichever occurs earlier. The date of progression for the 
primary analyses will be determined based on assessments made by the investigators.  
All treated patients will be included.
Kaplan–Meier curve and associated summary table will be produced for PFS.
Table 7.5.2: 1 describes rules that can be used for sensitivity analyses to determine 
whether or not patients have had a PFS event (progression or death) along with the 
date of event or date of censoring (for those with no event).  

Overall survival (OS), defined as the time from the date of treatment start date to the 
date of death.
      Kaplan–Meier curve and associated summary table will be produced for overall survival.

Tumour shrinkage
Waterfall plots (and associated tables) of the maximum percentage reduction from baseline 
sum of target lesion diameters will be presented for each cohort.


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Table 7.5.2: 1   Rules to determine events and censoring for sensitivity analyses of PFS
Rule #
Situation
Outcome 
(event or 
censored)
Date of PFS event or 
censoring
1
No baseline tumour assessment (no death 
before second scheduled assessment)
censored
Date of the start of study 
treatment
2
Progressed from  imaging (no missed 
radiologic assessments)
event
Date of PD
3a
Non-PD from  imaging1, death before next 
scheduled assessment
event
Date of death
3b
Non-PD from  imaging1, one missed 
assessment, death or progression after date 
of missed assessment, but before a second 
scheduled assessment
event
Date of PD or death
3c
Non-PD from  imaging1, more than one 
consecutive missed assessment, death or 
progression after date of second missed 
assessment
censored
Date of last imaging before 
missed assessment
3d
Non-PD from  imaging1, more than one 
consecutive missed assessment, non-PD 
according to imaging after missed 
assessments
censored
Date of last non-PD imaging
4
New anti-cancer medication before 
progression or death
censored
Date of last imaging before 
new anti-cancer medication
5
Death before the scheduled date of first 
imaging
event
Date of death
6a
No imaging performed post-baseline, patient 
dies between first and second scheduled 
assessments
event
Date of death
6b
No imaging performed post-baseline, patient 
dies after second scheduled assessment
censored
Date of the start of study 
treatment
6c
No imaging performed post-baseline, vital 
status is unknown or patient known to be 
alive
censored
Date of the start of study 
treatment
7
Alive and not progressed from  imaging (no 
missed assessments)
censored
Date of last imaging
  1 From the last assessment at which CR, PR or SD was assessed.


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7.7
EXTENT OF EXPOSURE
Total treatment time (days and number of courses) will be calculated for each patient; 
off-drug periods due to non-compliance or toxicity prior to permanent discontinuation will be 
included as treatment time.  In addition, the total treatment time will be summed over all 
patients and transformed to patient years.  Standard descriptive summaries of these data will 
be provided for the treated set of patients.
Further summaries will also be produced:

Treatment time (days) broken down by each dose level of study treatment (40 mg and 
30 mg of afatinib with pembrolizumab).

Number and proportion of patients on each dose level over time.

Time to first dose reduction and duration (days) of off-drug periods prior to first dose 
reduction.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. 
7.8.1
Adverse events
The analyses of adverse events (AEs) will be descriptive in nature. All analyses of AEs will 
be based on the number of patients with AEs and NOT on the number of AEs.
The analyses will be based on BI standards. Adverse events will be coded with the most 
recent version of MedDRA. The severity of AEs will be scaled according to CTCAE version 
4.05.
Furthermore, for analysis of AE attributes such as duration, severity, etc. multiple AE 
occurrence data on the CRF, will be collapsed into AE episodes provided that all of the 
following applies:
•
The same MedDRA lowest level term was reported for the occurrences.
•
The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 
occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence).
•
Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence.


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AE episodes will be condensed into AE records provided that the episodes were reported with 
the same term on the respective MedDRA level and that the episodes are assigned to the same 
treatment. For further details on summarization of AE data, please refer to the guideline 
'Handling and summarization of adverse event data for clinical trial reports and integrated 
summaries'. (4)
For further details on summarization of AE data, please refer to (3, 4).
The analysis of AEs will include all events with onset in the on-treatment period (between 
treatment start date and (last date of trial medication + 30 days)) and residual effect period.  
Events occurring before first drug intake will be assigned to ‘screening', and all events 
occurring after the residual effect period will be assigned to ‘Post-study/follow-up’. 

An overall summary of AEs will be presented. 
The frequency of patients with AEs will be summarised by highest CTC grade (grade 3, 4, 5 
and all grades to allow both cohorts to fit on one page), treatment, primary system organ class 
and preferred term (PT). Separate tables will be provided for patients with each of the 
following AE categories:

AEs by treatment, highest CTCAE grade, using SOC and PT

Drug related AEs, as assessed by investigators, by treatment, highest CTCAE, using SOC 
and PT

AEs leading to dose reduction by treatment, highest CTCAE, using SOC and PT

AEs leading to discontinuation of either study drug by treatment, highest CTCAE, using 
SOC and PT

AEs leading to discontinuation of afatinib by treatment, highest CTCAE, using SOC and 
PT

AEs leading to discontinuation of pembrolizumab by treatment, highest CTCAE, using 
SOC and PT

Serious AEs by treatment, highest CTCAE, using SOC and PT

Non-serious AEs by treatment, highest CTCAE, using SOC and PT

Drug related serious AEs by treatment, highest CTCAE, using SOC and PT

AEs leading to death by treatment, SOC and PT

Other significant AEs using SOC and PT (see definition below)

Protocol specified adverse events of special interest(discussed below)

AEs of special search category (discussed below)
The system organ classes will be sorted according to the standard sort order specified by 
European Medicines Agency (EMA), preferred terms will be sorted by frequency (within 
system organ class).
Protocol defined adverse events of special interest
Some pre-defined AEs are considered to be of special interest (AESIs). The following are 
considered as AESIs:


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
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:
For patients with normal liver function (ALT, AST, bilirubin within normal limits) at
baseline:
i)
An elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as determined 
by way of protocol-specified laboratory testing or unscheduled laboratory testing.
For patients with abnormal liver function at baseline (AST and/or ALT>ULN)):
ii)
An elevated AST or ALT lab value that is greater than or equal to 5X the upper 
limit of normal and an elevated total bilirubin lab value greater than or equal to 
2X upper limit of normal measured in the same blood draw sample, with the 
exclusion of causes due to underlying diseases.

Dose Limiting Toxicities
Dose Limiting Toxicities (DLT) occurring during the first cycle in patients 
included in the safety run in will be considered protocol specified AESI. Please 
refer to section 5.2.5 in clinical trial protocol.
Separate summary tables will be reported for hepatic injury and dose limiting toxicity. A 
separate listings will be prepared for patients who are identified as having experienced any of 
the following AEs.  
AEs of special search category
A separate summary and listing will be reported for “AEs of special search category”.
Identification will be based upon modified MedDRA SMQ and HLT groupings.  Details of 
AESI are provided in table 7.8.1: 1.
Table 7.8.1: 1 Adverse event of special search category
Search Category
Search criterion 
1.
Diarrhoea
-
PT Diarrhoea
-
PT Diarrhoea in association with PT 
dehydration
-
PT Diarrhoea in association with SMQ 
(broad) Acute renal failure
2.
Skin toxicity, including rash/acne 
2.1. Severe skin reactions
-
SMQ (narrow) Severe cutaneous adverse 
reactions


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Table 7.8.1: 1 Adverse event of special search category (Contd.)
Search Category
Search criterion 
Skin toxicity, including rash/acne (contd.)
2.2. Rash/acne (contd.)
-
PT Acne
-
PT Acne conglobata
-
PT Acne cystic
-
PT Acne fulminans
-
PT Acne infantileTria
-
PT Acne pustular
-
PT Acne varioliformis
-
PT Dermatitis acneiform
Skin toxicity, including rash/acne (contd.)
-
PT Blister
-
PT Dermatitis 
-
PT Dermatitis bullous 
-
PT Dermatitis exfoliative 
-
PT Dermatitis exfoliative generalised 
-
PT Dermatosis 
-
PT Drug eruption 
-
PT Eczema
Skin toxicity, including rash/acne (contd.)
-
PT Epidermal necrosis
-
PT Erythema
-
PT Exfoliative rash
-
PT Folliculitis
-
PT Generalised erythema
-
PT Mucocutaneous rash
-
PT Oedema blister
Skin toxicity, including rash/acne (contd.)
-
PT Rash
-
PT Rash erythematous
-
PT Rash follicular
-
PT Rash generalised
-
PT Rash macular
-
PT Rash maculo-papular
-
PT Rash maculovesicular
-
PT Rash morbilliform
-
PT Rash papular
-
PT Rash papulosquamous
-
PT Rash pruritic
Skin toxicity, including rash/acne (contd.)
-
PT Rash pustular
-
PT Rash rubelliform
-
PT Rash scarlatiniform
-
PT Rash vesicular
-
PT Skin disorder
-
PT Skin erosion
-
PT Skin exfoliation
-
PT Skin fissures
Skin toxicity, including rash/acne
-
PT Skin induration
-
PT Skin irritation
-
PT Skin lesion
-
PT Skin necrosis
-
PT Skin reaction
-
PT Skin swelling
-
PT Skin toxicity
-
PT Skin ulcer


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Table 7.8.1: 1 Adverse event of special search category (Contd.)
Search Category
Search criterion 
3.
Pneumonitis / ILD like events
-
SMQ (broad) for Interstitial lung disease
4.
Hepatic impairment
-
SMQ (Broad) Liver related investigations, 
signs and symptoms
-
SMQ (Broad) Hepatic failure, fibrosis and 
cirrhosis and other liver damage-related 
conditions
-
SMQ (Broad) Hepatitis, non-infectious
-
SMQ (Broad) Cholestasis and jaundice of 
hepatic origin
5.
Paronychia
-
PT Nail bed infection
-
PT Nail infection
-
PT Paronychia
6.
Pyrexia
-
PT Pyrexia
-
PT Body temperature increased
-
PT Hyperthermia
Other significant AEs
Other significant AEs are defined as serious and non-serious AEs that lead to dose reduction
or permanent discontinuation of study medication. Their incidence will be reported by
severity according to CTCAE grades. A listing of patients who developed ‘other significant’ 
AEs will be provided and a flag for serious and non-serious will be included.


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (6). CTCAE version 4.05 grades will be applied to laboratory parameters using the 
current BI oncology standard as detailed in the document ‘Conversion of laboratory 
parameters to CTCAE grades within BI’ (5).
Primary laboratory tests are defined as:
Table 7.8.2: 1 List of laboratory tests
Category
Parameters
Hematology
Red blood cell count (RBC), haemoglobin,
haematocrit, platelet count, reticulocytes, white 
blood cell count (WBC) with differential 
(neutrophils, bands, lymphocytes, monocytes, 
eosinophils, basophils)
Coagulation
International Normalised Ratio (INR), activated 
Partial Thromboplastin Time (aPTT)
Electrolytes
Sodium, potassium, calcium, magnesium,
chloride, bicarbonate (HCO3)
Liver function tests
Alkaline phosphatase, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), γ-
glutamyltransferase (GGT), total bilirubin
Renal function parameters
Blood urea (preferred) or blood urea nitrogen (BUN), 
creatinine; creatinine clearance at screening
Pancreatic function parameters
Amylase, Lipase
Other
Glucose, albumin, cholesterol, triglycerides,
phosphorus, lactate dehydrogenase (LDH), total 
protein, uric acid, creatine phosphokinase (CPK)
Urinalysis
pH, protein, glucose, blood, leucocytes, nitrite; in 
case of pathological finding further evaluation should 
be performed and results documented
Pregnancy test
β-HCG testing in urine or serum in women of 
childbearing potential (WOCBP)
Thyroid function testing
Triiodothyronine (T3) or Free Triiodothyronine 
(FT3), Free thyroxine (FT4), Thyroid stimulating
hormone (TSH)
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.


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Frequency and time of onset of liver enzyme elevations will be tabulated. Additional, more 
in-depth analyses will be performed as needed. These analyses will examine the influence of 
extent of exposure and time to event onset.
Note: Section 5.2.3 in protocol has detailed list of lab parameters which will be summarized 
beside important lab parameter mentioned above. 
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
ECG data will be collected as described in CTP section 5.2.4. Clinically significant findings 
in ECG data will be reported under “Adverse events” if applicable and will be analysed 
accordingly. 


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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
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D et al.: New 
response evaluation criteria in solid tumors: revised RECIST guideline (version 
1.1). Eur J Cancer 2009; 45:228-247 [R09-0262].
3
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
4
001-MCG-156: "Handling and summarization of adverse event data for clinical 
trial reports and integrated summaries", current version; IDEA for CON.
5
BI Guidance document “Conversion of laboratory values to CTCAE grades within 
Boehringer Ingelheim”.
6
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current 
version; IDEA for CON.
7
001-MCG-159: “Reporting of Clinical Trials and Project Summaries”, current 
version; IDEA for CON.
8
001-MCG-159_RD-03: “Standard table shells for inferential and descriptive End-
of-Text tables (EoT-Catalogue)”, current version; IDEA for CON.
9
Bohnsack O, Ludajic K, Hoos A. “Adaptation of the immune-related response
criteria: irRECIST. 39th Ann Cong of the European Society for Medical
Oncology (ESMO)”, Madrid, 26 - 30 Sep 2014 (Poster)


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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 V1.0
14-May-19
None
This is the final TSAP without any 
modification