Conditions: Metastatic Non Small Cell Lung Cancer
Keywords: Dacomitinib Metastatic Non Small Cell Lung Cancer EGFR-activating mutations NSCLC
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 101
Healthy volunteers: no

Brief summary:
This is a Phase 4, open label, single arm, multi-center, prospective clinical trial of dacomitinib that will be performed in India. This study will enroll a sufficient number of participants to ensure that 100 participants are treated with dacomitinib. The primary objective of this study is to assess the safety and tolerability of dacomitinib. The secondary objective is to evaluate antitumor activity of dacomitinib by objective response rate and duration of response.

Detailed description:
This is a Phase 4, open label, single arm, multi-center, prospective clinical trial of dacomitinib that will be performed in India. This study will enroll a sufficient number of participants to ensure that 100 participants are treated with dacomitinib. The primary objective of this study is to assess the safety and tolerability of dacomitinib. The secondary objective is to evaluate antitumor activity of dacomitinib by objective response rate and duration of response. Drug administration: Dacomitinib will be supplied by Pfizer and administered in accordance with the India Local Product Document (LPD). The recommended dosage of dacomitinib is 45 mg taken orally once a day at approximately the same time each day, until disease progression, participant refusal/lost to follow-up, or unacceptable toxicity occurs.

STUDY PROCEDURES:

Screening: Participants will be screened within 28 days prior to first dosing of dacomitinib to confirm that they meet the eligibility criteria for the study.

Follow-up Visit: All participants will return to the study site up to 28 days after the last dose of study drug administration for assessment of potential AEs, recording of concomitant treatment use and to confirm appropriate contraception usage.

ASSESSMENTS Tumor Assessments: Tumor assessments will include all known or suspected disease sites. Computerized tomography (CT) or Magnetic resonance imaging (MRI) scans of Chest Abdomen and Pelvis and MRI of the brain will be performed at Screening and repeated every 12 weeks ±1 week until the end of treatment. For all tumor assessments, the method of assessment that was used at Screening will be used throughout the study. Tumor assessment will be repeated at the end of treatment if more than 6 weeks have passed since the last evaluation. Assessment of response will be made using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Confirmation of response will be required ≥4 weeks after initial response is observed.

Safety Assessments: The following parameters will be assessed - Physical examination, vital signs, Eastern Cooperative Oncology Group Performance score (ECOG PS), safety lab data, 12 lead electrocardiogram (ECG). Unscheduled clinical laboratory measurements may be obtained at any time during the study to assess any perceived safety concerns.

Adverse event reporting: All observed or volunteered AEs regardless of treatment group or suspected causal relationship to the investigational product(s) will be reported as per regulatory requirements.

End of Study: The end of study is defined as 1 year after the last participant first visit (LPFV) date in the study. At the end of study, participants who are on treatment and benefiting from dacomitinib treatment will be switched to commercially available dacomitinib if considered appropriate by the investigator, as soon as feasible.

Arms:
arm 1: The recommended dosage of dacomitinib is 45 mg taken orally once a day at approximately the same time each day, until disease progression, participant refusal/lost to follow-up, or unacceptable toxicity occurs.

Interventions: intervention 1: Dacomitinib
Intervention descriptions: intervention 1: Dacomitinib is a kinase inhibitor indicated for the first line treatment of patients with metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations.

Protocol document:
Prot_000.pdf: 
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SINGLE ARM STUDY TO EVALUATE THE SAFETY OF DACOMITINIB FOR 
THE FIRST-LINE TREATMENT OF PARTICIPANTS IN INDIA WITH 
METASTATIC NON-SMALL CELL LUNG CANCER WITH EPIDERMAL 
GROWTH FACTOR RECEPTOR (EGFR)-ACTIVATING MUTATIONS
Protocol Number:
A7471064
Medicinal product:
Dacomitinib (PF-00299804)
United States (US) Investigational New 
Drug (IND) Number:
Not Applicable (N/A)
European Clinical Trial Database 
(EudraCT) Number:
Not Applicable (N/A)
Universal Trial Number:
Not Applicable (N/A)
Phase:
Phase 4
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.


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Document History
Document
Version Date
Summary of Changes
Original protocol
01 April 2020
Not Applicable (N/A)


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Abbreviations
This is a list of abbreviations used in the protocol template.  All of these abbreviations may 
or may not be used in the protocol.  
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATP
adenosine triphosphate
CAP
Chest, Abdomen, Pelvis
CI
confidence interval
CNS
central nervous system
CR
complete response
CRF
case report form
CSA
clinical study agreement
CT
computerized tomography
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DCIS
ductal carcinoma in situ
DDR
discoidin domain receptor
DoR
duration of response
EC
ethics committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDP
exposure during pregnancy
EGFR
epidermal growth factor receptor
EPHA6
ephrin type-A receptor 6
EudraCT
European Clinical Trials Database
GCP
Good Clinical Practice
H2
histamine 2
HDPE
High Density PolyEthylene
HER
human epidermal growth factor receptor
HR
hazard ratio
ICH
International Council for Harmonisation
IEC
independent ethics committee
IND
investigational new drug application
INR
international normalized ratio
IRB
institutional review board
IRC
Independent Radiologic Central
IUD
intrauterine device


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Abbreviation
Term
IVRS
interactive voice response system
IWRS
interactive web response system
LCK
lymphocyte cell-specific protein tyrosine kinase
LFT
liver function test
LPD
Local Product Document
LPFV
last participant first visit
MedDRA
Medical Dictionary for Regulatory Activities
MNK
mitogen-activated protein kinase-interacting serine/threonine-protein 
kinase
MRI
magnetic resonance imaging
N/A
Not Applicable
NCI
National Cancer Institute
NE
not evaluable
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PASS
Post-Authorization Safety Study
PD
progressive disease
PET
positron emission tomography
PFS
Progression-Free Survival
PPI
proton pump inhibitor
PR
partial response
PS
performance status
PT
prothrombin time
QTc
QT interval corrected for heart rate
QTcF
QT interval calculated using Fridericia’s correction factor
RECIST
Response Evaluation Criteria in Solid Tumor
RNA
ribonucleic acid
RTK
receptor tyrosine kinase
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SRSD
single reference safety document
TKI
tyrosine kinase inhibitor
ULN
upper limit of normal


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PROTOCOL SUMMARY
Background
A subpopulation of patients with NSCLC harbors EGFR (also known as 
HER1/erbB1)-activating mutations in their tumors that are important oncogenic drivers for 
NSCLC.  EGFR TKIs, including gefitinib, erlotinib, and afatinib, have been approved for use 
in this disease and are accepted standard first-line therapies, based on demonstrated 
improvement in tumor response and PFS compared with platinum-based doublet 
chemotherapy.1,2,3,4
Dacomitinib is a selective, ATP-competitive, irreversible, small-molecule inhibitor of HER 
of RTKs, including the EGFR (HER1), the HER2 receptor (erbB2), the HER4 receptor 
(erbB4), and their oncogenic variants (eg, EGFR with exon 19 deletion or exon 21 L858R 
substitution mutations).5,6,7 Dacomitinib inhibited the activity of HER1, HER2, and HER4 in 
biochemical kinase assays, demonstrated dose-dependent inhibition of the HER1 and HER2 
RTK phosphorylation in tumor xenografts expressing these RTK targets in vivo, and 
demonstrated inhibition of tumor growth or tumor regression in experimental models of 
cancer.8  In in vitro studies, dacomitinib has shown greater potency when compared with 
gefitinib in NSCLC models characterized by EGFR-sensitive and -resistant mutations.5  
Dacomitinib potentially offers a therapeutic advantage over selective reversible EGFR TKIs 
(such as gefitinib or erlotinib) because the irreversible inhibition and highly selective 
properties of dacomitinib for the EGFR family of kinases result in sustained suppression of 
RTK activity.  The long-lasting inhibition of receptor phosphorylation reduces concern over 
the potentially short plasma half-lives of the first-generation TKIs.  Furthermore, the low 
nanomolar potency and irreversible binding of the intended targets reduce the need for high 
peak plasma levels, which in turn could minimize target-nonspecific toxicities.  It has been 
shown that participants with NSCLC with EGFR-activating mutations may develop treatment 
resistance by the development of a gatekeeper mutation in exon 20 with a secondary point 
mutation T790M.  Preclinical studies using dacomitinib inhibited the growth of cells 
harboring this secondary mutation, but this has not been demonstrated clinically.
Rationale
The pivotal study for regulatory approval of dacomitinib for first-line treatment of patients
with NSCLC with EGFR activating mutations was Study A7471050. Study A7471050 was a 
multinational, randomized, open-label, Phase 3 efficacy and safety study comparing 
dacomitinib with gefitinib in patients with EGFR mutation positive locally advanced or 
metastatic newly diagnosed NSCLC or with recurrent NSCLC if the patient was treated with 
neoadjuvant or adjuvant therapy and had a 12-month disease-free interval. 
This study met its primary objective by demonstrating that dacomitinib was superior to 
gefitinib in prolonging PFS as determined by blinded IRC review in the first-line treatment of 
patients with locally advanced or metastatic EGFR-activating mutation-positive NSCLC 
(HR: 0.589; 95% CI: 0.469, 0.739; 1-sided p <0.0001).  The estimated median PFS was


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14.7 months (95% CI: 11.1, 16.6) for the dacomitinib arm versus 9.2 months (95% CI: 9.1, 
11.0) for the gefitinib arm (data cutoff date: 29 July 2016).
However, since none of the participating study sites of Study A7471050 were located in 
India, the Central Drugs Standard Control Organization (India) requested the Sponsor to 
conduct a clinical study. The goal of Study A7471064, which is also a PASS, is to fulfill this 
regulatory request.
Study Objectives and Endpoints
Primary Objective

To assess safety and tolerability of dacomitinib.
Secondary Objective

To evaluate antitumor activity of dacomitinib by ORR and DoR.
Primary endpoint

Incidence of AEs.
Secondary endpoint

Confirmed ORR and DoR as assessed by the investigator using RECIST version 1.1.
Study Design
This is a Phase 4, open-label, single arm, multicenter, prospective clinical trial of dacomitinib 
for the first-line treatment of adult participants with metastatic NSCLC with EGFR exon
19 deletion or exon 21 L858R substitution mutations.  This study will enroll a sufficient 
number of participants to ensure that 100 participants are treated with dacomitinib. 
Study Treatments
Participants will take dacomitinib at the approved starting dose of 45 mg once a day. 
Participants will be treated until disease progression, participant refusal/lost to follow-up, or
unacceptable toxicity.
Statistical Methods
The study’s objectives are to assess the safety, tolerability and antitumor activityof 
dacomitinib. This study will enroll a sufficient number of participants to ensure that
100 participants are treated with dacomitinib.  The number of participants is based on a
request from the Central Drugs Standard Control Organization (India).  With 
100 participants, the rate of any AE can be estimated with the maximum standard error of 


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0.05.  All participants who receive at least 1 dose of dacomitinib in this study will be
included in the safety and antitumor activity analyses unless otherwise specified.
Analysis of Primary Endpoint:
AEs will be graded by the investigator according to the CTCAE version 4.03 and coded by 
the Sponsor using MedDRA.  The focus of AE summaries will be on treatment-emergent
AEs, those with initial onset or increasing in severity after the first dose of study medication.  
The number and percentage of participants who experienced any AE, SAE, treatment-related 
AE, or treatment-related SAE will be summarized descriptively.
Additional Safety Analyses
Other safety parameters, including study treatment exposure, laboratory tests, ECG, vital 
signs measurements, dose reductions associated with AEs, and temporary and permanent 
discontinuations associated with AEs will be summarized descriptively.  
Analysis of Secondary Endpoint:
Confirmed ORR and DoR as assessed by the investigator using RECIST version 1.1 will be 
summarized.
End of Study
The end of study is defined as 1 year after the LPFV date in the study.  At the end of the
study, participants who are on treatment and benefiting from dacomitinib treatment will be 
switched to commercially available dacomitinib if considered appropriate by the investigator, 
as soon as feasible.


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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  
Refer to Study Procedures and Assessments sections of the protocol for detailed information 
on each procedure and assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities, in order to conduct evaluations or assessments required to protect the 
wellbeing of the participant.
Visit Identifier
Screening
Cycle 1
(28 days)
Day 1 of Every Cycle 
End of 
Treatment
Follow up (up to 
28 days)1
Visit Window
≤28 days
Day 1 
±2 days
±7 days
Informed consent2
X
Tumor history
X
Medical history
X
Physical examination and 
vital signs
X
X
X
X
ECOG PS
X
X
X
X
Contraception check3 for 
women of childbearing
potential
X
X
X
X
Laboratory
Hematology
X
(X)*
X
X
Blood chemistry
X
(X)*
X
X
Pregnancy test4
X
(X)*
X
X
Cardiac Monitoring 
12-Lead ECG5
X
(X)*
Treatment
Dacomitinib
Orally once a day, continuously 
Tumor Assessments
CT or MRI Imaging6
X
(every 12 weeks ±1 week)
X7
Other Clinical Assessments 
AEs8
X
X
X
X
X
Concomitant 
medications and 
non-drug supportive 
interventions9
X
X
X
X
X
*(X) No need to repeat the assessment if it is performed within 7 days prior to Cycle 1 Day 1.
1.
All participants will return to the study site up to 28 days after the last dose of study drug administration for 
assessment of potential AEs, recording of concomitant treatment use and to confirm appropriate 
contraception usage.
2.
Informed consent: informed consent must be obtained prior to undergoing any study-specific procedures 
that are not considered standard of care.
3.
Contraceptive check: female participants of childbearing potential and at risk for pregnancy must agree to 
use a highly effective method of contraception from the time of the first negative pregnancy test at 
Screening, throughout the study and for at least 17 days after the last dose of dacomitinib.
4.
For female participants of childbearing potential, a serum or urine pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed before investigational product administration at the screening visit, on 
Day 1 of every cycle* and at the end of treatment visit.  A negative pregnancy result is required before the 
participant may receive the investigational product.  Pregnancy tests will also be done whenever one 
menstrual cycle is missed during the active treatment period (or when potential pregnancy is otherwise 


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suspected) to confirm the participant has not become pregnant during the study.  In the case of a confirmed 
pregnancy, the participant will be withdrawn from study medication and from the study.  Pregnancy tests 
may also be repeated as per request of IRB/IECs or if required by local regulations. 
5.
Triplicate 12-lead ECGs: 3 consecutive 12-lead ECGs pre-dose will be performed approximately 2 minutes 
apart to determine mean PR interval, QRS complex, and QTcF at baseline (Screening and Cycle 1 Day 1, if 
the ECG at Screening was performed more than 7 days before Cycle 1 Day 1). Additional ECGs may be 
collected as clinically indicated and as single ECGs.
6.
Tumor assessment: tumor assessments will include all known or suspected disease sites.  CT or MRI scans 
of the CAP and MRI of the brain will be performed at Screening and repeated every 12 weeks until the end 
of treatment.  For all tumor assessments, the method of assessment that was used at Screening should be the 
same method used throughout the study.  Responses will be confirmed ≥4 weeks after first occurrence of 
response, according to RECIST version 1.1 criteria. 
7.
Tumor assessment should be repeated at the end of treatment if more than 6 weeks have passed since the 
last evaluation.
8.
AE assessments: AEs should be documented and recorded into the eCRF at each visit using NCI CTCAE
version 4.03.  
For SAEs, the active reporting period to Pfizer or its designated representative begins from the time that the 
participant provides informed consent, which is obtained prior to the participant’s participation in the study, 
ie, prior to undergoing any study-related procedure and/or receiving investigational product, through and 
including 28 calendar days after the last administration of the investigational product.  SAEs occurring to a 
participant after the active reporting period has ended should be reported to the Sponsor if the investigator 
becomes aware of them; at a minimum, all SAEs that the investigator believes have at least a reasonable 
possibility of being related to study drug are to be reported to the Sponsor. AEs (serious and nonserious) 
should be recorded on the CRF from the time the participant has taken at least 1 dose of study treatment 
through the last participant visit. If a participant begins a new anticancer therapy, the AE recording period 
for nonserious AEs ends at the time the new treatment is started. SAEs and deaths must be recorded and 
reported if they occur during the SAE reporting period after the last dose of investigational product, 
irrespective of any intervening treatment.  Note that a switch to a commercially available version of the 
study intervention is considered as a new anticancer therapy for the purposes of SAE reporting.
9.
Concomitant medications and non-drug supportive interventions: all concomitant medications and 
non-drug supportive interventions should be recorded in the CRF from 28 days prior to start of study 
treatment and up to 28 days after the last dose of study treatment.


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................12
APPENDICES .........................................................................................................................13
1. INTRODUCTION ...............................................................................................................14
1.1. Mechanism of Action/Indication.............................................................................14
1.2. Background and Rationale ......................................................................................14
1.2.1. Background.................................................................................................14
1.2.2. Rationale.....................................................................................................15
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................15
3. STUDY DESIGN.................................................................................................................16
4. PARTICIPANT SELECTION.............................................................................................16
4.1. Inclusion Criteria.....................................................................................................16
4.2. Exclusion Criteria....................................................................................................17
4.3. Life Style Guidelines...............................................................................................18
4.3.1. Contraception..............................................................................................18
4.3.2. Sunlight Exposure.......................................................................................19
5. STUDY INTERVENTION..................................................................................................19
5.1. Allocation to Intervention/Treatment......................................................................20
5.2. Drug Supplies..........................................................................................................20
5.2.1. Dosage Form(s) and Packaging..................................................................20
5.3. Administration.........................................................................................................21
5.4. Drug Storage ...........................................................................................................22
5.5. Drug Accountability................................................................................................23
5.6. Concomitant Treatment(s).......................................................................................23
5.6.1. Prohibited Concomitant Treatments...........................................................24
6. STUDY PROCEDURES .....................................................................................................24
6.1. Screening.................................................................................................................24
6.2. Study Period ............................................................................................................24
6.3. Follow-up Visit .......................................................................................................24
6.4. Participant Withdrawal............................................................................................24
7. ASSESSMENTS..................................................................................................................25


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7.1. Antitumor Activity Assessments.............................................................................25
7.1.1. Tumor Assessments....................................................................................25
7.2. Safety Assessments .................................................................................................26
7.2.1. Physical Examinations and Vital Signs ......................................................26
7.2.2. Electrocardiograms.....................................................................................26
7.2.3. ECOG PS....................................................................................................27
7.2.4. Clinical Safety Laboratory Assessments ....................................................27
7.2.5. Pregnancy Testing ......................................................................................27
8. ADVERSE EVENT REPORTING......................................................................................27
8.1. Adverse Events........................................................................................................27
8.2. Reporting Period .....................................................................................................28
8.3. Definition of an Adverse Event...............................................................................28
8.4. Medication Errors....................................................................................................29
8.5. Abnormal Test Findings..........................................................................................29
8.6. Serious Adverse Events...........................................................................................30
8.6.1. Protocol-Specified Serious Adverse Events...............................................31
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................31
8.7. Hospitalization ........................................................................................................32
8.8. Severity Assessment................................................................................................33
8.9. Causality Assessment..............................................................................................33
8.10. Exposure During Pregnancy..................................................................................34
8.11. Withdrawal Due to Adverse Events (See Also Section on Participant 
Withdrawal)...............................................................................................................35
8.12. Eliciting Adverse Event Information ....................................................................35
8.13. Reporting Requirements........................................................................................35
8.13.1. Serious Adverse Event Reporting Requirements .....................................35
8.13.2. Nonserious Adverse Event Reporting Requirements ...............................36
8.13.3. Sponsor Reporting Requirements to Regulatory Authorities ...................36
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................36
9.1. Estimands and Statistical Hypotheses.....................................................................36
9.1.1. Estimands....................................................................................................37
9.2. Sample Size Determination.....................................................................................37


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9.3. Data Sources............................................................................................................37
9.4. Antitumor Activity Analysis ...................................................................................37
9.4.1. Analysis of Primary Endpoint ....................................................................37
9.4.2. Analysis of Secondary Endpoints...............................................................37
9.5. Analysis of Other Endpoints ...................................................................................38
9.6. Safety Analysis........................................................................................................38
9.6.1. Analysis of Primary Endpoint ....................................................................38
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................39
11. DATA HANDLING AND RECORD KEEPING .............................................................40
11.1. Case Report Forms/Electronic Data Record .........................................................40
11.2. Record Retention...................................................................................................40
12. ETHICS..............................................................................................................................41
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)...................................41
12.2. Ethical Conduct of the Study ................................................................................41
12.3. Participant Information and Consent.....................................................................41
12.4. Participant Recruitment.........................................................................................42
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................43
13. DEFINITION OF END OF STUDY.................................................................................43
13.1. End of Study..........................................................................................................43
14. SPONSOR DISCONTINUATION CRITERIA ................................................................43
15. PUBLICATION OF STUDY RESULTS..........................................................................43
15.1. Communication of Results by Pfizer ....................................................................43
15.2. Publications by Investigators ................................................................................44
16. REFERENCES ..................................................................................................................45
LIST OF TABLES
Table 1.
Dacomitinib Recommended Dose Reductions for Adverse 
Reactions...................................................................................................21
Table 2.
Dacomitinib Dose Modifications for Adverse Reactions.........................21
Table 3.
Response Evaluation Criteria in Solid Tumors ........................................50
Table 4.
Protocol Required Safety Laboratory Assessments..................................52


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APPENDICES
Appendix 1. RECIST version 1.1 Tumor Assessment Criteria ...............................................46
Appendix 2. ECOG Classification of Performance Status ......................................................51
Appendix 3. Clinical Laboratory Tests....................................................................................52


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Dacomitinib is an irreversible inhibitor of the kinase activity of the human EGFR family 
(EGFR/HER1, HER2, and HER4) and certain EGFR-activating mutations (exon 19 deletion 
or the exon 21 L858R substitution mutation).5,6,7 In vitro dacomitinib also inhibited the 
activity of DDR1, EPHA6, LCK, DDR2, and MNK1 at clinically relevant concentrations.  
Dacomitinib demonstrated dose-dependent inhibition of EGFR and HER2
autophosphorylation and tumor growth in mice bearing subcutaneously implanted human 
tumor xenografts driven by HER family targets including mutated EGFR. Dacomitinib also 
exhibited antitumor activity in orally-dosed mice bearing intracranial human tumor 
xenografts driven by EGFR amplifications.
Dacomitinib is a kinase inhibitor indicated for the first-line treatment of patients with
metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations.
1.2. Background and Rationale
1.2.1. Background
A subpopulation of patients with NSCLC harbors EGFR (also known as 
HER1/erbB1)-activating mutations in their tumors that are important oncogenic drivers for 
NSCLC.  EGFR TKIs, including gefitinib, erlotinib, and afatinib, have been approved for use 
in this disease and are accepted standard first-line therapies, based on demonstrated 
improvement in tumor response and PFS compared with platinum-based doublet 
chemotherapy.1,2,3,4
Dacomitinib is a selective, ATP-competitive, irreversible, small-molecule inhibitor of HER 
of RTKs, including the EGFR (HER1), the HER2 receptor (erbB2), the HER4 receptor 
(erbB4), and their oncogenic variants (eg, EGFR with exon 19 deletion or exon 21 L858R 
substitution mutations).5,6,7  
In in vitro studies, dacomitinib has shown greater potency when compared with gefitinib in
NSCLC models characterized by EGFR-sensitive and -resistant mutations.5  Dacomitinib
potentially offers a therapeutic advantage over selective reversible EGFR TKIs (such as 
gefitinib or erlotinib) because the irreversible inhibition and highly selective properties of 
dacomitinib for the EGFR family of kinases result in sustained suppression of RTK activity.  
The long-lasting inhibition of receptor phosphorylation reduces concern over the potentially
short plasma half-lives of the first-generation TKIs.  Furthermore, the low nanomolar 
potency and irreversible binding of the intended targets reduce the need for high peak plasma 
levels, which in turn could minimize target-nonspecific toxicities.  It has been shown that 
participants with NSCLC with EGFR-activating mutations may develop treatment resistance 
by the development of a gatekeeper mutation in exon 20 with a secondary point mutation, 
T790M.  Preclinical studies using dacomitinib inhibited the growth of cells harboring this 
secondary mutation, but this has not been demonstrated clinically.


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1.2.2. Rationale
The pivotal study for regulatory approval of dacomitinib for first-line treatment of patients
with NSCLC with EGFR activating mutations was Study A7471050.  Study A7471050 was a
multinational, randomized, open-label, Phase 3 efficacy and safety study comparing
dacomitinib with gefitinib in patients with EGFR mutation positive locally advanced or 
metastatic newly diagnosed NSCLC or with recurrent NSCLC if the patient was treated with
neoadjuvant or adjuvant therapy and had a 12-month disease-free interval. 
This study met its primary objective by demonstrating that dacomitinib was superior to 
gefitinib in prolonging PFS as determined by blinded IRC review in the first-line treatment of 
patients with locally advanced or metastatic EGFR-activating mutation-positive NSCLC 
(HR: 0.589; 95% CI: 0.469, 0.739; 1-sided p <0.0001, representing a 41.1% reduction in risk 
of disease progression or death). The estimated median PFS was 14.7 months (95% CI: 11.1, 
16.6) for the dacomitinib arm versus 9.2 months (95% CI: 9.1, 11.0) for the gefitinib arm 
(data cutoff date: 29 July 2016).  
However, since none of the participating study sites of Study A7471050 were located in 
India, the Central Drugs Standard Control Organization (India), requested the Sponsor to 
conduct a clinical study. The goal of Study A7471064, which is also a PASS, is to fulfill this 
regulatory request.
Complete information for this compound may be found in the SRSD, which for this study is
the India LPD.
2. STUDY OBJECTIVES AND ENDPOINTS
Objectives
Estimands
Endpoints
Primary

To assess safety 
and tolerability 
of dacomitinib.

The primary estimand is the incidence of AEs
from the time of first dose to 28 days post last 
dosing date or the date of initiation of a new 
anticancer therapy, whichever occurs first for all 
participants who receive at least one dose of 
dacomitinib, regardless of dosing interruptions or 
dosing compliance.

Incidence of AEs.
Secondary

To evaluate 
antitumor 
activity of 
dacomitinib by 
ORR and DoR.

The secondary estimand is the treatment effect of 
dacomitinib as assessed by the investigator from 
time of first dose (for ORR) or time of first tumor 
response (for DoR) until disease progression, 
death or initiation of a new anticancer therapy, 
whichever occurs first for all participants who
receive at least one dose of dacomitinib without 
regard to tolerability or discontinuation from 
treatment.

Confirmed ORR and 
DoR as assessed by 
the investigator using 
RECIST version 1.1.


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3. STUDY DESIGN 
This is a Phase 4, open-label, single arm, multicenter, prospective clinical trial of dacomitinib 
for the first-line treatment of newly diagnosed adult participants with metastatic NSCLC with 
EGFR exon 19 deletion or exon 21 L858R substitution mutations.  This study will enroll a 
sufficient number of participants to ensure that 100 participants are treated with dacomitinib.
4. PARTICIPANT SELECTION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom the protocol 
intervention is considered appropriate by their health care provider.
4.1. Inclusion Criteria
Participant eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before participants are included in the study.
Participants must meet all of the following inclusion criteria to be eligible for enrollment into 
the study:
1. Evidence of histologically or cytologically confirmed diagnosis of metastatic NSCLC 
with EGFR-activating mutations (exon 19 deletion mutation or L858R substitution 
mutation in exon 21) as detected by an appropriate test.

It is acceptable for participants with the presence of the exon 20 T790M mutation
together with either EGFR-activating mutation (exon 19 deletion mutation or the 
L858R substitution mutation in exon 21) to be included in this study.
2. No prior treatment with systemic therapy for metastatic NSCLC.  Completed 
neoadjuvant/adjuvant chemotherapy and/or combined modality
chemotherapy/radiation therapy permitted only in cases in which there is a minimum 
of 12 months disease-free interval between completion of systemic therapy and 
recurrence of NSCLC.  Prior treatment with an EGFR-TKI or other TKIs is not 
allowed.
3. Participants with asymptomatic CNS metastases (including participants controlled 
with stable or decreasing steroid use within the last 2 weeks prior to study entry) will 
be eligible.
4. Age ≥18 years.
5. ECOG PS of 0-2.
6. Adequate hematologic, renal and liver function as defined as:
a.
ANC ≥1,000/mm3;


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b. Platelets ≥50,000/mm3;
c.
Hemoglobin ≥8 g/dL;
d. Estimated creatinine clearance ≥30 mL/min as calculated using the method 
standard for the institution;
e.
Total serum bilirubin <1.5 × ULN;
f.
AST and ALT ≤2.5 × ULN (≤5.0 × ULN in case of liver metastases).
7. Acute effects of any prior therapy resolved to baseline severity or to CTCAE 
Grade <1 except for AEs that in the investigator's judgment do not constitute a safety 
risk for the participant. 
8. Serum or urine pregnancy test (for females of childbearing potential) negative at 
Screening.  Female participants of childbearing potential and at risk for pregnancy 
must agree to use a highly effective method of contraception from the time of the first 
negative pregnancy test at Screening, throughout the study and for at least 17 days
after the last dose of assigned treatment.
9. Evidence of a personally signed and dated informed consent document indicating that
the participant or a legally acceptable representative has been informed of all 
pertinent aspects of the study.  
10. Willingness and ability to comply with the study scheduled visits, treatment plans,
laboratory tests and other procedures.
4.2. Exclusion Criteria
Participants presenting with any of the following will not be included in the study:
1. Any evidence of mixed histology that includes elements of small cell or carcinoid 
lung cancer.
2. Any other mutation other than exon 19 deletion or L858R in exon 21, with or without 
the presence of the exon 20 T790M mutation.
3. Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study 
entry.  Palliative radiation (<10 fractions) must have been completed at least 48 hours 
prior to study entry. Stereotactic or small field brain irradiation must have completed
at least 2 weeks prior to study entry. Whole brain radiation must have completed at 
least 4 weeks prior to study entry. Prior irradiation to >25% of the bone marrow.
4. Major surgery within 4 weeks prior to first dose of dacomitinib.  Minor surgical 
procedures (eg, port insertion) are not excluded, but sufficient time should have 
passed for adequate wound healing.


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5. Known prior or suspected severe hypersensitivity to dacomitinib or any component of 
its formulation.
6. History or known presence of interstitial fibrosis, interstitial lung disease, 
pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, obliterative 
bronchiolitis, and pulmonary fibrosis.
7. Other severe acute or chronic medical or psychiatric condition, including recent 
(within the past year) or active suicidal ideation or behavior, or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the participant
inappropriate for entry into this study.
8. Evidence of active malignancy (other than current NSCLC, non-melanoma skin 
cancer, in situ cervical cancer, papillary thyroid cancer, DCIS of the breast or 
localized and presumed cured prostate cancer) within the last 3 years prior to first 
dose of dacomitinib.
9. Breastfeeding female participants. 
10. Participation in other studies involving investigational drug(s) (Phases 1-4) within
2 weeks before the current study begins and/or during study participation.
11. Participants who are investigational site staff members directly involved in the 
conduct of the study and their family members, site staff members otherwise 
supervised by the investigator, or participants who are Pfizer employees directly 
involved in the conduct of the study.
12. Pregnant female participants; female participants of childbearing potential who are 
unwilling or unable to use a highly effective method of contraception as outlined in
this protocol (Section 4.3.1) for the duration of the study and for up to 17 days after 
the last dose of investigational product.
4.3. Life Style Guidelines
4.3.1. Contraception
Female participants of childbearing potential and at risk for pregnancy must agree to use a 
highly effective method of contraception from the time of the first negative pregnancy test at 
Screening, throughout the study and for at least 17 days after the last dose of dacomitinib.
All female participants who, in the opinion of the investigator, are biologically capable of 
having children and are sexually active must agree to use a highly effective method of 
contraception consistently and correctly for the duration of the active treatment period and 
for at least 17 days after the last dose of investigational product.  The investigator or his/her
designee, in consultation with the participant, will select the most appropriate method of


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contraception for the individual participant from the permitted list of contraception methods 
(see below) and instruct the participant in its consistent and correct use.  Participants need to 
affirm that they meet at least one of the selected methods of contraception.  The investigator 
or his/her designee, at each study visit, will discuss with the participant the need to use highly 
effective contraception consistently and correctly and document such conversation in the 
participant’s chart.  In addition, the investigator or his/her designee will instruct the 
participant to call immediately if the selected contraception method is discontinued or if 
pregnancy is known or suspected.  Male participants should use a condom, if their partners
are pregnant or if they plan to father a child.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of oral, inserted, injected, or implanted hormonal methods of 
contraception is allowed provided the participant plans to remain on the same
treatment throughout the entire study and has been using that hormonal contraceptive
for an adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing IUD. 
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository).  For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate.
5. Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
4.3.2. Sunlight Exposure
Participants should avoid extended unprotected exposure to sunlight (eg, sunbathing) or 
tanning for the duration of the study period and for approximately 4 weeks after last dose of 
study drug.  At the time of initiation of dacomitinib, use of moisturizers and appropriate 
measures to limit sun exposure should be initiated.
5. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.  


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ARM name
Dacomitinib 45 mg 
Intervention name
Dacomitinib
Type
Small molecule
Dosage form
Tablet
Dose strength
15 mg
Dosage
Starting dose of 45 mg once a day
Route of administration
Oral
Sourcing
Provided centrally by the Sponsor
Packaging and labeling
Study intervention will be provided in bottles. Each bottle will be 
labeled as required per country requirement
Current/former name(s) or
alias(es)
PF-00299804/dacomitinib
5.1. Allocation to Intervention/Treatment
This is an open-label study; however, the specific intervention to be taken by a participant
will be assigned using an IVRS/IWRS.  The site will contact the IVRS/IWRS prior to the 
start of study intervention administration for each participant.  The site will record the 
intervention assignment on the applicable CRF, if required.
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled.
5.2. Drug Supplies
5.2.1. Dosage Form(s) and Packaging
Dacomitinib will be supplied by Pfizer Global Clinical Supply for oral administration as 
15 mg tablets in HDPE bottles with desiccant and labeled according to local regulatory 
requirements.
Packaging and labeling for all study drugs will be in accordance with applicable local 
regulatory requirements and applicable Good Manufacturing Practice guidelines.  The
information on the study drug will be in accordance with approved submission documents.
Drug supplies will be shipped to the study sites with a Drug Shipment and Proof of Receipt
form.  This form will be completed and filed, as directed on the bottom of the Drug Shipment 
and Proof of Receipt form.  The investigator must take responsibility for and must take all 
steps to maintain appropriate records and ensure appropriate supply, storage, handling, 
distribution, and usage of investigational product in accordance with the protocol and any 
applicable laws and regulations.
Refer to the Investigational Product Manual for further details.


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5.3. Administration
The product will be administered in accordance with the India LPD.
The recommended dosage of dacomitinib is 45 mg taken orally once a day at approximately 
the same time each day, until disease progression, participant refusal/lost to follow-up, or
unacceptable toxicity occurs. Dacomitinib can be taken with or without food.  
The participant should take dacomitinib the same time each day.  If the participant vomits or 
misses a dose, he/she should not take an additional dose or make up a missed dose but 
continue with the next scheduled dose.
The dose of dacomitinib should be reduced for adverse reactions as described in Table 1.  
Dose modifications for specific adverse reactions are provided in Table 2.  
Table 1.
Dacomitinib Recommended Dose Reductions for Adverse Reactions
Dose level
Dose (Once a Day)
First dose reduction
30 mg
Second dose reduction
15 mg
Table 2.
Dacomitinib Dose Modifications for Adverse Reactions
Adverse Reaction
Severitya
Dosage Modification
Interstitial lung 
disease
Any Grade 

Permanently discontinue dacomitinib.
Diarrhea
Grade 2

Withhold dacomitinib until recovery to less than or equal to 
Grade 1; then resume dacomitinib at the same dose level.

For recurrent Grade 2 diarrhea, withhold until recovery to less 
than or equal to Grade 1; then resume dacomitinib at a reduced 
dose.
Grade 3 or 4

Withhold dacomitinib until recovery to less than or equal to 
Grade 1; then resume dacomitinib at a reduced dose.
Dermatologic 
Adverse Reactions
Grade 2

Withhold dacomitinib for persistent dermatologic adverse 
reactions; upon recovery to less than or equal to Grade 1, 
resume dacomitinib at the same dose level.

For recurrent persistent Grade 2 dermatologic adverse reactions, 
withhold until recovery to less than or equal to Grade 1; then 
resume dacomitinib at a reduced dose.
Grade 3 or 4

Withhold dacomitinib until recovery to less than or equal to 
Grade 1; then resume dacomitinib at a reduced dose.
Other
Grade 3 or 4

Withhold dacomitinib until recovery to less than or equal to
Grade 2; then resume dacomitinib at a reduced dose.
a NCI CTCAE Version 4.03.


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If a participant cannot tolerate treatment after a dose reduction to 15 mg, treatment will be 
permanently discontinued.
If a participant fails to recover within 2 weeks of interruption for a drug-related AE,
treatment will be discontinued unless there is discussion of the clinical circumstance with the 
Sponsor and agreement that the participant may resume treatment after an interruption of 
greater than 2 weeks.
If a participant subsequently tolerates treatment well at the reduced level in the judgment of 
the investigator, the dose may be increased to the next dose level.  
5.4. Drug Storage 
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any comparative agents and/or marketed products are
stored in a secured area with controlled access under recommended storage conditions and in 
accordance with applicable regulatory requirements.
Investigational product should be stored in its original container and in accordance with the
India LPD.  See the Investigational Product Manual for storage conditions of the product.
Storage conditions stated in the SRSD will be superseded by the storage conditions stated in 
the labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout study, on all business
days.  Even for continuous monitoring systems, a log or site procedure which ensures active 
daily evaluation for excursions should be available.  The operation of the temperature 
monitoring device and storage unit (for example, refrigerator), as applicable, should be 
regularly inspected to ensure it is maintained in working order. 
Any excursions from the India LPD storage conditions should be reported upon discovery. 
The site should actively pursue options for returning the product to labeled storage 
conditions, as soon as possible.  Deviations from the storage requirements, including any 
actions taken, must be documented and reported to the Sponsor.
Once an excursion is identified, the investigational product must be quarantined and not used 
until the Sponsor provides documentation of permission to use the investigational product.  
Specific details regarding information the site should report for each excursion will be 
provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of labeled temperature range are not considered excursions.


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Site staff will instruct participants on the storage requirements for take home medications 
including how to report temperature excursions. 
The Investigational Product Manual should be referenced for any additional guidance on 
storage conditions and actions to be taken when conditions are outside the specified range.
5.5. Drug Accountability
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). All study interventions will be 
accounted for using an investigational product accountability form/record.  Further guidance 
and information for the final disposition of unused study interventions are provided in the 
Investigational Product Manual.
Participants will be required to return all unused dacomitinib tablets at every cycle.  The 
number of tablets returned by the participant should be counted, documented, and recorded 
by site personnel to support the accountability process.  Study site personnel must make 
reasonable efforts to obtain study drug packaging and any unused tablets from participants
who do not routinely return them at study site visits.  Unreturned tablets will be considered to 
have been taken unless reported otherwise by the participant. For additional information 
regarding accountability, please refer to the Investigational Product Manual.
The Sponsor or designee will provide guidance on the destruction of unused study 
intervention (eg, at the site).  If destruction is authorized to take place at the investigator site,
the investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.6. Concomitant Treatment(s) 
The use of permitted concomitant medication must be in accordance with the India LPD.
All concomitant medications and non-drug supportive interventions should be recorded in the 
CRF from 28 days prior to start of study treatment and up to 28 days after the last dose of
study treatment.
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins,
or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with reason for use and dates of administration
including start and end dates.  
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.


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5.6.1. Prohibited Concomitant Treatments
Concomitant use with a PPI decreases dacomitinib concentrations, which may reduce
dacomitinib efficacy.  The concomitant use of PPIs with dacomitinib should be avoided.  As
an alternative to PPIs, use locally-acting antacids or an H2-receptor antagonist.  Dacomitinib 
should be administered at least 6 hours before or 10 hours after taking an H2-receptor 
antagonist.
Concomitant use of dacomitinib increases the concentration of drugs that are CYP2D6 
substrates which may increase the risk of toxicities of these drugs.  The concomitant use of 
dacomitinib with CYP2D6 substrates should be avoided as minimal increases in 
concentration of the CYP2D6 substrate may lead to serious or life-threatening toxicities.
Other Antitumor or Experimental Drugs
No additional systemic antitumor therapy will be permitted while participants are receiving
a study therapy.
6. STUDY PROCEDURES
6.1. Screening
All participants being considered for the study and eligible for Screening must sign an 
informed consent for the study before completing any study-specific procedures.  Participants 
will be screened within 28 days prior to first dosing of dacomitinib to confirm that they meet 
the eligibility criteria for the study.  The required Screening assessments are summarized in 
the Schedule of Activities and Section 7 Assessments.  
6.2. Study Period
For study treatment period procedures, see Schedule of Activities and Section 7 Assessments.
6.3. Follow-up Visit
All participants will return to the study site up to 28 days after the last dose of study drug
administration for assessment of potential AEs, recording of concomitant treatment use and 
to confirm appropriate contraception usage.
6.4. Participant Withdrawal
Withdrawal of Consent: Participants who request to discontinue study treatment will remain
in the study and must continue to be followed for protocol-specified follow-up procedures.  
The only exception to this is when a participant specifically withdraws consent for any 
further contact with him/her or persons previously authorized by participant to provide this 
information.  Participants should notify the investigator of the decision to withdraw consent 
from future follow-up in writing, whenever possible.  The withdrawal of consent should be
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
from further treatment with study drug only or also from study procedures and/or post 
treatment study follow-up, and entered on the appropriate CRF page.  


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Lost to Follow-Up: All reasonable efforts must be made to locate participants to determine 
and report their ongoing status.  This includes follow-up with persons authorized by the 
participant as noted above. Lost to follow-up is defined by the inability to reach the 
participant after a minimum of 3 documented phone calls, faxes, or emails as well as lack of 
response by participant to 1 registered mail letter.  All attempts should be documented in the 
participant’s medical records.  If it is determined that the participant has died, the site will
use permissible local methods to obtain the date and cause of death.  If investigator’s use of 
third-party representative to assist in the follow-up portion of the study has been included in 
the participant’s informed consent, then the investigator may use a Sponsor retained 
third-party representative to assist site staff with obtaining participant’s contact information
or other public vital status data necessary to complete the follow-up portion of the study.  
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.  If after all attempts, 
the participant remains lost to follow-up, then the last known alive date as determined by the
investigator should be reported and documented in the participant’s medical records.
Participants may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator. 
If a participant does not return for a scheduled visit, every effort should be made to contact 
the participant.  All attempts to contact the participant and information received during 
contact attempts must be documented in the participant’s medical record.  In any 
circumstance, every effort should be made to document participant outcome, if possible.  The
investigator should inquire about the reason for withdrawal, request the participant to return 
for a final visit, if applicable, and follow up with the participant regarding any unresolved 
AEs.
If the participant withdraws from the study, and also withdraws consent for disclosure of 
future information, no further evaluations should be performed, and no additional data should 
be collected.  The Sponsor may retain and continue to use any data collected before such
withdrawal of consent.
7. ASSESSMENTS
7.1. Antitumor Activity Assessments
7.1.1. Tumor Assessments
Tumor assessments will include all known or suspected disease sites.  CT or MRI scans of
CAP and MRI of the brain will be performed at Screening and repeated every 12 weeks 
±1 week until the end of treatment.  For all tumor assessments, the method of assessment that 
was used at Screening should be the same method used throughout the study. Tumor 
assessment should be repeated at the end of treatment if more than 6 weeks have passed since 
the last evaluation.
Assessment of response will be made using RECIST version 1.1 (Appendix 1).9  
Confirmation of response will be required ≥4 weeks after initial response is observed.


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7.2. Safety Assessments
The following parameters will be assessed at time points detailed in Schedule of Activities.  
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety concerns.

Physical examinations and vital signs;

ECOG PS;

Safety laboratory data;

12-lead ECG.
7.2.1. Physical Examinations and Vital Signs
Participants will have a physical examination to include major body systems, body weight, 
blood pressure and pulse rate at the time points described in the Schedule of Activities.  
Blood pressure and pulse rate should be taken pre-dose with the participant in the seated
position after the participant has been sitting quietly for at least 5 minutes.  Investigators 
should pay special attention to clinical signs related to previous serious illnesses.  
7.2.2. Electrocardiograms
ECG will be obtained as outlined in the Schedule of Activities using an ECG machine that 
automatically calculates the heart rate and measures PR interval, QRS complex, QT interval, 
and QTcF.
Three (3) consecutive 12-lead ECGs pre-dose will be performed approximately 2 minutes 
apart to determine mean PR interval, QRS complex, and QTcF at baseline (Screening and
Cycle 1 Day 1, if the ECG at Screening was performed more than 7 days before Cycle 1 
Day 1).  Additional ECGs may be collected as clinically indicated and as single ECGs.
If the participant experiences signs or symptoms of a cardiac or neurologic disorder
(specifically syncope, dizziness, seizures, or stroke), ECG should be obtained at the time of 
the event.
If there is finding of QTcF >500 msec, the ECG must be repeated. If there is finding of 
QTcF >500 msec again (ie, ≥CTCAE Grade 3), the ECG must be reviewed by qualified 
personnel at the site as soon as the finding is made, including verifying that the machine 
reading is accurate and that the Fridericia’s correction formula is applied. 
An electronic reading of prolonged QTc must be confirmed by a manual reading.  Before 
concluding that an episode of QTc prolongation is due to study drug, thorough consideration 
should be given to potential precipitating factors (eg, a change in the participant’s clinical 
condition, the effect of concurrent medication, electrolyte disturbance) and a possible 
evaluation by a specialist.  If the QTcF reverts to ≤500 msec, and it is the opinion of the 


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investigator and the Sponsor that the prolongation was not due to the study drug, treatment 
may be continued with regular ECG monitoring.
7.2.3. ECOG PS
Refer to Appendix 2 for ECOG PS criteria.
7.2.4. Clinical Safety Laboratory Assessments
The required laboratory tests are listed in Appendix 3.  Hematology and blood chemistry will 
be collected at the time points described in the Schedule of Activities table and analyzed at 
local laboratories.  Laboratory tests may also be performed when clinically indicated.  Local 
laboratory certification(s) and reference ranges should be provided to the Sponsor prior to 
study participant screening activity.
7.2.5. Pregnancy Testing
For female participants of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed before investigational product 
administration at the screening visit, on Day 1 of every cycle and at the end of treatment 
visit. A negative pregnancy result is required before the participant may receive the 
investigational product.  Pregnancy tests will also be done whenever one menstrual cycle is 
missed during the active treatment period (or when potential pregnancy is otherwise 
suspected) to confirm the participant has not become pregnant during the study.  In the case 
of a confirmed pregnancy, the participant will be withdrawn from study medication and from
the study.  Pregnancy tests may also be repeated as per request of IRB/IECs or if required by 
local regulations.
8. ADVERSE EVENT REPORTING 
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE
requiring immediate notification to Pfizer or its designated representative.  For all AEs,
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  Follow-up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any nonserious AE that is
determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  To 
assist in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.  


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8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the participant provides informed consent, which is obtained prior to the 
participant’s participation in the study, ie, prior to undergoing any study-related procedure 
and/or receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs occurring to a participant after the active 
reporting period has ended should be reported to the Sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to study drug are to be reported to the Sponsor.
AEs (serious and nonserious) should be recorded on the CRF from the time the participant
has taken at least 1 dose of study treatment through the last participant visit.
If a participant begins a new anticancer therapy, the AE recording period for nonserious AEs 
ends at the time the new treatment is started.  SAEs and deaths must be recorded and reported 
if they occur during the SAE reporting period after the last dose of investigational product, 
irrespective of any intervening treatment.  Note that a switch to a commercially available
version of the study intervention is considered as a new anticancer therapy for the purposes 
of SAE reporting.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation participant
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage.  Examples of AEs include but are not limited to:

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 


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
Drug interactions;

Extravasation;

EDP;

Exposure via breastfeeding;

Medication error;

Occupational exposure;

Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong drug, by the wrong participant, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the AE page of 
the CRFs and on the SAE form when appropriate.  In the event of medication dosing error, 
the Sponsor should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving participant exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating participant.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error and, if applicable, any associated AE(s) are captured on an 
AE CRF page (refer to Section 8 Adverse Event Reporting section for further details).
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or


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
Test result leads to a change in study dosing or discontinuation from the study,
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or Sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death.

Is life-threatening (immediate risk of death).

Requires inpatient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions).

Results in congenital anomaly/birth defect.

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE.  If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death
must be recorded as an AE and as an SAE with CTC Grade 5 (see Section 8.8
Severity Assessment).

Lack of efficacy should be reported as an AE when it is associated with an SAE.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  The important medical event should be reported as serious, 
if it is determined that the event may jeopardize the participant or may require intervention to 
prevent one of the other AE outcomes.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.


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8.6.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections and will be handled as SAEs in the safety 
database (see section on Serious Adverse Event Reporting Requirements). 
8.6.2. Potential Cases of Drug-Induced Liver Injury
Abnormal values in AST and/or ALT levels concurrent with abnormal elevations in total 
bilirubin level that meet the criteria outlined below in the absence of other causes of liver 
injury are considered potential cases of drug-induced liver injury (potential Hy’s law cases) 
and should always be considered important medical events.  
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the participant’s individual baseline values and underlying conditions.
Participants who present with the following laboratory abnormalities should be evaluated 
further to definitively determine the etiology of the abnormal laboratory values:

Participants with AST or ALT and total bilirubin baseline values within the normal 
range who subsequently present with AST or ALT values ≥3 × ULN concurrent with 
a total bilirubin value ≥2 × ULN with no evidence of hemolysis and an alkaline 
phosphatase value ≤2 × ULN or not available;

For participants with preexisting ALT OR AST OR total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:

For participants with preexisting AST or ALT baseline values above the normal 
range: AST or ALT values ≥2 times the baseline values and ≥3 × ULN, or 
≥8 × ULN (whichever is smaller).
Concurrent with

For participants with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased by 1 × ULN or ≥3 × ULN (whichever is smaller).
The participant should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, PT/INR, and alkaline phosphatase.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen, recreational drug and supplement 
consumption, family history, occupational exposure, sexual history, travel history, history of 
contact with a jaundiced person, surgery, blood transfusion, history of liver or allergic 
disease, and work exposure, should be collected.  Further testing for acute hepatitis A, B, or 


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C infection and liver imaging (eg, biliary tract) may be warranted. All cases confirmed on 
repeat testing as meeting the laboratory criteria defined above, with no other cause for LFT 
abnormalities identified at the time, should be considered potential Hy’s law cases 
irrespective of availability of all the results of the investigations performed to determine 
etiology of the abnormal LFTs.  Such potential Hy’s law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute an 
hospitalization; however, the event leading to the emergency room visit should be assessed 
for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, participant has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);


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
Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual participant;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
GRADE
Clinical Description of Severity
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the participant's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally, the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor (see Section 8.13 on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records.  


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In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For investigational products and for marketed products, an exposure during pregnancy occurs 
if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product; 
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male participant has been exposed (eg, because of treatment or environmental 
exposure) to the investigational product prior to or around the time of conception 
and/or is exposed during his partner’s pregnancy. 
If a study participant or study participant’s partner becomes or is found to be pregnant during 
the study participant’s treatment with the investigational product, the investigator must
submit this information to the Pfizer drug safety unit on an SAE Report Form and EDP 
supplemental form, regardless of whether an SAE has occurred.  In addition, the investigator 
must submit information regarding environmental exposure to a Pfizer product in a pregnant
woman (eg, a participant reports that she is pregnant and has been exposed to a cytotoxic
product by inhalation or spillage) using the EDP supplemental form.  This must be done 
irrespective of whether an AE has occurred and within 24 hours of awareness of the
exposure.  The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion or until pregnancy termination) and notify Pfizer of the outcome as a follow-up to 
the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).


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If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to investigational product. 
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays).  In the case of paternal 
exposure, the investigator will provide the study participant with the Pregnant Partner 
Release of Information Form to deliver to his partner.  The investigator must document in the 
source documents that the participant was given the Pregnant Partner Release of Information 
Form to provide to his partner.
8.11. Withdrawal Due to Adverse Events (See Also Section on Participant Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.  
When a participant withdraws because of an SAE, the SAE must be reported in accordance 
with the reporting requirements defined below.
8.12. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study participant/legally acceptable representative.  In addition, each study participant/ 
legally acceptable representative will be questioned about AEs.
8.13. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.13.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event. 


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In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as
well as to the initial and follow-up reporting of exposure during pregnancy and exposure via
breastfeeding cases.  
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study participant initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above. In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a participant death, 
a summary of available autopsy findings must be submitted as soon as possible to Pfizer or 
its designated representative. 
8.13.2. Nonserious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF. It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.13.3. Sponsor Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in an SAP, which will be maintained by the Sponsor.  This document 
may modify the plans outlined in the protocol; however, any major modifications of the 
primary endpoint definition and/or its analysis will also be reflected in a protocol 
amendment.
9.1. Estimands and Statistical Hypotheses
This is a single arm study with no statistical hypothesis testing.  The primary objective of the 
trial is to evaluate the safety and tolerability of single-agent dacomitinib for the first-line
treatment of participants in India with metastatic NSCLC with EGFR activating mutations.


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9.1.1. Estimands
The primary estimand is the incidence of AEs from the time of first dose to 28 days post last 
dosing date or the date of initiation of a new anticancer therapy, whichever occurs first for all 
participants who receive at least one dose of dacomitinib, regardless of dosing interruptions 
or dosing compliance.  
The secondary estimand is the treatment effect of dacomitinib as assessed by the investigator 
from time of first dose (for ORR) or time of first tumor response (for DoR) until disease
progression, death or initiation of a new anticancer therapy, whichever occurs first for all 
participants who receive at least one dose of dacomitinib without regard to tolerability or 
discontinuation from treatment.
9.2. Sample Size Determination
The study’s objectives are to assess the safety, tolerability and antitumor activity of
dacomitinib. This study will enroll enough participants to ensure that 100 participants are 
treated with dacomitinib.  The number of participants is based on a request from the Central 
Drugs Standard Control Organization (India). With 100 participants, the rate of any AE can 
be estimated with the maximum standard error of 0.05.  All participants who receive at least 
1 dose of dacomitinib in this study will be included in the safety set which will be used in the 
safety and antitumor activity analyses unless otherwise specified.
9.3. Data Sources
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are to be filed at the investigator site.
Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained.  The investigator may need to 
request previous medical records or transfer records, depending on the study.  Also, current
medical records must be available.  
9.4. Antitumor Activity Analysis
All antitumor activity analyses will be performed on the safety set.  Treated participants who 
do not have adequate baseline or post-baseline tumor assessment will be considered as 
non-responders.
9.4.1. Analysis of Primary Endpoint
Not Applicable.
9.4.2. Analysis of Secondary Endpoints
Secondary endpoints are confirmed ORR and DoR as assessed by the investigator using 
RECIST version 1.1.


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ORR: ORR is defined as the percent of participants with best overall response as confirmed 
CR or confirmed PR according to RECIST version 1.1.  ORR will be provided along with the 
corresponding 95% CI based on Wilson’s Score Method. 
DoR: DoR is defined as the time from the first documentation of objective tumor response 
(CR or PR) to the first documentation of disease progression or death due to any cause,
whichever occurs first.  For participants whose responses proceed from PR to CR, the onset
of PR is taken as the onset of response.  DoR will be summarized in the population of 
participants with a confirmed CR or confirmed PR using the Kaplan Meier method and will 
be displayed graphically where appropriate. The median event time (if appropriate) and 
2-sided 95% CI for the median will be provided.  Censoring for DoR will be described in the
SAP.  In case the number of participants with Progressive Disease after a confirmed CR or
confirmed PR is small, the use of Kaplan Meier method may be limited, and descriptive 
statistics may be provided.
9.5. Analysis of Other Endpoints
Not Applicable.
9.6. Safety Analysis
All safety analysis will be conducted on the safety set and will include all data collected from 
the time of first dose to 28 days post last dosing date or the date of initiation of a new 
anti-cancer therapy, regardless of dosing interruptions or dosing compliance.
9.6.1. Analysis of Primary Endpoint
The primary endpoint is the incidence of AEs.  AEs will be summarized by type, frequency,
severity (as graded by the investigator according to NCI CTCAE version 4.03 and coded by 
the Sponsor using MedDRA), timing, seriousness and relationship to dacomitinib.  The focus 
of AE summaries will be on treatment-emergent AEs, those with initial onset or increasing in
severity after the first dose of study medication.  The number and percentage of participants
who experienced any AE, SAE, treatment-related AE, or treatment-related SAE will be 
summarized descriptively.  AEs leading to death or discontinuation of study treatment, events 
classified as Grade ≥3, treatment-related events, and SAEs will also be summarized.  
Detailed information collected for each AE will be listed with a description of the event, 
duration, whether the AE was serious, intensity, relationship to study treatment, action taken, 
and clinical outcome.
Study Treatment Exposure
Drug exposure will be summarized using descriptive statistics.  The number and percentage 
of participants with dose reduction, temporary/permanent discontinuations and the 
corresponding reasons will also be summarized.  The number and percentage of participants 
with dose reductions/modifications and the corresponding reasons will also be summarized.


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Laboratory Tests
Laboratory test results will be graded according to NCI CTCAE version 4.03.  Data will be 
summarized by the type of laboratory test.  Summary of laboratory abnormalities will be 
presented by maximum CTCAE Grade. For laboratory tests without an NCI CTCAE grade 
definition, results will be categorized as normal (within normal ranges), abnormal, or not 
done. Shift tables will be provided to examine the distribution of laboratory abnormalities.
Vital Signs
Vital signs data will be summarized using descriptive statistics (mean, standard deviation, 
median, quartiles, minimum, and maximum) of actual values and change from baseline for 
each nominal visit over time (ie, unscheduled assessments will be excluded). 
Electrocardiograms
All ECGs obtained during the study will be evaluated for safety.  The triplicate data will be 
averaged, and all summary statistics and data presentations will use the triplicate averaged 
data.  
QTc using standard correction factors (ie, Fridericia’s [default correction], Bazett’s [if
necessary], and possibly a study-specific factor, as appropriate). Data will be summarized 
and listed for QT interval, HR, RR interval, PR interval, QRS complex, QTcF.
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) of 
QTcF and other ECG parameters will be used to summarize baseline values.
10. QUALITY CONTROL AND QUALITY ASSURANCE 
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and GCPs are being followed.  The monitors may review source documents 
to confirm that the data recorded on CRFs is accurate.  The investigator and institution will 
allow Pfizer monitors/auditors or its agents and appropriate regulatory authorities direct 
access to source documents to perform this verification.
The study site may be subject to review by the IRB/EC, and/or to quality assurance audits 
performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to inspection 
by appropriate regulatory authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.


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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included participant.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic form and will be password 
protected or secured in a locked room to prevent access by unauthorized third parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the
data contained on the CRFs is true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the participant’s chart in the hospital or the 
physician's office.  In these cases data collected on the CRFs must match the data in those 
charts.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating participants (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports). The records should be 
retained by the investigator according to ICH, according to local regulations, or as specified 
in the CSA, whichever is longer. The investigator must ensure that the records continue to be 
stored securely for so long as they are retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified. The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.


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The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS 
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)
It is the responsibility of the investigator to have prospective approval of the study protocol,
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the Investigator file. Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the participants.  
In that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical
Research Involving Human Patients (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 & 2008) and Schedule Y, Drugs and Cosmetics Act 1940 and 
Rules 1945.
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local India regulatory requirements and laws.
12.3. Participant Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant personal data. 
Such measures will include OMITTING participant names or other directly identifiable data 
in any reports, publications, or other disclosures, except where required by applicable laws.
The personal data will be stored at the study site in encrypted electronic form and will be 
password protected to ensure that only authorized study staff have access.  The study site will 
implement appropriate technical and organizational measures to ensure that the personal data 
can be recovered in the event of disaster.  In the event of a potential personal data breach, the 
study site shall be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law.


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To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data is compiled for transfer to Pfizer and other authorized parties, 
participant names, addresses, and other identifiable data will be replaced by a numerical code 
consisting of a numbering system provided by Pfizer in order to de-identify study
participants.  The study site will maintain a confidential list of participants who participated 
in the study linking their numerical code to the participant’s actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of participant
personal data consistent with applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local India 
regulatory requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be 
reviewed by the Sponsor, approved by the IRB/EC before use, and available for inspection.
The investigator must ensure that each study participant, or his or her legally acceptable 
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation.  
Whenever consent is obtained from a participant’s legally acceptable representative, the 
participant’s assent (affirmative agreement) must subsequently be obtained when the 
participant has the capacity to provide assent, as determined by the IRB/EC.  If the 
investigator determines that a participant’s decisional capacity is so limited he/she cannot 
reasonably be consulted, as permitted by the IRB/EC and consistent with local regulatory and 
legal requirements, then the participant’s assent may be waived with source documentation 
of the reason assent was not obtained.  If the study participant does not provide his/her own 
consent, the source documents must record why the participant did not provide consent 
(eg, decisionally impaired adult), how the investigator determined that the person signing the 
consent was the participant’s legally acceptable representative, the consent signer’s
relationship to the study participant (eg, parent, spouse) and that the participant’s assent was 
obtained, or waived.  If assent is obtained verbally it must be documented in the source 
documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each participant or the participant's legally acceptable representative, when 
applicable, before any study-specific activity is performed.  The investigator will retain the 
original of each participant's signed consent/assent document.
12.4. Participant Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.


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12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.
13. DEFINITION OF END OF STUDY
13.1. End of Study 
The end of study is defined as 1 year after the LPFV date in the study.  At the end of study, 
participants who are on treatment and benefiting from dacomitinib treatment will be switched 
to commercially available dacomitinib if considered appropriate by the investigator, as soon 
as feasible.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, drug safety problems, or at the discretion of Pfizer.  
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating participants 
and the hospital pharmacy (if applicable) within 7 days.  As directed by Pfizer, all study
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), www.pfizer.com, and/or the 
EudraCT, www.ctri.nic.in (Clinical Trials Registry-India) and other public registries in 
accordance with applicable local laws/regulations.
www.clinicaltrials.gov
Pfizer posts clinical trial Basic Results on www.clinicaltrials.gov for all Pfizer-sponsored 
interventional studies that evaluate the safety and/or efficacy of a Pfizer product. 


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15.2. Publications by Investigators
Pfizer has no objection to publication by investigator of any information collected or 
generated by investigator, whether or not the results are favorable to the investigational drug.  
However, to ensure against inadvertent disclosure of confidential information or unprotected
inventions, investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure before it is submitted or otherwise disclosed.
The investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed.  If any
patent action is required to protect intellectual property rights, the investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential
information (other than the Study results themselves) before disclosure.
If the study is part of a multicenter study, the investigator agrees that the first publication is
to be a joint publication covering all centers.  However, if a joint manuscript has not been
submitted for publication within 12 months of completion or termination of the study at all 
participating sites, investigator is free to publish separately, subject to the other requirements 
of this section.
For all publications relating to the study, institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement. 


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16. REFERENCES
1.
Morita S, Okamoto I, Kobayashi K, et al. Combined survival analysis of prospective 
clinical trials of gefitinib for non-small cell lung cancer with EGFR mutations. Clin 
Cancer Res 2009;15(13):4493-8.
2.
Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for 
non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-8.
3.
Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first
line treatment for European patients with advanced EGFR mutation-positive non-small 
cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet 
Oncol 2012;13(3):239-46.
4.
Yang JCH, Schuler MH, Yamamoto N, et al. LUX-Lung 3: A randomized, open-label, 
phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for 
patients with advanced adenocarcinoma of the lung harboring EGFR-activating 
mutations. J Clin Oncol 2012;30(Suppl):Abstr LBA7500.
5.
Engelman J, Zejnullahu K, Gale CM, et al. PF00299804, an irreversible pan-ERBB 
inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are 
resistant to gefitinib. Cancer Res 2007;67:11924-32.
6.
Gonzales AJ, Hook KE, Althaus IW, et al. Antitumor activity and pharmacokinetic 
properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine 
kinase inhibitor. Mol Cancer Ther 2008;7:1880-9.
7.
Schwartz PA, Kuzmic P, Solowiej J, et al. Covalent EGFR inhibitor analysis reveals 
importance of reversible interactions to potency and mechanisms of drug resistance. 
Proc Natl Acad Sci USA 2014;111(1):173-8.
8.
Kalous O, Conklin D, Desai AJ, et al. Dacomitinib (PF-00299804), an irreversible 
Pan-HER inhibitor, inhibits proliferation of HER2-amplified breast cancer cell lines 
resistant to trastuzumab and lapatinib. Mol Cancer Ther 2012;11(9):1978-87.
9.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47.


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Appendix 1. RECIST version 1.1 Tumor Assessment Criteria
At baseline, individual tumor lesions will be categorized by the investigator as either
measurable or not, according to the criteria summarized below:
1. Measurable Lesions.
Lesions that can be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 

10 mm for lesions other than lymph nodes and assessed by CT scan (CT scan slice 
thickness no greater than 5 mm).

10 mm for lesions assessed clinically by caliper measurement (lesions which cannot 
be accurately measured with calipers should be recorded as non-measurable).

20 mm for lesions assessed by chest X-ray.

15 mm in short axis for lymph nodes when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).
2. Non-measurable Lesions.
Non-measurable lesions include small lesions (longest diameter <10 mm or pathological 
lymph nodes with a ≥10 but <15 mm short axis) as well as truly non-measurable lesions.  
Truly non-measurable lesions include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses identified by physical examination and not measurable by reproducible imaging 
techniques.
Nodes that have a short axis <10 mm are considered non-pathological and should not be 
recorded or followed. 
3. Special Considerations Regarding Specific Lesions.
Bone lesions:

Bone scan, PET scan or plain films are not considered adequate imaging techniques 
to measure bone lesions.  However, these techniques can be used to confirm the 
presence or disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above.


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
Blastic bone lesions are non-measurable. 
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same participant, these are preferred 
for selection as target lesions.
Lesions with prior local treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.
Solitary lesions:

If a measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
Recording Tumor Measurements
All measurable lesions up to a maximum of 2 lesions per organ and up to 5 in total and 
representative of all involved organs should be identified as target lesions and measured and 
recorded at baseline and at the stipulated intervals during treatment.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameters) and their suitability for 
accurate repetitive measurements (either by imaging techniques or clinically). 
The longest diameter will be recorded for each target lesion. The sum of the longest 
diameter of all target lesions will be calculated and recorded as the baseline sum diameter to 
be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease during treatment. 
One (1) exception to the above described approach is related to pathological lymph nodes.  
Pathological lymph nodes are defined as measurable lesions and may be identified as target 
lesions if the criterion of a short axis of ≥15 mm by CT scan is met.  Only the short axis of 
these nodes will contribute to the baseline sum.  Nodal size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT scan this is almost always the 
axial plane; for MRI the plane of acquisition may be axial, sagittal or coronal).  The smaller 
of these measures is the short axis. 


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A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease.
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’, ‘absent’, or in rare cases ‘unequivocal progression’. In addition, it is 
possible to record multiple non-target lesions involving the same organ as a single item on 
the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’).
Definition of Tumor Response 
Target Lesions
Response in target lesions is defined as follows:

Complete Response (CR): disappearance of all target lesions. 

Partial Response (PR): at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.

Progressive Disease (PD): at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm.  The appearance of one 
or more new lesions is also considered a sign of progression.

Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (<10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it be based on increase in size of the nodes.  As noted earlier, this means 
that participants with CR may not have a total sum of ‘zero’ on the CRF.
Non-Target Lesions
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 


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Response in non-target lesions is defined as follows:

Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor 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 lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 

Progressive Disease (PD): Unequivocal progression of existing non-target lesions.  
(Note: the appearance of one or more new lesions is also considered progression).
Cytology, histology 
These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in germ cell tumors).  When effusions are known to 
be a potential adverse effect of treatment (eg, taxane compounds or angiogenesis inhibitors), 
the cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment can be considered if the measurable tumor has met criteria for response or 
stable disease in order to differentiate between response or stable disease and progressive 
disease.
For participants having effusions or ascites, only cases having cytological proof of 
malignancy should be recorded on the CRF.  Effusions that have not been evaluated using 
cytology or were found to be non-malignant should not be recorded on the CRF. 
New Lesions 
The appearance of new malignant lesions indicates PD. New lesion should be unequivocal 
(eg, not attributable to differences in imaging technique, or change in imaging modality or 
findings not attributable to tumor).  If a new lesion is equivocal, for example due to its small 
size, continued therapy and follow-up assessment will clarify the etiology of the disease.  If 
repeat scans confirm there is definitely a new lesion, then progression should be declared 
using the date of the initial scan. 
Confirmation of Tumor Response 
Confirmation of response is required for non-randomized trials with primary endpoint of
response but is not required in randomized studies since the control arm serves as appropriate 
means of interpretation of data.
Determination of Overall Response by the RECIST 1.1 Criteria
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  The overall assessment of response will involve all parameters as depicted in 
Table 3.


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Table 3.
Response Evaluation Criteria in Solid Tumors
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 all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations: CR = complete response; NE = not evaluable; SD = stable disease; PD = progressive disease;
PR = partial response.
Best overall response
The best overall response is determined once all the data for the participant is known.  Best 
response in trials in which confirmation of complete or partial response is not required 
(ie, randomized trails) is defined as the best response across all time points (for example, a 
participant who has SD at first assessment, PR at second assessment, and PD on last 
assessment has a best overall response of PR). When SD is believed to be the best response, 
it must also meet the protocol specified minimum time from baseline.  If the minimum time 
is not met when SD is otherwise the best time point response, the participant’s best response 
depends on the subsequent assessments. For example, a participant who has SD at first 
assessment, PD at second and does not meet minimum duration for SD, will have a best 
response of PD.  The same participant lost to follow-up after the first SD assessment would 
be considered not evaluable. 
When confirmation of CR and PR is required (ie, non-randomized trials with primary 
endpoint of response), the best overall response is defined according to the tumor response 
along the study.  Complete or partial responses may be claimed only if the criteria for each 
are met at a following time point as specified in the protocol (generally 4 weeks later).
Participants 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 objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy.  The objective response status of
such participants is to be determined by evaluation of target and non-target lesions.
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of CR depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response.  


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Appendix 2. ECOG Classification of Performance Status
Score
Definition
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, eg, light house work or office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair.
5
Dead.


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Appendix 3. Clinical Laboratory Tests
The tests detailed in Table 4 will be performed by the local laboratory.  Protocol-specific 
requirements for inclusion or exclusion of participants are detailed in Section 4 of the 
protocol.  Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.  Investigators must document 
their review of each laboratory safety report.
Table 4.
Protocol Required Safety Laboratory Assessments
Hematology
Clinical Chemistry1
Other
Hemoglobin
Platelet count
WBC count 
Absolute neutrophil count
Absolute lymphocyte count
Absolute monocyte count
Creatinine
Alkaline phosphatase
AST, ALT
Total bilirubin
Calcium (total or ionized)
Lactate dehydrogenase 
Magnesium
Potassium
Glucose, random
Sodium
BUN or urea
Albumin
Pregnancy test (urine or serum) will be
performed at the screening visit, on Day 1 
of every cycle, at the end of treatment visit, 
and additionally whenever one menstrual 
cycle is missed or when potential pregnancy 
is otherwise suspected.
1. In case of potential cases of Drug-Induced Liver Injury, please also refer to protocol Section 8.6.2 Potential 
Cases of Drug-Induced Liver Injury.

SAP_001.pdf: 
Protocol A7471064 (PF-00299804) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol A7471064
SINGLE ARM STUDY TO EVALUATE THE SAFETY OF DACOMITINIB FOR 
THE FIRST-LINE TREATMENT OF PARTICIPANTS IN INDIA WITH 
METASTATIC NON-SMALL CELL LUNG CANCER WITH EPIDERMAL 
GROWTH FACTOR RECEPTOR (EGFR)-ACTIVATING MUTATIONS
Statistical Analysis Plan 
(SAP)
Version:
1
Date:
01 Jun 2020


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives, Endpoints, and Estimands............................................................5
2.1.1. Primary Estimand .........................................................................................6
2.1.2. Secondary Estimands....................................................................................6
2.1.3. Additional Estimand(s).................................................................................7
2.2. Study Design .............................................................................................................7
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................8
3.1. Primary Endpoint ......................................................................................................8
3.2. Secondary Endpoints.................................................................................................8
3.2.1. Overall Response Rate..................................................................................8
3.2.2. Duration of Response ...................................................................................9
3.3. Other Endpoint(s)......................................................................................................9
3.4. Baseline Variables.....................................................................................................9
3.5. Safety Endpoints .....................................................................................................10
3.5.1. Laboratory Data..........................................................................................10
3.5.2. Vital Signs ..................................................................................................10
3.5.3. Electrocardiograms.....................................................................................10
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................10
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................11
5.1. Hypotheses and Decision Rules ..............................................................................11
5.1.1. Hypotheses and Sample Size......................................................................11
5.1.2. Decision Rules............................................................................................11
5.2. General Methods .....................................................................................................11
5.2.1. Definition of Study Day..............................................................................11
5.2.2. Definition of Cycle and Cycle Day ............................................................11
5.2.3. Definition of Start of New Anticancer Therapy .........................................12
5.2.4. Date of Last Contact ...................................................................................12
5.2.5. Tumor Assessment Date.............................................................................13
5.2.6. Adequate Baseline Tumor Assessment ......................................................13


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5.2.7. Adequate Post-baseline Tumor Assessment...............................................13
5.2.8. Nominal and Unscheduled Visits ...............................................................14
5.2.9. Standard Derivations and Reporting Conventions .....................................14
5.2.10. Analyses for Continuous and Qualitative Variables.................................14
5.2.11. Analyses for Time-to-Event Endpoints ....................................................14
5.3. Methods to Manage Missing Data ..........................................................................15
5.3.1. Missing ECG Data......................................................................................15
5.3.2. Handling of Incomplete or Missing Dates..................................................15
5.3.2.1. Adverse Events..........................................................................15
5.3.2.2. Exposure....................................................................................16
5.3.2.3. Date of Death ............................................................................16
5.3.2.4. Date of Start of New Anticancer Therapy.................................17
5.3.2.5. Other Dates................................................................................19
5.3.3. Missing Toxicity Grade of Adverse Events................................................19
6. ANALYSES AND SUMMARIES ......................................................................................19
6.1. Primary Endpoint(s) ................................................................................................19
6.1.1. Adverse Events...........................................................................................19
6.2. Secondary Endpoint(s) ............................................................................................21
6.2.1. Overall Response Rate................................................................................21
6.2.2. Duration of Response .................................................................................22
6.3. Other Endpoint(s)....................................................................................................24
6.4. Subset Analyses.......................................................................................................24
6.5. Baseline and Other Summaries and Analyses.........................................................24
6.5.1. Baseline Summaries....................................................................................24
6.5.1.1. Demographic Characteristics ....................................................24
6.5.1.2. Medical History.........................................................................25
6.5.1.3. Disease Characteristics..............................................................25
6.5.1.4. Prior Anticancer Therapy..........................................................25
6.5.2. Study Conduct and Participant Disposition................................................26
6.5.2.1. Disposition ................................................................................26
6.5.2.2. Protocol Deviations...................................................................26
6.5.3. Study Treatment Exposure .........................................................................26
6.5.3.1. Exposure to dacomitinib............................................................26


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6.5.3.2. Dose Reductions, Interruptions, and Delays .............................27
6.5.4. Concomitant Medications and Nondrug Treatments..................................28
6.5.5. Subsequent anticancer therapies.................................................................28
6.6. Safety Summaries and Analyses .............................................................................28
6.6.1. Laboratory Data..........................................................................................29
6.6.2. Vital Signs ..................................................................................................31
6.6.3. Electrocardiograms.....................................................................................32
6.6.4. Performance Status.....................................................................................32
6.6.5. Physical Examination .................................................................................32
7. INTERIM ANALYSES.......................................................................................................32
7.1. Introduction .............................................................................................................32
7.2. Interim Analyses and Summaries............................................................................32
8. APPENDICES .....................................................................................................................33
8.1. Appendix 1. List of Abbreviations..........................................................................33
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................5
Table 2.
Outcome and Event Dates for DoR Analyses...........................................23
Table 3.
Censoring Reasons and Hierarchy for DoR Analyses..............................24


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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study A7471064 is based on the protocol dated 
01APR2020.  
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1
01 Jun 2020
Original 
01 April 2020
N/A
N/A
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study A7471064.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
Any deviations from this analysis plan will be described in the Clinical Study Report.
All summaries and analyses will include all data in the database at the end of study which is 
defined as 1 year after the last participant first visit date in the study.
2.1. Study Objectives, Endpoints, and Estimands
Objectives
Estimands
Endpoints
Primary

To assess safety 
and tolerability of 
dacomitinib 

The primary estimand is the 
incidence of Adverse Events (AEs)
from the time of first dose to 28 days 
post last dosing date or the date of 
initiation of a new anticancer
therapy, whichever occurs first for 
all participants who receive at least 
one dose of dacomitinib, regardless 
of dosing interruptions or dosing 
compliance.

Incidence of AEs 
Secondary

To evaluate 
antitumor activity 

The secondary estimand is the 
treatment effect of dacomitinib as 

Confirmed ORR 
and DoR as 


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of dacomitinib by 
Objective Response 
Rate (ORR) and 
Duration of 
Response (DoR)
assessed by the investigator from 
time of first dose (for ORR) or time 
of first tumor response (for DoR) 
until disease progression, death or 
initiation of a new anticancer
therapy, whichever occurs first for 
all participants who receive at least 
one dose of dacomitinib without 
regard to tolerability or 
discontinuation from treatment
assessed by the 
investigator using 
Response 
Evaluation 
Criteria in Solid 
Tumors
(RECIST)
version 1.1
2.1.1. Primary Estimand
The primary estimand is the incidence of adverse events from the time of first dose to 28 
days post last dosing date or the date prior to initiation of a new anticancer therapy, 
whichever occurs first for all participants who receive at least one dose of dacomitinib, 
regardless of dosing interruptions or dosing compliance.  It includes the following 4 
attributes:

Population: Participants with metastatic Non-Small Cell Lung Cancer (NSCLC) with 
EGFR exon 19 deletion or exon 21 L858R substitution mutations as defined by the 
inclusion and exclusion criteria, and who receive at least one dose of dacomitinib;

Variable: Binary indicator of whether any AE occurred at least once;

Intercurrent event(s): All data after the intercurrent event “initiation of a new 
anticancer therapy (-1 day)” or “treatment discontinuation (+28 days post last dosing 
date)” will be excluded. Dosing interruptions or dosing compliance are not considered 
as intercurrent event for this analysis;

Population-level summary: Incidence of AEs defined as the number of participants 
with AEs from the time of first dose to 28 days post last dosing date or the date prior 
to initiation of a new anticancer therapy, divided by the number of participants in the 
Population.
2.1.2. Secondary Estimands
A secondary estimand is the treatment effect of dacomitinib based on ORR with confirmed 
response as assessed by the investigator from the time of first dose until disease progression, 
death or initiation of a new anticancer therapy, whichever occurs first for all participants who 
receive at least one dose of dacomitinib regardless of tolerability or duration on treatment. It 
includes the following 4 attributes:

Population: Participants with metastatic NSCLC with EGFR exon 19 deletion or exon 
21 L858R substitution mutations as defined by the inclusion and exclusion criteria, 
and who receive at least one dose of dacomitinib;


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
Variable: Confirmed objective response according to RECIST v1.1 per investigator, 
defined as Partial Response (PR) or Complete Response (CR) from the date of first 
dose until disease progression, death or initiation of a new anticancer therapy, 
whichever occurs first;

Intercurrent event: All tumor assessments are considered regardless of gaps in 
assessments. All data after the intercurrent event “initiation of a new anticancer
therapy” will be excluded. Dosing interruptions and dosing compliance are not 
considered as intercurrent event for this analysis;

Population-level summary: ORR, ie percentage of participants with confirmed CR or 
confirmed PR and corresponding 95% confidence interval (CI) based on Wilson’s 
Score Method. 
Another secondary estimand is the treatment effect of dacomitinib based on DoR from the 
time of first tumor response until disease progression, death or initiation of a new anticancer
therapy, whichever occurs first for all participants who receive at least one dose of 
dacomitinib and who show a confirmed objective response per investigator, regardless of 
tolerability or duration on treatment. It includes the following 4 attributes:

Population: Participants with metastatic NSCLC with EGFR exon 19 deletion or exon 
21 L858R substitution mutations as defined by the inclusion and exclusion criteria, 
and who receive at least one dose of dacomitinib and showing a confirmed OR per 
investigator;

Variable: DoR;

Intercurrent event: All data after the intercurrent events “initiation of a new anticancer
therapy” or “extended gap in tumor assessment, defined as 2 or more missed tumor 
assessments prior to disease progression or death” will be excluded. Dosing 
interruptions and dosing compliance are not considered as intercurrent event for this 
analysis;

Population-level summary: Kaplan-Meier Median of DoR and 2-sided 95% CI.
2.1.3. Additional Estimand(s)
Not applicable.
2.2. Study Design
This is a Phase 4, open-label, single arm, multicenter, prospective clinical trial of dacomitinib 
for the first-line treatment of newly diagnosed adult participants with metastatic NSCLC with 
EGFR exon 19 deletion or exon 21 L858R substitution mutations. This study will enroll a 
sufficient number of participants to ensure that 100 participants are treated with dacomitinib.


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Participants will continue with the study treatment until disease progression, participant 
refusal/lost to follow-up, or unacceptable  toxicity.  At the end of the study, participants who 
are on treatment and benefiting from dacomitinib treatment will be switched to commercially 
available dacomitinib if considered appropriate by the investigator, as soon as feasible.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint
The primary endpoint is the incidence of AEs, defined as the number of participants with 
treatment-emergent adverse events (TEAEs) from the time of first dose to 28 days post last 
dosing date or the date prior to initiation of a new anticancer therapy, divided by the number 
of participants in the Safety Set (see Section 4).
An adverse event is considered treatment-emergent if any of the following apply:

The event occurs on-treatment (defined in Section 3.5) and was not seen prior to the 
start of treatment.

The event was seen prior to the start of treatment but increased in National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03
grade while on-treatment.
Treatment-emergent adverse events will be characterized by type, frequency, severity (as 
graded by the investigator according to NCI CTCAE version 4.03 and coded by the Sponsor 
using Medical Dictionary for Regulatory Activities [MedDRA]), timing, seriousness, and 
relationship to dacomitinib.
3.2. Secondary Endpoints
3.2.1. Overall Response Rate
Objective response based on investigator assessment is defined as CR or PR according to 
RECIST v1.1. Both CR and PR must be confirmed by repeat assessments performed no less 
than 4 weeks after the criteria for response are first met. Participants without a CR or PR or 
with death prior to first post-baseline assessment, inadequate baseline assessment, new 
anticancer therapy started prior to first post-baseline assessment, and all post-baseline disease 
assessments missing will be considered as non-responders.
The Best Overall Response (BOR) is the best response recorded from date of first dose until 
documented Progressive Disease (PD) or start of new anticancer therapy without regard to 
tolerability or discontinuation from treatment. Additional details are provided in
Section 6.2.1.
The Overall Response Rate (ORR) is defined as the proportion of participants with a BOR 
characterized as either a CR or PR relative to the Safety Set.


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3.2.2. Duration of Response
DoR based on investigator assessment is defined, for participants with a confirmed objective 
response, as the time from first documentation of objective response (CR or PR per RECIST 
v1.1, whichever is earlier) to the date of first documentation of PD or death due to any cause, 
whichever occurs first. The censoring rules for DoR are presented in Section 6.2.2.
3.3. Other Endpoint(s)
Not applicable.
3.4. Baseline Variables
Start and end dates of study treatment:
The date of first dose (start date) of study treatment is the earliest date of non-zero dosing of 
the study drug.
The date of last dose of study treatment is the latest date of non-zero dosing of the study 
drug.
Definition of baseline: 
No windowing will be applied when defining baseline. Any deviations from the protocol 
specified window will be documented as protocol deviations. A separate definition of 
adequate baseline will be provided for antitumor activity endpoints. 
For antitumor activity analyses and baseline characteristics associated with tumor 
assessments, the last assessment prior to date of the first dose of study treatment will serve as 
the baseline assessment.  
For safety (including Eastern Cooperative Oncology Group (ECOG) performance status), the 
last assessment performed on or prior to date of the first dose of study treatment  will serve as 
the baseline assessment.  If there are no observations meeting these criteria, then baseline is 
considered missing.  
Participants who start treatment and discontinue from the study on the same day may have 
two different sets of data collected on study day 1 (one during study and one in the End of 
Treatment (EOT) visit. Data reported at the EOT visit are not eligible for baseline selection.
Triplicate electrocardiograms (ECGs) are collected pre-dose; therefore the baseline for each 
ECG measurement is the average of the pre-dose measurements.


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3.5. Safety Endpoints
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified.
On-treatment is defined as the time from the first dose of study treatment through end of 
study follow-up (ie, 28 days after last dose) or the date prior to initiation of a new anticancer 
therapy, whichever occurs first.  The start of new anticancer therapy after the first dose of 
study treatment is derived as outlined in Section 5.2.3. Adverse events occurring on the same 
day as the first dose of study treatment will be considered to have occurred during the on-
treatment period. All other assessments which occur on the same day as the first dose of 
study treatment will be considered baseline assessments (see Section 3.4 for baseline 
definition).
Safety data collected outside the on-treatment period will be listed but not summarized.
3.5.1. Laboratory Data
Hematology and chemistry result will be programmatically graded according to the NCI 
CTCAE version 4.03 for relevant parameters.  A shift summary of baseline grade by 
maximum post-baseline grade will be presented.  Parameters which cannot be graded will be 
summarized relative to the normal range (ie, normal range high or normal range low).  
Additional details are provided in Section 6.6.1.
3.5.2. Vital Signs
Vital signs data include weight, pulse rate, systolic blood pressure, and diastolic blood 
pressure. Measurements were only to be provided once per timepoint. If multiple 
assessments are provided per timepoint, the maximum value will be used for reporting. 
Additional details are provided in Section 6.6.2.
3.5.3. Electrocardiograms
Three consecutive 12-lead ECGs pre-dose will be performed approximately 2 minutes apart 
to determine mean HR, RR, QT interval, PR interval, QRS complex, and QTcF at baseline. 
Additional ECGs may be collected as clinically indicated and as single ECGs. All ECG 
recordings will be listed. However, only the mean score calculated for the replicate 
measurements will be summarized. Additional details are provided in Section 6.6.3.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to releasing the database and classifications will 
be documented per standard operating procedures.
Only participants who signed informed consent will be included in the analysis sets below.


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Population
Description
Enrolled
All participants who sign the informed consent document.
Safety
All participants who receive at least 1 dose of dacomitinib.
5. GENERAL METHODOLOGY AND CONVENTIONS
All analyses will be performed at study participant data set release at the end of study, 
defined as 1 year after the last participant first visit (LPFV) date in the study. 
5.1. Hypotheses and Decision Rules
5.1.1. Hypotheses and Sample Size 
This is a single arm study with no statistical hypothesis testing. The primary objective of the 
trial is to evaluate the safety and tolerability of single-agent dacomitinib for the first-line 
treatment of participants in India with metastatic NSCLC with EGFR activating mutations.
This study will enroll a sufficient number of participants to ensure that 100 participants are 
treated with dacomitinib.
5.1.2. Decision Rules
Not applicable.
5.2. General Methods
5.2.1. Definition of Study Day
The study day for assessments occurring on or after the first dose of study treatment 
(eg, adverse event onset, tumor measurement) will be calculated as:
Study day = Date of the assessment/event - start date of study treatment + 1. 
The study day for assessments occurring prior to the first dose of study treatment 
(eg, baseline characteristics, medical history) will be negative and calculated as:
Study day = Date of the assessment/event - start date of study treatment.
The study day will be displayed in all relevant data listings.
5.2.2. Definition of Cycle and Cycle Day
Cycle start and end dates are derived per participant. Treatment will be dispensed at the 
beginning of every 28-day cycle. 

For Cycle X, the actual cycle start date for each participant is:

The earliest start date of dosing (dose>0 at that visit) in Cycle X visit case report 
form (CRF) exposure page.


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
For all but the last cycle.

Actual cycle stop date is calculated as the start date of the next cycle minus one 
day. 

Actual cycle duration is calculated from Day 1 of a cycle to the day prior to Day 1 
of the next cycle, as follows: 
Actual Cycle Duration (weeks) = (cycle stop date – cycle start date +1)/7.

For the last cycle, actual cycle duration is calculated as follows: 

Actual Cycle Duration (weeks) = (last date of study treatment– cycle start date 
+1)/7.
The cycle day will be calculated as:
Cycle day = Date of the assessment/event – cycle start date + 1.
5.2.3. Definition of Start of New Anticancer Therapy
Start date of new anticancer therapy (drug, radiation, surgery) is used to determine the end of 
the on-treatment period (see Section 3.5) and for censoring in antitumor activity analyses (see 
Section 6.2).
The start date of new anticancer therapy is the earliest date after first dose of dacomitinib 
amongst the following:

Start date of anticancer drug therapy recorded in the ‘Concomitant Medications’ CRF 
pages with ‘Category of medication’ = ‘Follow-up Cancer Therapy’;

Start date of radiation therapy recorded in ‘Radiation Treatment’ CRF pages with 
‘Subcategory’ = ‘Curative in intent’;

Surgery date recorded in ‘Non-drug Treatments’ CRF pages with ‘Category’ = ‘On-
study Cancer Surgery’ and ‘Outcome of Procedure’ = ‘Resected’ or ‘Partially 
Resected’.  
When start date of anticancer therapy is missing or partially missing, the imputation rules 
described in Section 5.3.2.4 should be applied using ‘Concomitant Medications’, ‘Radiation 
Treatment’, and ‘Non-drug Treatments’ CRF pages.
5.2.4. Date of Last Contact
The date of last contact will be derived for participants not known to have died at the end of 
study using the latest complete date (ie, imputed dates will not be used in the derivation) 
among the following:

All participant assessment dates eg, tumor assessments;


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
Start and stop dates of concomitant therapies including non-drug treatments or 
procedures;

Start and end dates of anticancer therapies administered after study treatment 
discontinuation including systemic therapy, radiation, and surgeries;

AE start and end dates;

Date of first and last dose;

Vital sign, ECG and laboratory assessment;

Date of discontinuation on disposition CRF pages (do not use if reason for 
discontinuation is lost to follow-up or death).
Only dates associated with actual examinations of the participant will be used in the 
derivation.  Assessment dates after the end of study will not be applied to derive the last 
contact date.
5.2.5. Tumor Assessment Date
The date of tumor assessment at each nominal timepoint as provided by the investigator on 
the Investigator Overall Tumor Assessment (IOTA) CRF will be utilized for the antitumor 
activity analyses.  
5.2.6. Adequate Baseline Tumor Assessment
Adequate baseline is defined using the following criteria:

All baseline assessments must be within 35 days prior to and including the date of 
first dose of dacomitinib.

All documented lesions must have non-missing assessments (ie, non missing 
measurements for target lesions and non missing lesions status at baseline for non-
target lesions).

Measurable disease at baseline, defined as at least one non-nodal target lesion with 
longest diameter >10 mm by computerized tomography (CT) or magnetic resonance 
imaging (MRI) or calliper for superficial lesion, or at least one malignant lymph node 
with short axis >15mm.
5.2.7. Adequate Post-baseline Tumor Assessment
An adequate assessment is defined as an assessment where a response of CR, PR, Stable 
Disease (SD), non-CR/non-PD, or PD has been provided by the investigator.  Timepoints 
where the response is not evaluable or no assessment was performed will not be used for 
determining the censoring date.


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5.2.8. Nominal and Unscheduled Visits
For all algorithms and analyses, visit labels as specified on the CRF will be used as the 
nominal timepoint (ie, assessment will not be slotted).
Unless otherwise specified, unscheduled assessments will not be displayed in summary tables 
by nominal visit/timepoint. Unscheduled assessments will be used when deriving baseline 
and worst case on-treatment for adverse events, laboratory and vital signs assessments. 
Additionally, unscheduled tumor assessments will be used for antitumor activity analyses 
(eg, defining date of progression/censoring, best overall response, date of last contact).
5.2.9. Standard Derivations and Reporting Conventions
The following conversion factors will be used to convert days into weeks, months or years:   
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days.
Demographics and physical measurements:

Age [years]: 

(year of given informed consent - year of birth).
For reporting conventions, mean and median should generally be displayed one more 
decimal place than the raw data and standard deviation (Std Dev) should be displayed to two 
more decimal places than the raw data. Percentages will be reported to one decimal place.
The rounding will be performed to closest integer/first decimal using the common mid-point 
between the two consecutive values eg, 5.1 to 5.4 will be rounded to an integer of 5, and 
5.5 to 5.9 will be rounded to an integer of 6.
5.2.10. Analyses for Continuous and Qualitative Variables
Continuous variables will be summarized using descriptive statistics ie, number of non-
missing values and number of missing values [ie, n (missing)], mean, median, Std Dev, 
minimum, maximum and first and third quartile (Q1 and Q3). 
Qualitative variables will be summarized by frequency counts and percentages. Unless 
otherwise specified, the calculation of proportions will include the missing category. 
Therefore counts of missing observations will be included in the denominator and presented 
as a separate category.
In case the analysis refers only to certain visits, percentages will be based on the number of 
participants still present in the study at that visit, unless otherwise specified.
5.2.11. Analyses for Time-to-Event Endpoints
Time to event endpoint will be summarized using the Kaplan-Meier method and estimated 
survival curves will be displayed graphically if appropriate. The median event time (if 
appropriate) and 2-sided 95% CI for the median will be provided based on the Brookmeyer-
Crowley method. In case the number of participants with PD after a confirmed CR or 
confirmed PR is small for the Kaplan-Meier method, descriptive statistics will be provided.


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5.3. Methods to Manage Missing Data
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used.
Any imputations will occur at the analysis dataset level.  Additionally, in all data listings 
imputed values will be presented and flagged as imputed.
Missing statistics, eg, when they cannot be calculated, should be presented as ‘ND’ for not 
done, ‘NR’ for not reached or ‘NA’ for not applicable.  For example, if N=1, the measure of 
variability cannot be computed and should be presented as ‘ND’ or ‘NA’. 
5.3.1. Missing ECG Data
For QTc analyses, no values will be imputed for missing data. If one or two of the triplicate 
measurements for an ECG parameter are missed, the average of the remaining two 
measurements or the single measurement can be used in the analyses. If all triplicate 
measurements are missing at baseline for an ECG parameter, no values will be imputed.  
5.3.2. Handling of Incomplete or Missing Dates
5.3.2.1. Adverse Events
AE Onset Date:
The following imputation rules apply if the event is unique for a participant or it is the first of 
a series of similar events; otherwise, the AE Onset Date will not be imputed:

If the AE Collection Date is not missing, is less than the Date of First Exposure to 
Treatment, and is less than the AE Stop Date, then AE Onset Date is set to the Date of 
AE Collection.

If the Previous Visit Date is greater than the Date of First Exposure to Treatment and 
less than the AE Stop Date, the AE Onset Date is set to the previous visit date.

If the Date of First Exposure to Treatment is greater than the previous visit date and 
less than the AE Stop Date, the AE Onset Date is set to the Date of First Exposure to 
Treatment.

Otherwise AE Onset date is set to the AE Stop date.
AE Stop Date:
Ongoing events will have the AE Stop Date set to one of the following values:

Date of Death, if the participant died and a date of death exists.

Maximum of (Withdraw date, AE Onset Date, AE Collection Date) if the participant
withdrew from the study and a date of withdraw exists.


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
Maximum of (AE Onset Date, Subject Summary Collection Date, AE Collection 
Date) if the Subject Summary CRF page exists but a date of withdraw does not exists.

Maximum of (Last Treatment Date, AE Onset Date) if no Subject Summary page 
exits.
Imputation will only occur if event is unique for the participant, or it is the last of a series of 
similar events; otherwise the Stop Date will not be imputed.  Adverse Events are deemed 
similar if they have the same verbatim term.
Resolved events will have the AE Stop Date set to the maximum of the AE collection date 
and the AE Onset date.
5.3.2.2. Exposure
No imputation will be done for first dose date.  Date of last dose of study treatment, if 
unknown or partially unknown, will be imputed as follows:

If the last date of study treatment is completely missing and there is no EOT CRF 
page and no death date, the participant should be considered to be ongoing and use 
the data cutoff date for the analysis as the last dosing date; or

If the last date of study treatment is completely or partially missing and there is 
EITHER an EOT CRF page OR a death date available (on or prior to the data cutoff 
date), then impute this date as the last dose date:
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, 
death date),
= Last day of the month, if both Year and Month are available and Year = Year 
of min (EOT date, death date) and Month < the month of min (EOT date, death 
date), or
= min (EOT date, death date), for all other cases.
5.3.2.3. Date of Death
Missing or partial death dates will be imputed based on the last contact date:

If the date is missing it will be imputed as the day after the date of last contact 

If the day or both day and month is missing, death will be imputed to the maximum of 
the full (non-imputed) day after the date of last contact and the following:

Missing day:
1st day of the month and year of death;

Missing day and month:
January 1st of the year of death.


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5.3.2.4. Date of Start of New Anticancer Therapy
Incomplete dates for start date of new anticancer therapy (drug therapy, radiation, surgery) 
will be imputed as follows and will be used for determining censoring dates for antitumor 
activity analyses and in the derivation of the end of on-treatment period.  PD date below 
refers to PD date by investigator assessment.

The end date of new anticancer therapy will be included in the imputations for start 
date of new anticancer therapy.  If the end date of new anticancer therapy is:

Completely missing then it will be ignored in the imputations below;

Partially missing with only year (YYYY) available then the imputations below 
will consider 31DECYYYY as the end date of the new anticancer therapy;

Partially missing with only month and year  available then the imputations below 
will consider the last day of the month for MMMYYYY as the end date of the 
new anticancer therapy.

For participants who have not discontinued study treatment at the analysis cutoff date, 
last dose of study treatment is set to the analysis cutoff date in the imputations below. 

If the start date of new anticancer therapy is completely or partially missing then the 
imputed start date of new anticancer therapy is derived as follows:

Start date of new anticancer therapy is completely missing.
Imputed start date = min [max(PD date +1, last dose of study treatment +1), end 
date of new anticancer therapy].

Only year (YYYY) for start of anticancer therapy is available.
IF YYYY < Year of min [max(PD date +1, last dose of study treatment +1), end 
date of new anticancer therapy] THEN imputed start date = 31DECYYYY.
ELSE IF YYYY = Year of min [max(PD date +1, last dose of study treatment 
+1), end date of new anticancer therapy].
THEN imputed start date = min [max(PD date +1, last dose of study treatment 
+1), end date of new anticancer therapy].
ELSE IF YYYY > Year of min [max(PD date +1, last dose of study treatment 
+1), end date of new anticancer therapy].
THEN imputed start date = 01JANYYYY.

Both Year (YYYY) and Month (MMM) for start of anticancer therapy are 
available.


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IF
YYYY = Year of min [max(PD date + 1, last dose of study treatment +1), end 
date of new anticancer therapy], AND
MMM < Month of min [max(PD date + 1 day, last dose of study treatment +1 
day), end date of new anticancer therapy].
THEN 
imputed start date = DAY (Last day of MMM) MMM YYYY.
ELSE IF
YYYY = Year of min [max(PD date +1, last dose of study treatment +1), end date 
of new anticancer therapy], AND
MMM = Month of min [max(PD date +1 day, last dose of study treatment +1 
day), end date of new anticancer therapy].
THEN 
imputed start date = min [max(PD date + 1 day, last dose of study treatment +1 
day), end date of new anticancer therapy]).
ELSE IF
YYYY = Year of min [max(PD date +1, last dose of study treatment +1), end date 
of new anticancer therapy], AND
MMM > Month of min [max(PD date +1 day, last dose of study treatment +1 
day), end date of new anticancer therapy].
THEN 
imputed start date = 01 MMM YYYY.
ELSE IF
YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anticancer therapy].
THEN 
imputed start date = DAY (Last day of MMM) MMM YYYY.
ELSE IF
YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anticancer therapy].
THEN.
imputed start date = 01 MMM YYYY.


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5.3.2.5. Other Dates
Imputation methods for other partial dates as follows: 

If the day of the month is missing for a start date used in a calculation, the first day of 
the month will be used to replace the missing date. 

If both the day and month are missing, the first day of the year is used. 

For stop dates, the last day of the month, or last day of the year is used if the day or 
day and month are missing, respectively. 

If the date is completely missing, no imputation will be performed.
5.3.3. Missing Toxicity Grade of Adverse Events
Prior to Study Treatment: If no toxicity grade is available or the grade is reported as 
unknown for an adverse event prior to the first study treatment, then Grade 1 will be assumed 
for purposes of defining a baseline grade.
In summaries which present maximum toxicity grade, the maximum of non-missing grades 
will be displayed. Missing grade will only be displayed for cases where a participant 
reported only one event and the grade is missing.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
6.1.1. Adverse Events
Analyses of adverse events will be conducted on the Safety Set and will include all data 
collected from the time of first dose to 28 days post last dosing date or the date prior to 
initiation of a new anticancer therapy, regardless of dosing interruptions or dosing 
compliance. All analyses will be based on treatment emergent events unless otherwise 
specified.  Treatment emergent is defined in Section 3.1.  AEs not considered treatment 
emergent will be flagged in data listings.
A high level summary of adverse events will include the number and percent of participants
with:

Any Adverse Event;

Serious AE;

Adverse Events with CTCAE Grade 3-4;

Grade 5 events;

AEs associated with dose interruptions;


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
AEs associated with dose reductions;

AEs associated with withdrawal.
Additionally, the number of events reported for each of the categories above will be 
provided.  Each unique adverse event at the Preferred Term (PT) level for a participant is 
included in the count. 
Seriousness, toxicity grade, action taken (interruption, reduction, and withdrawal) are as 
reported by the investigator on the adverse event CRF.
Summaries by System Organ Class (SOC) and PT in decreasing frequency will be provided 
for:

Treatment Emergent Events (All Causality);

Treatment Emergent Events by Maximum Toxicity Grade (All Causality);

Treatment Emergent Events (Treatment Related);

Treatment Emergent Events by Maximum Toxicity Grade (Treatment Related);

Serious Treatment Emergent Events (All Causality);

Serious Treatment Emergent Events (Treatment Related).
An event will be considered treatment related if the investigator considered the event related 
to the study drug or if causality information is unknown.
The following summaries will be provided by PT only (ie, summaries will not include SOC) 
in decreasing frequency for:

Treatment Emergent Events (All Causality) by Preferred Term and Maximum 
Toxicity Grade;

Treatment Emergent Grade 3-5 Events (All Causality) by Preferred Term and 
Maximum Toxicity Grade;

Treatment Emergent Adverse Events Leading to Dose Interruptions (All Causality);

Treatment Emergent Adverse Events Leading to Dose Interruptions (Treatment 
Related);

Treatment Emergent Adverse Events Leading to Dose Reductions (All Causality);

Treatment Emergent Adverse Events Leading to Dose Reductions (Treatment 
Related);


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
Treatment Emergent Adverse Events Leading to Permanent Withdrawal of Study 
Drug (All Causality);

Treatment Emergent Adverse Events Leading to Permanent Withdrawal of Study 
Drug (Treatment Related);

Serious Treatment Emergent Events (All Causality); and

Serious Treatment Emergent Events (Treatment Related).
Each participant will be counted only once within each SOC and PT.  
As described in Section 5.3.3, in case a participant has events with missing and non missing 
toxicity grades, the maximum of the non-missing grade will be displayed.  Missing grade will 
only be displayed in the event that only one event has been reported for a participant and the 
grade is missing.
6.2. Secondary Endpoint(s)
6.2.1. Overall Response Rate
Analysis of treatment effect based on Overall Response Rate (ORR) will be conducted on the 
Safety Set and will include all data collected from the time of first dose until disease 
progression, death or initiation of a new anticancer therapy, whichever occurs first,
regardless of tolerability or duration on treatment.
ORR is defined as the percentage of participants with a best overall confirmed response of 
CR or PR according to RECIST v1.1.  Participants without documented CR or PR will be 
considered as non-responders. The evaluation of ORR will be based on investigator 
assessment relative to the Safety Set.  
ORR will be calculated along with the two-sided 95% CI using the Wilson’s Score Method.
In addition, the frequency (number and percentage) of participants with BOR of CR, PR, SD, 
PD, non-CR/non-PD (applicable only to participants with non-measurable disease at 
baseline), and NE (not-evaluable) will be tabulated.
BOR will be assessed based on reported overall responses at different evaluation timepoints 
by the investigator from the date of first dose until documented disease progression or start of 
new anticancer therapy, according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart and documented before 
progression and start of new anticancer therapy

PR = at least two determinations of PR or better (and not qualifying for a CR) at least 
4 weeks apart and before progression and start of new anticancer


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
SD (for participants with at least one measurable lesion at baseline) = at least one SD 
assessment (or better and not qualifying for CR or PR) ≥  6 weeks after date of first 
dose and before progression and the start of new anticancer therapy 

Non-CR/Non-PD (for participants with only non-target disease at baseline) = at least 
one Non-CR/Non-PD assessment (or better and not qualifying for CR) ≥ 6 weeks 
after date of treatment start and before progression and the start of new anticancer
therapy

PD = progression ≤ 13 weeks after date of first dose and not qualifying for CR, PR or 
SD

Not Evaluable (NE) = all other cases.
Clinical deterioration will not be considered as documented disease progression.
Participants with BOR of NE will be summarized by reason for having NE status. The 
following reasons will be used:

Early death (defined as death prior to 6 weeks after date of first dose;

No post-baseline assessments, for reasons other than early death;

All post-baseline assessments have overall response NE;

New anticancer therapy started before first post-baseline assessment;

SD of insufficient duration (< 6 weeks after first dose);

PD too late (> 13 weeks after first dose).
Special and rare cases where BOR is NE due to both early SD and late PD will be classified 
as ‘SD of insufficient duration’.
6.2.2. Duration of Response
Analysis of treatment effect based on Duration of Response (defined in Section 3.2.2) will be 
conducted on participants from the Safety Set with a BOR of CR or PR and will include all 
data collected from the time of tumor response until disease progression, death or initiation 
of a new anticancer therapy, whichever occurs first, regardless of tolerability or duration on 
treatment.
DoR will be calculated as follows:
DoR (months) = [first date of PD or death/censoring – first date of CR/PR subsequently 
confirmed+1]/30.4375.


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DoR data will be censored as follows: 

For participants who start a new anticancer therapy prior to an event (PD or death), 
censoring will be at the last adequate tumor assessment (see Section 5.2.7) prior to the 
start of new anticancer therapy. Note: if date of progression occurs on the same date 
as the start of new anticancer therapy, the progression will be counted as an event. 

For participants with documented progression or death after two or more missing 
tumor assessments, censoring will occur at the last adequate tumor assessment prior 
to the missing assessments. In this study antitumor activity will be assessed through 
radiological tumor assessments conducted at screening and every 12 weeks until 
disease progression regardless of initiation of subsequent anticancer therapy. The 
allowable time window for disease assessments is ±1week while on treatment. 
Therefore time without adequate assessment is defined as 24 weeks plus 2 weeks. 

All other participants alive without objective progression will be censored on the date 
of the last adequate tumor assessment. 
The date of tumor response at each nominal timepoint based on the investigator assessments 
will be used for determining the dates of last adequate assessment for censoring purposes. 
The censoring and event date options to be considered for the DoR analysis are presented in 
Table 2.
Table 2.
Outcome and Event Dates for DoR Analyses
Scenario
Date of event/censoring
Outcome
Progression or death 
≤26 weeks after last adequate 
tumor assessment 
Date of progression or death 
Event 
Progression or death 
>26 weeks after the last 
adequate tumor assessment
Date of last adequate 
assessment documenting no 
PD prior to new anticancer
therapy or missed assessments 
Censored 
No progression 
New anticancer therapy given 
prior to PD 
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary 
of associated statistics including the median DoR time with two-sided 95% CIs. The CIs for 
the median will be calculated according to Brookmeyer and Crowley. When the number of 
participants with PD after a confirmed CR or PR is small, the use of Kaplan-Meier method is 
limited due to high number of censored observation, so the DoR will be summarized using 
number (%) of participants with events and of participants censored with DoR in the 
following categories: less than 6 months, ≥6 - <9 ,≥9-<12, ≥12-<15, ≥15-<18, ≥18-<21, 
≥21-<24, and ≥24 months.


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Frequency (number and percentage) of participants with each event type (PD or death) and 
censoring reasons will be presented along with the overall event and censor rates. 
Reasons for censoring will be summarized according to the categories in Table 3. If a 
participant meets multiple definitions for censoring the list will be used to define the 
hierarchy.
Table 3.
Censoring Reasons and Hierarchy for DoR Analyses
Hierarchy
Condition
Censoring Reason
1
Start of new anticancer therapy before event. 
Start of new anticancer
therapy
2
Event more than 26 weeks from last adequate 
post-baseline tumor assessment
Event after missing 
assessments a
3
No event and [withdrawal of consent date ≥ first 
date of CR/PR or End of study (EOS) = Subject 
refused further follow-up] 
Withdrawal of consent
4
No event and lost to follow-up in any 
disposition page 
Lost to follow-up
5
No event and none of the conditions in the prior 
hierarchy are met 
Ongoing without an event
a more than 26 weeks after last adequate tumor assessment.  
6.3. Other Endpoint(s)
Not applicable.
6.4. Subset Analyses
Not applicable.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
6.5.1.1. Demographic Characteristics
The following demographic and baseline characteristics will be summarized by number and 
percentage:

Gender (male, female);

Age (18-<45; 45- <65; ≥65);

Eastern Cooperative Oncology Group (ECOG) Performance status.


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Age (continuous) and weight (kg) will be summarized with descriptive statistics (mean, 
median, Std Dev, minimum, and maximum).  
6.5.1.2. Medical History
Medical history will be coded using the most current version of MedDRA and summarized 
by MedDRA’s SOC and PT from the ‘Medical History’ CRF page.  Each participant will be 
counted only once within each PT or SOC. Summaries will be ordered by primary SOC and 
PT in descending order of frequency.  Separate summaries will be provided for past and 
present conditions.
6.5.1.3. Disease Characteristics
The following baseline disease characteristics will be summarized by number and
percentage:

Measurable disease at baseline (yes/no);

Involved tumor sites at baseline;

Number of sites of disease at baseline (1, 2, ≥3).
Involved tumor sites at baseline will be derived from target and non target lesions at baseline.  
Each participant will be counted once per organ.  Similarly, number of sites of disease at 
baseline will be derived by counting the number of unique organ sites from target and non 
target lesions at baseline.  “Other” will be counted as one organ site.
6.5.1.4. Prior Anticancer Therapy
The prior anticancer therapies are collected under the ‘Response to Regimen’, ‘Prior 
Radiation Therapy’ and ‘Non-drug Treatments’ (with ‘Category’ = ‘Prior Cancer Surgery’)
CRF pages. 
The number and percentage of participants in each of the following anticancer therapy 
categories will be tabulated:

Participants with at least one type of prior anticancer treatment;

Participants with at least one prior anticancer drug therapy;

Participants with at least one prior anticancer radiotherapy;

Participants with at least one prior anticancer surgery.
Prior anticancer drug therapy will be summarized as follows based on the number and 
percentage of participants:

Number of prior anticancer therapy regimens: missing /1/2/3/≥4;

Type of prior anticancer therapy;


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
Intent of Therapy: Neo-Adjuvant / Adjuvant / Advanced – Metastatic.
The prior anticancer drugs will be coded in the World Health Organization (WHO) Drug 
coding dictionary.
6.5.2. Study Conduct and Participant Disposition
6.5.2.1. Disposition
A summary of the number of participants enrolled by site will be provided for the Enrolled 
Set.
Discontinuations from study (overall and by main reason for study discontinuation) will be 
summarized using the Enrolled Set. Discontinuations from study treatment (overall and by 
main reason for study treatment discontinuation) will be summarized using the Safety Set.
Discontinuations from study treatment due to adverse events will be identified as either 
related or not related to study treatment. If causality is missing, the event will be considered 
related to treatment. If multiple events lead to study treatment discontinuation and at least 
one was considered related, discontinuation will be reported as related to study treatment. 
6.5.2.2. Protocol Deviations
Protocol deviations will be compiled prior to database closure and will be summarized by 
category (n(%)) for the Enrolled Set.  Categories will be assigned by the study Clinician.
6.5.3. Study Treatment Exposure
Exposure will be summarized for the Safety Set.
6.5.3.1. Exposure to dacomitinib
The summary of treatment exposure for dacomitinib will include the following information:

Treatment duration (weeks);

Cumulative dose (mg);

Dose intensity (mg/week);

Relative dose intensity (%). 
The duration of dacomitinib (in weeks) is defined as:
Treatment duration (weeks) = (last dose date – first dose date +1)/7.
The cumulative dose (mg) of dacomitinib is the sum of the actual dose levels that the 
participant received (ie, total dose administered (mg)). 


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The dose intensity (DI) and the relative dose intensity (RDI) of dacomitinib will be 
calculated for each participant during the study. The DI (mg/week) of dacomitinib is defined 
as:
DI (mg/week) = [cumulative dose (mg)]/[treatment duration (weeks)].
The RDI of dacomitinib is defined as the ratio of the DI and planned dose intensity (d) and 
expressed in %.
RDI (%) = 100× [DI (mg/week]/[7×d (mg/week)].
6.5.3.2. Dose Reductions, Interruptions, and Delays
A dose reduction is defined as a non-zero dose that is less than the prior dose.
The number and percentage of participants with at least one dose reduction as well as a 
breakdown of dose reductions (1/2/3/≥4) will be summarized.  
Reasons for dose reductions will also be summarized.  Participants can contribute to more 
than one reason if multiple dose reductions occurred for different reasons, but will only be 
counted once per reason.  Percentages will be calculated based on the total number of 
participants in Safety Set.
An interruption is defined as 0 mg dose administered on one or more days.  (Note: A dose 
interruption is not considered a dose reduction). The number and percentage of participants
with dose interruptions and the corresponding reasons will be summarized. Participants can 
contribute to more than one reason if multiple dose interruptions occurred for different 
reasons, but will only be counted once per reason.  Percentages will be calculated based on 
the total number of participants in Safety Set.
The following defines how dose interruptions will be counted in the case of multiple dose 
interruptions:

If an interruption occurs consecutively for at least two days due to the same reason, 
then it will be counted only once.

If an interruption occurs consecutively for at least two days due to different reasons, 
then it will be counted for each reason

If an interruption occurs for more than one day due to the same reason, but the days 
are not consecutive, ie. there is at least one dosing day in between, then each dose 
interruption will be counted as a different occurrence. 


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6.5.4. Concomitant Medications and Nondrug Treatments
The following analyses will be based on the Safety Set.
Concomitant medications are medications, other than study medications, which started prior 
to first dose date of study treatment and continued on on-treatment period as well as those 
started during the on-treatment period. Concomitant non-drug treatments refer to concurrent 
procedures, which were undertaken any time during the on-treatment period. Prior 
medications and prior non-drug treatments are medications/procedures which are started 
before the first dose of study treatment. Prior and concomitant medications will be coded in 
the WHO Drug coding dictionary. Prior and concomitant non-drug treatments will be coded 
with the most current version of MedDRA dictionary.
Summary of prior and concomitant medications will include the number and percentage of 
participants by Anatomical Therapeutic Chemical (ATC) Classification level 2 and preferred 
term. A participant will be counted only once within a given drug class and within a given 
drug name, even if he/she received the same medication at different times. If any prior or 
concomitant medication is classified into multiple ATC classes, the medication will be 
summarized separately under each of these ATC classes. The summary tables will be sorted 
on decreasing frequency of drug class and decreasing frequency of drug name in a given drug 
class. In case of equal frequency regarding drug class (respectively drug name), alphabetical 
order will be used. In case any specific medication does not have ATC classification level 2 
coded term, it will be summarized under ‘Unavailable ATC classification’ category. 
Summary of prior and concomitant non-drug treatments will include the number and 
percentage of participants by MedDRA’s SOC and PT in descending order of frequency. 
Participants will be counted only once within an SOC or PT even if he/she received the same 
treatment multiple times.
6.5.5. Subsequent anticancer therapies
The following analyses will be based on the Safety Set.
Subsequent anticancer therapies are defined as medications/procedures entered in the 
‘Concomitant Medications’ (with ‘Category of Medication’ = ‘Follow-up Cancer Therapy’), 
‘Radiation Treatment’ (with ‘Subcategory’ = ‘Curative in intent’), and ‘Non-drug 
Treatments’ (with ‘Category’ = ‘On-study Cancer Surgery’ and ‘Outcome of Procedure’ = 
‘Resected’ or ‘Partially Resected’) CRF pages. The number and percentage of participants 
within each category (medication therapy, radiation therapy, and surgeries) will be provided. 
Medications will be coded using the WHO Drug coding dictionary and will be tabulated by 
preferred term in descending order of frequency.
6.6. Safety Summaries and Analyses
Summaries of safety parameters will be based on the Safety Set. 


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6.6.1. Laboratory Data
Laboratory results will be converted to International System of Units (Système International 
d'unités, SI) units which will be used for applying toxicity grades and for all summaries. 
Quantitative data will be summarized using simple descriptive statistics (mean, Std Dev, 
median, quartiles, minimum, and maximum) of actual values and change from baseline for 
each nominal visit over time (ie, unscheduled assessments will be excluded). The total 
number of participants for change from baseline will include all participants who have both a 
baseline and a value at the nominal visit.  
As described in Section 3.4, baseline will defined as the last assessment performed on or 
prior to date of the first dose of study treatment.  If there are multiple assessments that meet 
the baseline definition on the same day without the ability to determine which was truly last, 
then the worst grade will be assigned as the baseline grade.  Several of the CTCAE terms 
(including Hypo/Hypercalcemia, Chronic Kidney Disease, and Activated Partial
Thromboplastin) can be derived using several laboratory tests (analytes).
Results collected as strict inequalities (eg, >10, <10) will be converted to numeric values 
subtracting a factor of <0.001>.  Expressions of the form” ≥” or “≤” will be converted to the 
end point.  These numeric values will be evaluated for clinically significant abnormalities, 
but will not be included in calculations of summary statistics. 
Additionally, laboratory results will be programmatically classified according to NCI-
CTCAE version 4.03 grade.  Non-numerical qualifiers will not be taken into consideration in 
the derivation of grade (eg, hypokalemia Grade 1 and Grade 2 are only distinguished by a 
non-numerical qualifier and therefore Grade 2 will not be derived). In summary statistics the 
number and percentage of participants corresponding to grades that only include non-
quantitative criteria will be displayed as a blank or NA (not assessed) rather than 0.  If there 
is any overlap between grade criteria (eg, CTCAE grading criteria for Creatinine Increased –
a value can fall into one range based on comparison to Upper Limit of Normal (ULN) and 
another range based on comparison to baseline), the highest (worst) grade would be assigned 
to that record. Grade 5 is defined in the CTCAE criteria guidance as an event with an 
outcome of death. Since laboratory data does not collect an outcome, Grade 5 is not used 
when programmatically grading laboratory data.
Grade 0 or Outside Toxicity Reference (OTR) is not defined specifically by in the CTCAE 
guidance. However, programmatically this is used as a category to represent those 
participants who did not meet any of the Grades 1 to 4 criteria.  If the laboratory value is 
evaluable for CTCAE criteria grading (numeric value is present, valid units and ranges are 
present as required to allow conversion to standard units and grading), and does not qualify 
for any of the Grade 1-4 criteria for a given lab test, then the value is assigned as Grade 0 or 
OTR.
Several of the CTCAE terms (including Hypo/Hypercalcemia, Chronic Kidney Disease, and 
Activated Partial Thromboplastin) can be derived using several laboratory tests (analytes).  


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Abnormalities will be described using the worst grade by scheduled timepoint and overall.  
Worst case overall will be determined from scheduled and unscheduled visits.  Several 
laboratory tests have bi-directional grading criteria defined so that both low (hypo) and high 
(hyper) values can be graded separately.  Each criterion will be summarized separately.  In 
the cases where a value is graded as a Grade 1, 2, 3, or 4 for one of the directions, that value 
will also be assigned as a Grade 0 for the opposite direction for that test.  For example, a 
value meeting the criteria for Grade 3 Hypercalcemia will be classified as a Grade 0 
Hypocalcemia. For CTCAE terms that can be derived using one of several laboratory tests, 
the maximum post-baseline grade for a given participant and CTCAE term will be the 
maximum across all possible laboratory tests.
Additional laboratory results that are not part of NCI-CTCAE will be presented according to 
the following categories by scheduled timepoint as well as overall: below normal limit, 
within normal limits, and above normal limits. In the unlikely event that for a given 
participant, clinically significant abnormalities are noted in both directions (eg, > ULN and < 
Lower Limit of Normal (LLN)), then both abnormalities are counted.
Liver function tests: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), and total bilirubin (TBILI) are used to assess possible drug 
induced liver toxicity. The ratios of test result over the ULN will be calculated and classified 
for these three parameters during the on-treatment period.   
Summary of liver function tests will include the following categories.  The number and 
percentage of participants with each of the following during the on-treatment period will be 
summarized:

ALT ≥3×ULN, ALT ≥5xULN, ALT ≥10×ULN, ALT ≥20×ULN;

AST ≥3×ULN, AST ≥5xULN, AST ≥10×ULN, AST ≥20×ULN;

(ALT or AST) ≥3×ULN, (ALT or AST) ≥5×ULN, (ALT or AST) ≥10×ULN, (ALT 
or AST) ≥20×ULN;

TBILI ≥2×ULN;

Concurrent ALT ≥3×ULN and TBILI ≥2×ULN;

Concurrent AST ≥3×ULN and TBILI ≥2×ULN;

Concurrent (ALT or AST) ≥3×ULN and TBILI ≥2×ULN;

Concurrent (ALT or AST) ≥3×ULN and TBILI ≥2×ULN and ALP >2×ULN;

Concurrent (ALT or AST) ≥3×ULN and TBILI ≥2×ULN and ALP ≤2×ULN or 
missing.
Concurrent measurements are those occurring on the same date.


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Categories will be cumulative, ie, a participant with an elevation of AST ≥10×ULN will also 
appear in the categories ≥5×ULN and ≥3×ULN. Liver function elevation and possible Hy’s 
Law cases will be summarized using frequency counts and percentages. 
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, 
with different symbols, by graphically displaying

Peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at 
ALT=3×ULN and total bilirubin=2×ULN. 

Peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at  
AST=3×ULN and total bilirubin=2×ULN. 
In addition, a listing of all TBILI, ALT, AST and ALP values for participants with a post-
baseline TBILI ≥ 2×ULN, ALT≥ 3×ULN or AST ≥ 3×ULN will be provided.
6.6.2. Vital Signs
Vital sign summaries will include all vital sign assessments from the on-treatment period.  
All vital sign assessments will be listed, and those collected outside the on-treatment period 
will be flagged in the listing. 
All vital sign parameters will be summarized using descriptive statistics (mean, Std Dev, 
median, Q1, Q3, minimum, and maximum) of actual values and change from baseline for 
each nominal visit over time (unscheduled assessments will be excluded). The changes 
computed will be the differences from baseline. The total number of participants for change 
from baseline will include all participants who have both a baseline value and a value at the 
nominal visit. Baseline will be selected as defined in Section 3.4.
The number and percent of participants in each of the following minimum and maximum 
blood pressure, body weight, and pulse categories will be presented:

Maximum increase from baseline in Systolic Blood Pressure ≥40 mmHg;

Maximum decrease from baseline in Systolic Blood Pressure <-60 mmHg;

Maximum increase from baseline in Diastolic Blood Pressure ≥20 mmHg;

Maximum decrease from baseline in Diastolic Blood Pressure >-40 and <-20mmHg;

Maximum decrease from baseline in Diastolic Blood Pressure <-40mmHg;

Maximum increase from baseline in Body Weight ≥10%;

Maximum decrease from baseline in Body Weight <-10%;

Maximum post-baseline Pulse Rate >130 bpm;


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
Minimum pose-baseline Pulse Rate <50 bpm;

Maximum increase from baseline in pulse rate ≥30 bpm;

Maximum decrease from baseline in pulse rate <-30 bpm.
All assessments, including unscheduled assessments will be considered.  A participant can be 
included in multiple categories if different criteria are met at different timepoints.   
6.6.3. Electrocardiograms
Triplicate ECGs were required at baseline.  A mean score is calculated and reported for the
replicate measurements.
ECG summary will include ECG assessments at baseline.  All ECG assessments will be 
listed, and those collected during the on-treatment period for safety evaluation will be 
flagged in the listing.  
QT, HR, RR, PR, QRS, and QTcF will be summarized using descriptive statistics (mean, Std 
Dev, median, quartiles, minimum, and maximum) of actual values on baseline (see 
Section 3.4).
6.6.4. Performance Status
The ECOG shift from baseline to the highest score during the on-treatment period will be 
summarized. ECOG performance status with shift from ECOG=0 or 1 to ECOG 2 or higher 
will also be presented in a data listing.
6.6.5. Physical Examination
Physical examination findings will only be listed.
7. INTERIM ANALYSES
7.1. Introduction
Not applicable.
7.2. Interim Analyses and Summaries
Not applicable.


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8. APPENDICES
8.1. Appendix 1. List of Abbreviations
Abbreviation Term
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomic Therapeutic Chemical
BOR
Best Overall Response
CI
Confidence Interval
CR
Complete Response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computerized Tomography
DI
Dose Intensity
DoR
Duration of Response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eDISH
Evaluation of Drug-Induced Serious Hepatotoxicity
EGFR
Epidermal Growth Factor Receptor
EOS
End of Study
EOT
End of Treatment
IOTA
Investigator Overall Tumor Assessment
LPFV
Last Participant First Visit
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
N/A
Not Applicable
ND
Not Done
NE
Not Evaluable
NR
Not Reached
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NSCLC
Non-Small Cell Lung Cancer
ORR
Overall Response Rate
OTR
Outside Toxicity Reference
PD
Progressive Disease
PR
Partial Response
PT
Preferred Term
Q1
First Quartile
Q3
Third Quartile
QTc
QT interval corrected for heart rate
QTcF
QT interval calculated using Fridericia’s correction factor
RDI
Relative Dose Intensity
RECIST
Response Evaluation Criteria in Solid Tumors


Protocol A7471064 (PF-00299804) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 34
Abbreviation Term
SAP
Statistical Analysis Plan
SD
Stable Disease
SI
International System of Unit
SOC
System Organ Class
Std Dev
Standard Deviation
TBILI
Total Bilirubin
TEAE
Treatment Emergent Adverse Event
ULN
Upper Limit of Normal
WHO 
World Health Organization