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Clinical Trial Results:
ARCHER 1050: A RANDOMIZED, OPEN-LABEL, PHASE 3, EFFICACY AND SAFETY STUDY OF DACOMITINIB (PF 00299804) VERSUS GEFITINIB FOR THE FIRST LINE TREATMENT OF LOCALLY ADVANCED OR METASTATIC NON SMALL CELL LUNG CANCER (NSCLC) IN SUBJECTS WITH EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) ACTIVATING MUTATION(S)

Summary
EudraCT number	2012-004977-23
Trial protocol	ES IT PL
Global end of trial date

Results information
Results version number	v1
This version publication date	25 Oct 2018
First version publication date	25 Oct 2018
Other versions	v2

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

DP312804

ISRCTN number

US NCT number

NCT01774721

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer, Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States,

Public contact

WRS Oncology Europe, Pfizer Italia S.r.l., 0039 0241498 636, paola.tozzi@pfizer.com

Scientific contact

WRS Oncology Europe, Pfizer Italia S.r.l., 0039 0241498 636, paola.tozzi@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Interim

Date of interim/final analysis

15 Feb 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

29 Jul 2016

Global end of trial reached?

Main objective of the trial

To demonstrate that dacomitinib treatment was superior to gefitinib treatment with respect to Progression-Free Survival (PFS) as determined by blinded independent radiologic central (IRC) review, in the study population.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 May 2013

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

48 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 12

Country: Number of subjects enrolled

Spain: 53

Country: Number of subjects enrolled

Italy: 42

Country: Number of subjects enrolled

China: 231

Country: Number of subjects enrolled

Hong Kong: 4

Country: Number of subjects enrolled

Japan: 83

Country: Number of subjects enrolled

Korea, Republic of: 27

Worldwide total number of subjects

452

EEA total number of subjects

107

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

273

From 65 to 84 years

176

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of four hundred and fifty two subjects were enrolled at multiple centers in this study. The results reported are based on the data cut off date as of 29 July 2016.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Dacomitinib

Arm description

Subjects received 45 milligram (mg) of dacomitinib tablets orally once daily in each treatment cycle of 28 days, up to a maximum duration of 48 months or until disease progression, intolerable toxicities, withdrawal, death, or investigator decision dictated by protocol compliance, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Dacomitinib

Investigational medicinal product code

PF-00299804

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received 45 mg of dacomitinib tablets orally once daily in each treatment cycle of 28 days.

Gefitinib

Arm description

Subjects received 250 mg of gefitinib tablets orally once daily, in each treatment cycle of 28 days, up to a maximum duration of 48 months or until disease progression, intolerable toxicities, withdrawal, death, or investigator decision dictated by protocol compliance, whichever occurred first.

Arm type

Active comparator

Investigational medicinal product name

Gefitinib

Investigational medicinal product code

Other name

Iressa

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received 250 mg of gefitinib tablets orally once daily, in each treatment cycle of 28 days.

Number of subjects in period 1	Dacomitinib	Gefitinib
Started	227	225
Treated	227	224
Completed	0	0
Not completed	227	225
Ongoing in study	136	120
Death	76	91
Did not meet eligibility criteria	-	3
Lost to follow-up	1	1
Withdrawal by subject	14	10

Baseline characteristics

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Reporting group title

Dacomitinib

Reporting group description

Reporting group title

Gefitinib

Reporting group description

Reporting group values	Dacomitinib	Gefitinib	Total
Number of subjects	227	225	452
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	61.2 ± 11.26	60.9 ± 10.17	-
Gender categorical
Units: Subjects
Female	146	125	271
Male	81	100	181
Race (NIH/OMB)
Units: Subjects
Asian	170	176	346
Black or African American	1	0	1
White	56	49	105
Ethnicity (NIH/OMB)
Units: Subjects
Not Hispanic or Latino	227	225	452

End points

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Reporting group title

Dacomitinib

Reporting group description

Reporting group title

Gefitinib

Reporting group description

Primary: Progression Free Survival (PFS) Based on Independent Radiologic Central (IRC) Review

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End point title

Progression Free Survival (PFS) Based on Independent Radiologic Central (IRC) Review

End point description

Time from randomization to date of progression of disease (PD) as determined by IRC review as per Response evaluation Criteria in solid tumors (RECIST) v1.1 criteria or death due to any cause, whichever occurred first. PD for target lesions: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm; for non-target lesions: unequivocal progression of pre-existing lesions. Overall tumor burden increased sufficiently to merit discontinuation of therapy. In presence of stable disease (did not achieve partial response, complete response or PD) or partial response (>=30% decrease under baseline of sum of diameters of all target measurable lesions, short diameter used in the sum for target nodes, longest diameter used in sum for all other target lesions) in target disease; for new lesions: appearance of any new unequivocal malignant lesion indicated PD. Intent to treat (ITT) analysis set.

End point type

Primary

End point timeframe

Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression or death due to any cause, whichever occurred first (up to 48 months)

End point values	Dacomitinib	Gefitinib
Number of subjects analysed	227	225
Units: months
median (confidence interval 95%)	14.7 (11.1 to 16.6)	9.2 (9.1 to 11.0)

Dacomitinib vs Gefitinib

Statistical analysis description

Analysis of HR ratio was based on stratified Cox regression model.

Comparison groups

Dacomitinib v Gefitinib

Number of subjects included in analysis

452

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

1-sided stratified log-rank test

Parameter type

Hazard ratio (HR)

Point estimate

0.589

Confidence interval

level

95%

sides

2-sided

lower limit

0.469

upper limit

0.739

Secondary: Progression Free Survival (PFS) Based on Investigator Assessment

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End point title

Progression Free Survival (PFS) Based on Investigator Assessment

End point description

Time from randomization to date of PD as determined by investigator assessment as per RECIST v1.1 criteria or death due to any cause, whichever occurred first. PD for target lesions: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm; for non-target lesions: unequivocal progression of pre-existing lesions. Overall tumor burden increased sufficiently to merit discontinuation of therapy. In presence of stable disease (did not achieve partial response, complete response or PD) or partial response (>=30% decrease under baseline of sum of diameters of all target measurable lesions, short diameter used in the sum for target nodes, longest diameter used in sum for all other target lesions) in target disease; for new lesions: appearance of any new unequivocal malignant lesion indicated PD. ITT analysis set.

End point type

Secondary

End point timeframe

Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression or death due to any cause, whichever occurred first (up to 48 months)

End point values	Dacomitinib	Gefitinib
Number of subjects analysed	227	225
Units: months
median (confidence interval 95%)	16.6 (12.9 to 18.4)	11.0 (9.4 to 12.1)

Dacomitinib vs Gefitinib

Statistical analysis description

Analysis of HR ratio was based on stratified Cox regression model.

Comparison groups

Dacomitinib v Gefitinib

Number of subjects included in analysis

452

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

1-sided stratified log-rank test

Parameter type

Hazard ratio (HR)

Point estimate

0.622

Confidence interval

level

95%

sides

2-sided

lower limit

0.497

upper limit

0.779

Secondary: Number of Subjects With Best Overall Response (BOR) Based on IRC Review

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End point title

Number of Subjects With Best Overall Response (BOR) Based on IRC Review

End point description

Number of subjects with BOR based on IRC review (complete response[CR] or confirmed partial response[PR]) was recorded from randomization until disease progression based on RECISTv1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size; for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be ‘normal’ in size(<short axis <10 mm);for new lesions: repeated assessments of a new lesion if it was equivocal. PR:>=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm. ITT analysis set.

End point type

Secondary

End point timeframe

Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

End point values	Dacomitinib	Gefitinib
Number of subjects analysed	227	225
Units: Subjects
Complete response	12	4
Partial response	158	157

No statistical analyses for this end point

Secondary: Number of Subjects With Best Overall Response (BOR) Based on Investigator Assessment

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End point title

Number of Subjects With Best Overall Response (BOR) Based on Investigator Assessment

End point description

Number of subjects with BOR based on investigator assessment (CR or confirmed PR) was recorded from randomization until disease progression based on RECIST v1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size (short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be ‘normal’ in size (<short axis <10 mm); for new lesions: repeated assessments of a new lesion if it was equivocal. PR:>=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm. ITT analysis set.

End point type

Secondary

End point timeframe

Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

End point values	Dacomitinib	Gefitinib
Number of subjects analysed	227	225
Units: Subjects
Complete response	2	1
Partial response	169	157

No statistical analyses for this end point

Secondary: Objective Response Rate (ORR) Based on IRC Review

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End point title

Objective Response Rate (ORR) Based on IRC Review

End point description

Percentage of subjects with a BOR of either CR or PR based on IRC review recorded from randomization until disease progression based on RECIST v1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size (short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be ‘normal’ in size (<short axis <10 mm); for new lesions: repeated assessments of a new lesion if it was equivocal. PR: >=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm. ITT analysis set.

End point type

Secondary

End point timeframe

Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

End point values	Dacomitinib	Gefitinib
Number of subjects analysed	227	225
Units: percentage of subjects
number (confidence interval 95%)	74.9 (68.7 to 80.4)	71.6 (65.2 to 77.4)

No statistical analyses for this end point

Secondary: Objective Response Rate (ORR) Based on Investigator Assessment

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End point title

Objective Response Rate (ORR) Based on Investigator Assessment

End point description

Percentage of subjects with a BOR of either CR or PR based on investigator assessment recorded from randomization until disease progression based on RECIST v1.1. CR for target lesion:disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size (short axis <10 mm); for non-target lesions:disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be ‘normal’ in size (<short axis <10 mm); for new lesions: repeated assessments of a new lesion if it was equivocal. PR: >=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.ITT analysis set.

End point type

Secondary

End point timeframe

Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

End point values	Dacomitinib	Gefitinib
Number of subjects analysed	227	225
Units: percentage of subjects
number (confidence interval 95%)	75.3 (69.2 to 80.8)	70.2 (63.8 to 76.1)

No statistical analyses for this end point

Secondary: Duration of Response (DoR)

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End point title

Duration of Response (DoR)

End point description

It was defined as time from first documentation of objective response(CR or PR) to date of PD or death from any cause,whichever occurred first.CR for target lesion:disappearance of all target lesions with exception of nodal disease.All target nodes decreased to normal size;for non-target lesions:disappearance of all non-target lesions and normalization of tumor marker levels.All lymph nodes must be ‘normal’ in size(short axis <10 mm);for new lesions:repeated assessments of new lesion if it was equivocal.PR:>=30% decrease under baseline of sum of all target measurable lesions,short diameter used in sum for target nodes,longest diameter used in sum for all other target lesions.PD:20% increase in sum of diameters of target measurable lesions above the smallest sum observed(over baseline if no decrease in sum is observed),with a minimum absolute increase of 5 mm.DoR was recorded based on IRC review and investigator’s assessment.ITT analysis set.n=number evaluable for specific categories.

End point type

Secondary

End point timeframe

Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression or death due to any cause, whichever occurred first (up to 48 months)

End point values	Dacomitinib	Gefitinib
Number of subjects analysed	227	225
Units: months
median (confidence interval 95%)
DoR: IRC review (n =170, 161)	14.8 (12.0 to 17.4)	8.3 (7.4 to 9.2)
DoR: Investigator assessment (n =171, 158)	15.9 (13.8 to 17.6)	9.2 (8.2 to 11.0)

Dacomitinib vs Gefitinib

Statistical analysis description

Comparison of dacomitinib vs gefitinib based on IRC review. Analysis of HR ratio was based on stratified Cox regression model.

Comparison groups

Dacomitinib v Gefitinib

Number of subjects included in analysis

452

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

1-sided stratified log-rank test

Parameter type

Hazard ratio (HR)

Point estimate

0.403

Confidence interval

level

95%

sides

2-sided

lower limit

0.307

upper limit

0.529

Dacomitinib vs Gefitinib

Statistical analysis description

Comparison of dacomitinib vs gefitinib based on Investigator assessment. Analysis of HR ratio was based on stratified Cox regression model.

Comparison groups

Dacomitinib v Gefitinib

Number of subjects included in analysis

452

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

1-sided stratified log-rank test

Parameter type

Hazard ratio (HR)

Point estimate

0.545

Confidence interval

level

95%

sides

2-sided

lower limit

0.418

upper limit

0.711

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

End point description

An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were events between first dose of study drug and up to 28-35 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non- serious. Safety analysis set included all subjects who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.

End point type

Secondary

End point timeframe

From baseline up to 28-35 days after last dose of study drug (up to 48 months)

End point values	Dacomitinib	Gefitinib
Number of subjects analysed	227	224
Units: Subjects
AEs	226	220
SAEs	62	50

No statistical analyses for this end point

Secondary: Number of Subjects With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03: Biochemistry and Haematology

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End point title

Number of Subjects With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03: Biochemistry and Haematology

End point description

Laboratory parameters included haematological and biochemistry parameters. Haematology parameters included anaemia, activated partial thromboplastin time, haemoglobin, international normalized ratio, lymphocyte count, lymphopenia, neutrophils (absolute), platelets, prothrombin time and white blood cells. Biochemistry parameters included alanine aminotransferase (increased), alkaline phosphatase (increased), aspartate aminotransferase (increased), bilirubin (total), creatinine (increased), hypercalcaemia, hyperglycaemia, hyperkalaemia, hypermagnesaemia, hypernatraemia, hypoalbuminaemia, hypocalcaemia, hypoglycaemia, hypokalaemia, hypomagnesaemia, hyponatraemia. Test abnormalities were graded by AEs according to the Common Terminology Criteria for Adverse Events(NCI CTCAE) version 4.03 as Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Only categories with at least 1 subject with abnormality are reported in this endpoint.Safety analysis set.

End point type

Secondary

End point timeframe

From baseline up to 28-35 days after last dose of study drug (up to 48 months)

End point values	Dacomitinib	Gefitinib
Number of subjects analysed	227	224
Units: Subjects
Anaemia (Grade 3)	2	6
Haemoglobin (Grade 3)	0	1
Lymphopenia (Grade 3)	13	6
Lymphopenia (Grade 4)	1	0
Neutrophil count (absolute) (Grade 3)	0	1
WBC count (Grade 3)	1	1
Alanine aminotransferase increased (Grade 3)	3	26
Alanine aminotransferase increased (Grade 4)	0	2
Aspartate aminotransferase increased (Grade 3)	1	15
Aspartate aminotransferase increased (Grade 4)	0	2
Alkaline phosphatase increased (Grade 3)	2	6
Bilirubin increased (total) (Grade 3)	1	1
Creatinine increased (Grade 3)	0	1
Hypercalcaemia (Grade 3)	1	0
Hyperglycaemia (Grade 3)	2	5
Hyperkalaemia (Grade 4)	0	2
Hypermagnesaemia (Grade 3)	7	6
Hypocalcaemia (Grade 3)	3	4
Hypoglycaemia (Grade 3)	0	2
Hypoglycaemia (Grade 4)	1	0
Hypokalaemia (Grade 3)	13	5
Hypokalaemia (Grade 4)	2	0
Hypomagnesaemia (Grade 3)	2	0
Hyponatraemia (Grade 3)	6	5
Hyponatraemia (Grade 4)	1	1

No statistical analyses for this end point

Secondary: Number of Subjects With Laboratory Test Abnormalities: Urinalysis

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End point title

Number of Subjects With Laboratory Test Abnormalities: Urinalysis

End point description

Urinalysis parameter included urine protein, urine blood/haemoglobin, urine glucose and urine sediment. Test abnormalities was defined as deviation from normal range (higher or lower). Normal range of 24-hour urine protein test: less than 150 mg of protein per day, urine glucose: 0 to 0.8 mmol/L (millimole per liter), urine protein: 0 to 20 mg/dL (milligrams per deciliter). Urine blood/haemoglobin abnormality was defined as presence and absence of blood/haemoglobin in urine of subjects. Urine sediment abnormality was defined as the presence of any bacteria, casts, crystals, and epithelial cells. Only categories with at least 1 subject with abnormality are reported in this endpoint. Safety analysis set included all subjects who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.

End point type

Secondary

End point timeframe

From baseline up to 28-35 days after last dose of study drug (up to 48 months)

End point values	Dacomitinib	Gefitinib
Number of subjects analysed	227	224
Units: Subjects
High Urine Protein	1	1
Low Urine Glucose	1	0
High Urine Blood/Haemoglobin	4	4

No statistical analyses for this end point

Secondary: Number of Subjects With Clinically Significant Abnormalities in Vital Signs

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End point title

Number of Subjects With Clinically Significant Abnormalities in Vital Signs

End point description

Criteria for vital signs abnormalities: systolic pulse rate less than (<) 50 beats per minute (bpm) or greater than (>)130 bpm and maximum increase or decrease from baseline in pulse rate of 30 bpm. Systolic blood pressure of maximum increase from baseline (MIB) >=40 millimeters of mercury (mmHg), maximum decrease from baseline (MDB) in systolic blood pressure =<60 mmHg. Diastolic blood pressure of MIB >=20 mmHg and MDB in diastolic blood pressure >40 and =<20 mm Hg. Only categories with at least 1 subject with abnormality are reported in this endpoint. Safety analysis set included all subjects who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.

End point type

Secondary

End point timeframe

From baseline up to 28-35 days after last dose of study drug (up to 48 months)

End point values	Dacomitinib	Gefitinib
Number of subjects analysed	227	224
Units: Subjects
MIB in systolic BP >=40 mmHg	13	20
MDB in systolic BP <=-60 mmHg	0	1
MIB in diastolic BP >=20 mmHg	38	44
MDB in diastolic BP >-40 and <=-20mmHg	46	52
MDB in diastolic BP <=-40 mmHg	0	1
Maximum post baseline pulse rate >130 bpm	2	2
Minimum post baseline pulse rate <50 bpm	2	0
MIB in pulse rate >=30 bpm	13	12
MDB in pulse rate <=-30 bpm	17	16

No statistical analyses for this end point

Secondary: Number of Subjects With Clinically Significant Abnormality in Electrocardiogram (ECG)

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End point title

Number of Subjects With Clinically Significant Abnormality in Electrocardiogram (ECG)

End point description

ECG parameters included corrected QT interval using Bazett’s formula (QTcB) and corrected QT interval using Fridericia’s formula (QTcF). ECG criteria for abnormality: absolute value 450 - <480 msec, 480 - <500 msec >=500. The number of subjects with potentially clinically significant ECG findings at any visit were reported. Safety analysis set included all subjects who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received. Here, “N” (number of subjects analyzed) signifies subjects who were evaluable for this specified endpoint.

End point type

Secondary

End point timeframe

From baseline up to 28-35 days after last dose of study drug (up to 48 months)

End point values	Dacomitinib	Gefitinib
Number of subjects analysed	217	7
Units: Subjects
QTcF Criteria: 450-<480	5	0
QTcB Criteria: 450-<480	22	0
QTcB Criteria: 480-<500	3	0

No statistical analyses for this end point

Secondary: Number of Subjects With Maximum Relative Decrease From Baseline >20% in Left Ventricular Ejection Fraction (LVEF)

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End point title

Number of Subjects With Maximum Relative Decrease From Baseline >20% in Left Ventricular Ejection Fraction (LVEF)

End point description

An ejection fraction (EF) was the volumetric fraction of blood ejected from a ventricle of the heart with each heartbeat; it was a measure of the pumping efficiency of the heart. The EF of the left heart, known as the left ventricular ejection fraction, was a measure of the efficiency of pumping into the body’s systemic circulation. Safety analysis set included all subjects who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received. Here “N” signifies number of subjects who were evaluable for this specified endpoint.

End point type

Secondary

End point timeframe

From randomization up to 7 days of Cycle 4 (up to 91 days)

End point values	Dacomitinib	Gefitinib
Number of subjects analysed	191	199
Units: Subjects	5	5

No statistical analyses for this end point

Secondary: Health Related Quality of Life (HRQOL): Time to Deterioration (TTD) in Pain, Dyspnea, Fatigue or Cough

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End point title

Health Related Quality of Life (HRQOL): Time to Deterioration (TTD) in Pain, Dyspnea, Fatigue or Cough

End point description

HRQOL was measured by standardized questionnaires (European Organization for Research and Treatment of Cancer (EORTC)) quality of life questionnaires (OLQ-C30) and its lung cancer module (QLQ-LC13). TTD in pain (chest, arm/shoulder), dyspnea, fatigue or cough was defined as time between randomization and first occurrence of increase in score of 10 points or greater from baseline in any of these 4 symptoms for at least two consecutive cycles. For those who had not shown deterioration, the data was censored at the last date when the subjects completed an assessment for pain, dyspnea, fatigue or cough. Patient reported outcome (PRO) analysis set included all enrolled subjects, who started treatment and completed a baseline PRO assessments and at least one post-baseline PRO assessment after the first dose.

End point type

Secondary

End point timeframe

Randomization until the end of treatment (up to 48 months)

End point values	Dacomitinib	Gefitinib
Number of subjects analysed	226	222
Units: months
median (confidence interval 95%)	3.8 (2.3 to 4.8)	6.6 (3.8 to 9.3)

Dacomitinib vs Gefitinib

Comparison groups

Dacomitinib v Gefitinib

Number of subjects included in analysis

448

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5327

Method

2-sided Hochberg adjusted p-value

Parameter type

Cox proportional hazard

Point estimate

1.173

Confidence interval

level

95%

sides

2-sided

lower limit

0.928

upper limit

1.483

Secondary: Overall Mean Scores of Euro Quality of Life-5 Dimension Visual Analog Scale (EQ-5D VAS)

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End point title

Overall Mean Scores of Euro Quality of Life-5 Dimension Visual Analog Scale (EQ-5D VAS)

End point description

The Euro Quality of Life-5 dimension (EQ-5D) is a brief self-administered, validated reliable generic health status instrument. EQ-5D general health status can also be measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the subject’s self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state). PRO analysis set included all enrolled subjects, who started treatment and completed a baseline PRO assessments and at least one post-baseline PRO assessment after the first dose.

End point type

Secondary

End point timeframe

From Cycle 1 to 41 (up to 48 months)

End point values	Dacomitinib	Gefitinib
Number of subjects analysed	224	221
Units: units on a scale
least squares mean (confidence interval 95%)	73.3869 (71.608 to 75.166)	77.6923 (75.895 to 79.490)

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration (Cmax) of Dacomitinib and Its Metabolite PF-05199265

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End point title

Maximum Observed Plasma Concentration (Cmax) of Dacomitinib and Its Metabolite PF-05199265 ^[1]

End point description

PK analysis set included all subjects who were treated with dacomitinib with at least 1 measured plasma concentration and were dose-compliant (who received 45 mg dacomitinib daily without interruptions/dose reductions for at least 14 days prior to day of data collection). This endpoint was planned to be analyzed in Chinese subgroup only.

End point type

Secondary

End point timeframe

Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analysis was planned to be reported for Dacomitinib arm only.

End point values	Dacomitinib
Number of subjects analysed	19
Units: nanogram per milliliter (ng/mL)
arithmetic mean (standard deviation)
Dacomitinib	84.19 ± 21.90
PF-05199265	12.77 ± 7.58

No statistical analyses for this end point

Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Dacomitinib and Its Metabolite PF-05199265

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End point title

Time to Reach Maximum Observed Plasma Concentration (Tmax) of Dacomitinib and Its Metabolite PF-05199265 ^[2]

End point description

End point type

Secondary

End point timeframe

Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analysis was planned to be reported for Dacomitinib arm only.

End point values	Dacomitinib
Number of subjects analysed	19
Units: hour
median (full range (min-max))
Dacomitinib	4.03 (2.0 to 24.0)
PF-05199265	6.0 (0.0 to 25.0)

No statistical analyses for this end point

Secondary: Area Under the Plasma Concentration-Time Curve From Time 0 to End of Dosing Interval (AUCtau) of Dacomitinib and Its Metabolite PF-05199265

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End point title

Area Under the Plasma Concentration-Time Curve From Time 0 to End of Dosing Interval (AUCtau) of Dacomitinib and Its Metabolite PF-05199265 ^[3]

End point description

End point type

Secondary

End point timeframe

Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analysis was planned to be reported for Dacomitinib arm only.

End point values	Dacomitinib
Number of subjects analysed	19
Units: nanogramhour/milliliter (nghr/mL)
arithmetic mean (standard deviation)
Dacomitinib	1712.08 ± 413.61
PF-05199265	278.47 ± 163.53

No statistical analyses for this end point

Secondary: Averaged Plasma Concentration at Steady State (Cavg) of Dacomitinib and Its Metabolite PF-05199265

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End point title

Averaged Plasma Concentration at Steady State (Cavg) of Dacomitinib and Its Metabolite PF-05199265 ^[4]

End point description

End point type

Secondary

End point timeframe

Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analysis was planned to be reported for Dacomitinib arm only.

End point values	Dacomitinib
Number of subjects analysed	19
Units: ng/mL
arithmetic mean (standard deviation)
Dacomitinib	71.33 ± 17.23
PF-05199265	11.60 ± 6.81

No statistical analyses for this end point

Secondary: Minimum Observed Plasma Concentration (Cmin) of Dacomitinib and Its Metabolite PF-05199265

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End point title

Minimum Observed Plasma Concentration (Cmin) of Dacomitinib and Its Metabolite PF-05199265 ^[5]

End point description

End point type

Secondary

End point timeframe

Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analysis was planned to be reported for Dacomitinib arm only.

End point values	Dacomitinib
Number of subjects analysed	19
Units: ng/mL
arithmetic mean (standard deviation)
Dacomitinib	60.64 ± 14.85
PF-05199265	10.49 ± 6.26

No statistical analyses for this end point

Secondary: Fluctuation Coefficient Between Trough and Peak Plasma Concentration (DF) of Dacomitinib and Its Metabolite PF-05199265

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End point title

Fluctuation Coefficient Between Trough and Peak Plasma Concentration (DF) of Dacomitinib and Its Metabolite PF-05199265 ^[6]

End point description

Fluctuation coefficient between trough and peak plasma concentration was determined as Cmax-Ctrough divided by Cavg, where Cmax was the maximum observed concentration within the dosing interval, Ctrough was the observed concentration prior to dose administration and Cavg was averaged plasma concentration at steady state. PK analysis set included all subjects who were treated with dacomitinib with at least 1 measured plasma concentration and were dose-compliant (who received 45 mg dacomitinib daily without interruptions/dose reductions for at least 14 days prior to day of data collection). This endpoint was planned to be analyzed in Chinese subgroup only.

End point type

Secondary

End point timeframe

Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analysis was planned to be reported for Dacomitinib arm only.

End point values	Dacomitinib
Number of subjects analysed	19
Units: Fluctuation coefficient
arithmetic mean (standard deviation)
Dacomitinib	0.2883 ± 0.1460
PF-05199265	0.1105 ± 0.0827

No statistical analyses for this end point

Secondary: Apparent Clearance (CL) of Dacomitinib

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End point title

Apparent Clearance (CL) of Dacomitinib ^[7]

End point description

Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the blood (rate at which a drug is metabolized or eliminated by normal biological processes). PK analysis set included all subjects who were treated with dacomitinib with at least 1 measured plasma concentration and were dose-compliant (who received 45 mg dacomitinib daily without interruptions/dose reductions for at least 14 days prior to day of data collection). This endpoint was planned to be analyzed in Chinese subgroup only.

End point type

Secondary

End point timeframe

Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analysis was planned to be reported for Dacomitinib arm only.

End point values	Dacomitinib
Number of subjects analysed	19
Units: Liter/hour (L/h)
arithmetic mean (standard deviation)	27.61 ± 5.97

No statistical analyses for this end point

Secondary: Pre-dose Plasma Concentrations (Ctrough) of Dacomitinib and Its Metabolite PF-05199265

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End point title

Pre-dose Plasma Concentrations (Ctrough) of Dacomitinib and Its Metabolite PF-05199265 ^[8]

End point description

Trough plasma concentration was defined as the measured concentration at the end of a dosing interval at steady state (taken directly before next administration). PK analysis set included all subjects who were treated with dacomitinib with at least one measured plasma concentration and were dose-compliant. Dose-compliant subjects were those who received 45 mg dacomitinib daily without interruptions or dose reductions for at least 14 days prior to the day of data collection. Here, n signifies number of subjects evaluable at specified time points only.

End point type

Secondary

End point timeframe

Pre-dose on Day 1 of Cycle 2, 3, 4, 5 and 6

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Descriptive analysis was planned to be reported for Dacomitinib arm only.

End point values	Dacomitinib
Number of subjects analysed	188
Units: ng/mL
arithmetic mean (standard deviation)
Cycle 2 Day 1: Dacomitinib (n =176)	70.24 ± 27.16
Cycle 3 Day 1: Dacomitinib (n =143)	68.34 ± 25.80
Cycle 4 Day 1: Dacomitinib (n =112)	68.16 ± 25.49
Cycle 5 Day 1: Dacomitinib (n =85)	64.50 ± 25.52
Cycle 6 Day 1: Dacomitinib (n =74)	61.68 ± 22.58
Cycle 2 Day 1: PF-05199265 (n =176)	13.20 ± 8.55
Cycle 3 Day 1: PF-05199265 (n =143)	14.42 ± 9.10
Cycle 4 Day 1: PF-05199265 (n =112)	13.70 ± 8.33
Cycle 5 Day 1: PF-05199265 (n =85)	12.48 ± 6.69
Cycle 6 Day 1: PF-05199265 (n =74)	13.05 ± 6.52

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From baseline until 35 days after the last dose of study drug (up to 40 months)

Adverse event reporting additional description

The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another subject, or one subject may have experienced both a serious and non-serious event during the study.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Dacomitinib

Reporting group description

Subjects received 45 mg of dacomitinib tablets orally once daily in each treatment cycle of 28 days, up to a maximum duration of 48 months or until disease progression, intolerable toxicities, withdrawal, death, or investigator decision dictated by protocol compliance, whichever occurred first.

Reporting group title

Gefitinib

Reporting group description

Serious adverse events	Dacomitinib	Gefitinib
Total subjects affected by serious adverse events
subjects affected / exposed	62 / 227 (27.31%)	50 / 224 (22.32%)
number of deaths (all causes)	76	91
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic myeloid leukaemia
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to meninges
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Pancreatic carcinoma
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Disease progression
subjects affected / exposed	8 / 227 (3.52%)	11 / 224 (4.91%)
occurrences causally related to treatment / all	0 / 8	0 / 11
deaths causally related to treatment / all	0 / 9	0 / 11
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 227 (0.44%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Death
subjects affected / exposed	1 / 227 (0.44%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	1 / 1	1 / 1
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	5 / 227 (2.20%)	2 / 224 (0.89%)
occurrences causally related to treatment / all	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Haemoptysis
subjects affected / exposed	2 / 227 (0.88%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	2 / 227 (0.88%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	1 / 3	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Pneumothorax
subjects affected / exposed	2 / 227 (0.88%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	2 / 227 (0.88%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Dyspnoea
subjects affected / exposed	1 / 227 (0.44%)	4 / 224 (1.79%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 2
Interstitial lung disease
subjects affected / exposed	1 / 227 (0.44%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchospasm
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Organising pneumonia
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	0 / 227 (0.00%)	2 / 224 (0.89%)
occurrences causally related to treatment / all	0 / 0	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Facial bones fracture
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	1 / 227 (0.44%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Overdose
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Extradural haematoma
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 227 (0.00%)	2 / 224 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Cardiac tamponade
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebral infarction
subjects affected / exposed	1 / 227 (0.44%)	2 / 224 (0.89%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 1
Cerebral venous thrombosis
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cognitive disorder
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post herpetic neuralgia
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Leukocytosis
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Keratitis
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	5 / 227 (2.20%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	9 / 9	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Abdominal pain
subjects affected / exposed	2 / 227 (0.88%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal distension
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer haemorrhage
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mouth haemorrhage
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestinal obstruction
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Liver injury
subjects affected / exposed	2 / 227 (0.88%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	1 / 227 (0.44%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis acneiform
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Drug eruption
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Decubitus ulcer
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bone pain
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Polymyalgia rheumatica
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	5 / 227 (2.20%)	2 / 224 (0.89%)
occurrences causally related to treatment / all	1 / 8	2 / 3
deaths causally related to treatment / all	0 / 2	1 / 1
Respiratory tract infection
subjects affected / exposed	2 / 227 (0.88%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 227 (0.88%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Bronchitis
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopulmonary aspergillosis
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Diverticulitis
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 227 (0.00%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 227 (0.44%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 227 (0.88%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	1 / 227 (0.44%)	0 / 224 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	1 / 227 (0.44%)	1 / 224 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Hyponatraemia
subjects affected / exposed	0 / 227 (0.00%)	2 / 224 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Dacomitinib	Gefitinib
Total subjects affected by non serious adverse events
subjects affected / exposed	224 / 227 (98.68%)	217 / 224 (96.88%)
Investigations
Weight decreased
subjects affected / exposed	58 / 227 (25.55%)	37 / 224 (16.52%)
occurrences all number	100	54
Alanine aminotransferase increased
subjects affected / exposed	44 / 227 (19.38%)	88 / 224 (39.29%)
occurrences all number	75	201
Aspartate aminotransferase increased
subjects affected / exposed	42 / 227 (18.50%)	81 / 224 (36.16%)
occurrences all number	62	169
Blood bilirubin increased
subjects affected / exposed	20 / 227 (8.81%)	19 / 224 (8.48%)
occurrences all number	40	37
Blood alkaline phosphatase increased
subjects affected / exposed	14 / 227 (6.17%)	7 / 224 (3.13%)
occurrences all number	18	16
Gamma-glutamyltransferase increased
subjects affected / exposed	14 / 227 (6.17%)	20 / 224 (8.93%)
occurrences all number	16	37
White blood cell count decreased
subjects affected / exposed	6 / 227 (2.64%)	14 / 224 (6.25%)
occurrences all number	8	20
Weight increased
subjects affected / exposed	5 / 227 (2.20%)	12 / 224 (5.36%)
occurrences all number	13	27
Vascular disorders
Hypertension
subjects affected / exposed	13 / 227 (5.73%)	10 / 224 (4.46%)
occurrences all number	15	15
Nervous system disorders
Dysgeusia
subjects affected / exposed	16 / 227 (7.05%)	11 / 224 (4.91%)
occurrences all number	33	12
Paraesthesia
subjects affected / exposed	16 / 227 (7.05%)	11 / 224 (4.91%)
occurrences all number	32	14
Headache
subjects affected / exposed	14 / 227 (6.17%)	19 / 224 (8.48%)
occurrences all number	16	22
Dizziness
subjects affected / exposed	11 / 227 (4.85%)	17 / 224 (7.59%)
occurrences all number	12	18
Blood and lymphatic system disorders
Anaemia
Additional description: Same event may appear as both an adverse event and serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another, or a subject may have experienced both a se
subjects affected / exposed	22 / 227 (9.69%)	16 / 224 (7.14%)
occurrences all number	41	41
General disorders and administration site conditions
Asthenia
subjects affected / exposed	29 / 227 (12.78%)	28 / 224 (12.50%)
occurrences all number	62	55
Chest pain
subjects affected / exposed	22 / 227 (9.69%)	32 / 224 (14.29%)
occurrences all number	35	41
Fatigue
subjects affected / exposed	21 / 227 (9.25%)	19 / 224 (8.48%)
occurrences all number	37	29
Mucosal inflammation
subjects affected / exposed	21 / 227 (9.25%)	8 / 224 (3.57%)
occurrences all number	37	9
Pyrexia
subjects affected / exposed	19 / 227 (8.37%)	17 / 224 (7.59%)
occurrences all number	24	18
Oedema peripheral
subjects affected / exposed	13 / 227 (5.73%)	7 / 224 (3.13%)
occurrences all number	15	9
Pain
subjects affected / exposed	11 / 227 (4.85%)	12 / 224 (5.36%)
occurrences all number	12	15
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	198 / 227 (87.22%)	125 / 224 (55.80%)
occurrences all number	576	253
Stomatitis
subjects affected / exposed	99 / 227 (43.61%)	40 / 224 (17.86%)
occurrences all number	254	74
Nausea
subjects affected / exposed	43 / 227 (18.94%)	49 / 224 (21.88%)
occurrences all number	68	63
Constipation
subjects affected / exposed	30 / 227 (13.22%)	31 / 224 (13.84%)
occurrences all number	48	38
Mouth ulceration
subjects affected / exposed	28 / 227 (12.33%)	13 / 224 (5.80%)
occurrences all number	46	16
Vomiting
subjects affected / exposed	20 / 227 (8.81%)	29 / 224 (12.95%)
occurrences all number	24	37
Aphthous ulcer
subjects affected / exposed	13 / 227 (5.73%)	6 / 224 (2.68%)
occurrences all number	17	7
Oral pain
subjects affected / exposed	12 / 227 (5.29%)	1 / 224 (0.45%)
occurrences all number	23	1
Abdominal pain
subjects affected / exposed	10 / 227 (4.41%)	12 / 224 (5.36%)
occurrences all number	12	17
Dysphagia
subjects affected / exposed	10 / 227 (4.41%)	12 / 224 (5.36%)
occurrences all number	20	18
Abdominal pain upper
subjects affected / exposed	9 / 227 (3.96%)	14 / 224 (6.25%)
occurrences all number	11	16
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	48 / 227 (21.15%)	42 / 224 (18.75%)
occurrences all number	65	67
Dyspnoea
subjects affected / exposed	29 / 227 (12.78%)	28 / 224 (12.50%)
occurrences all number	40	56
Epistaxis
subjects affected / exposed	21 / 227 (9.25%)	5 / 224 (2.23%)
occurrences all number	24	5
Nasal inflammation
subjects affected / exposed	15 / 227 (6.61%)	3 / 224 (1.34%)
occurrences all number	22	5
Haemoptysis
subjects affected / exposed	10 / 227 (4.41%)	13 / 224 (5.80%)
occurrences all number	10	13
Productive cough
subjects affected / exposed	9 / 227 (3.96%)	12 / 224 (5.36%)
occurrences all number	9	13
Skin and subcutaneous tissue disorders
Dermatitis acneiform
subjects affected / exposed	111 / 227 (48.90%)	64 / 224 (28.57%)
occurrences all number	360	112
Dry skin
subjects affected / exposed	63 / 227 (27.75%)	38 / 224 (16.96%)
occurrences all number	105	49
Alopecia
subjects affected / exposed	53 / 227 (23.35%)	28 / 224 (12.50%)
occurrences all number	79	43
Pruritus
subjects affected / exposed	45 / 227 (19.82%)	32 / 224 (14.29%)
occurrences all number	67	48
Rash
subjects affected / exposed	40 / 227 (17.62%)	24 / 224 (10.71%)
occurrences all number	97	31
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	33 / 227 (14.54%)	7 / 224 (3.13%)
occurrences all number	58	8
Rash maculo-papular
subjects affected / exposed	28 / 227 (12.33%)	27 / 224 (12.05%)
occurrences all number	99	46
Dermatitis
subjects affected / exposed	25 / 227 (11.01%)	9 / 224 (4.02%)
occurrences all number	67	13
Skin fissures
subjects affected / exposed	21 / 227 (9.25%)	6 / 224 (2.68%)
occurrences all number	35	7
Acne
subjects affected / exposed	20 / 227 (8.81%)	13 / 224 (5.80%)
occurrences all number	66	18
Erythema
subjects affected / exposed	12 / 227 (5.29%)	3 / 224 (1.34%)
occurrences all number	23	4
Psychiatric disorders
Insomnia
subjects affected / exposed	24 / 227 (10.57%)	33 / 224 (14.73%)
occurrences all number	36	46
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	31 / 227 (13.66%)	26 / 224 (11.61%)
occurrences all number	50	42
Musculoskeletal pain
subjects affected / exposed	26 / 227 (11.45%)	28 / 224 (12.50%)
occurrences all number	59	38
Back pain
subjects affected / exposed	18 / 227 (7.93%)	34 / 224 (15.18%)
occurrences all number	23	44
Arthralgia
subjects affected / exposed	16 / 227 (7.05%)	15 / 224 (6.70%)
occurrences all number	20	22
Infections and infestations
Paronychia
subjects affected / exposed	140 / 227 (61.67%)	45 / 224 (20.09%)
occurrences all number	395	88
Conjunctivitis
subjects affected / exposed	43 / 227 (18.94%)	9 / 224 (4.02%)
occurrences all number	55	10
Upper respiratory tract infection
subjects affected / exposed	27 / 227 (11.89%)	28 / 224 (12.50%)
occurrences all number	44	45
Nasopharyngitis
subjects affected / exposed	21 / 227 (9.25%)	19 / 224 (8.48%)
occurrences all number	37	27
Rash pustular
subjects affected / exposed	14 / 227 (6.17%)	3 / 224 (1.34%)
occurrences all number	63	6
Urinary tract infection
subjects affected / exposed	14 / 227 (6.17%)	8 / 224 (3.57%)
occurrences all number	21	10
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	69 / 227 (30.40%)	56 / 224 (25.00%)
occurrences all number	126	83
Hypokalaemia
subjects affected / exposed	22 / 227 (9.69%)	13 / 224 (5.80%)
occurrences all number	51	17

More information

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Were there any global substantial amendments to the protocol? Yes

17 Jun 2013

1) To include subjects who had evidence of both EGFR -activating mutations (exon 19 deletion and L858R mutation in exon 21) within a tumor specimen (allowing for the presence of the T790M mutation in exon 20). 2) To update emerging information on dacomitinib PK characteristics and metabolism in subjects and implemented related changes in the dosing instructions and concomitant medications.3) Provided instructions for preparation of tumor tissue specimens for EGFR mutational analysis and pathology/histology study to ensure that sufficient tumor specimens would be available for protocol-required testing; clarified that confirmation of adenocarcinoma histology and presence of an EGFR-activating mutation in tumor tissue were required for eligibility screening. 4) Stated that CYP2D6 genotyping would be performed in patients treated in the dacomitinib arm who were undergoing multiple PK sampling on C2D1. 5) Stated that dacomitinib could be dosed with or without food; added that concomitant use of proton-pump inhibitors and H 2 antagonists with dacomitinib should be avoided if possible. 6) Clarified that potential dose reductions to manage treatment-related toxicity applied only to dacomitinib (not gefitinib); added guidelines for interruption and resumption of gefitinib dosing for management of toxicity.

01 Oct 2013

Expanded eligibility to subjects with recurrent NSCLC (in addition to those with newly diagnosed disease), if there was a disease-free interval of at least 12 months’ duration between completion of prior systemic therapy (neoadjuvant/adjuvant chemotherapy and/or combined modality chemotherapy/radiation therapy) and recurrence of NSCLC.

30 Jun 2015

1) Extended the maximum duration of study participation (including long-term follow-up for progression and survival) to 48 months from date of first dose of study treatment per the current protocol (changed from 32 months), to improve the potential to obtain at least 201 overall survival (OS) events.

04 Nov 2015

1) Clarified that patients who had PD per RECIST v1.1 confirmed by IRC review, and for whom the investigator believed it was in their best interest to continue on their respective study therapy, would be allowed to continue on their respective study therapy with or without concomitant local therapy. 2) Clarified follow-up procedures for subjects who continued on their respective study therapy after disease progression assessed by IRC review; specified that long-term follow-up for all subejcts was to include survival status and subsequent cancer therapies. 3) Clarified inclusion criterion: In the case of subjects with recurrent NSCLC who had received prior neoadjuvant/adjuvant chemotherapy, the tumor specimen was to be obtained at the time of recurrence after completion of neoadjuvant/adjuvant therapy. 3)Implemented retrospective CYP2D6 genotyping for all subjects treated in the dacomitinib arm that provided specific consent to participate.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Data for overall survival is not reported at Primary completion date and will be reported after the study completion date.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression Free Survival (PFS) Based on Independent Radiologic Central (IRC) Review

Primary: Progression Free Survival (PFS) Based on Independent Radiologic Central (IRC) Review

Secondary: Progression Free Survival (PFS) Based on Investigator Assessment

Secondary: Progression Free Survival (PFS) Based on Investigator Assessment

Secondary: Number of Subjects With Best Overall Response (BOR) Based on IRC Review

Secondary: Number of Subjects With Best Overall Response (BOR) Based on IRC Review

Secondary: Number of Subjects With Best Overall Response (BOR) Based on Investigator Assessment

Secondary: Number of Subjects With Best Overall Response (BOR) Based on Investigator Assessment

Secondary: Objective Response Rate (ORR) Based on IRC Review

Secondary: Objective Response Rate (ORR) Based on IRC Review

Secondary: Objective Response Rate (ORR) Based on Investigator Assessment

Secondary: Objective Response Rate (ORR) Based on Investigator Assessment

Secondary: Duration of Response (DoR)

Secondary: Duration of Response (DoR)

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Number of Subjects With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03: Biochemistry and Haematology

Secondary: Number of Subjects With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03: Biochemistry and Haematology

Secondary: Number of Subjects With Laboratory Test Abnormalities: Urinalysis

Secondary: Number of Subjects With Laboratory Test Abnormalities: Urinalysis

Secondary: Number of Subjects With Clinically Significant Abnormalities in Vital Signs

Secondary: Number of Subjects With Clinically Significant Abnormalities in Vital Signs

Secondary: Number of Subjects With Clinically Significant Abnormality in Electrocardiogram (ECG)

Secondary: Number of Subjects With Clinically Significant Abnormality in Electrocardiogram (ECG)

Secondary: Number of Subjects With Maximum Relative Decrease From Baseline >20% in Left Ventricular Ejection Fraction (LVEF)

Secondary: Number of Subjects With Maximum Relative Decrease From Baseline >20% in Left Ventricular Ejection Fraction (LVEF)

Secondary: Health Related Quality of Life (HRQOL): Time to Deterioration (TTD) in Pain, Dyspnea, Fatigue or Cough

Secondary: Health Related Quality of Life (HRQOL): Time to Deterioration (TTD) in Pain, Dyspnea, Fatigue or Cough

Secondary: Overall Mean Scores of Euro Quality of Life-5 Dimension Visual Analog Scale (EQ-5D VAS)

Secondary: Overall Mean Scores of Euro Quality of Life-5 Dimension Visual Analog Scale (EQ-5D VAS)

Secondary: Maximum Observed Plasma Concentration (Cmax) of Dacomitinib and Its Metabolite PF-05199265

Secondary: Maximum Observed Plasma Concentration (Cmax) of Dacomitinib and Its Metabolite PF-05199265

Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Dacomitinib and Its Metabolite PF-05199265

Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Dacomitinib and Its Metabolite PF-05199265

Secondary: Area Under the Plasma Concentration-Time Curve From Time 0 to End of Dosing Interval (AUCtau) of Dacomitinib and Its Metabolite PF-05199265

Secondary: Area Under the Plasma Concentration-Time Curve From Time 0 to End of Dosing Interval (AUCtau) of Dacomitinib and Its Metabolite PF-05199265

Secondary: Averaged Plasma Concentration at Steady State (Cavg) of Dacomitinib and Its Metabolite PF-05199265

Secondary: Averaged Plasma Concentration at Steady State (Cavg) of Dacomitinib and Its Metabolite PF-05199265

Secondary: Minimum Observed Plasma Concentration (Cmin) of Dacomitinib and Its Metabolite PF-05199265

Secondary: Minimum Observed Plasma Concentration (Cmin) of Dacomitinib and Its Metabolite PF-05199265

Secondary: Fluctuation Coefficient Between Trough and Peak Plasma Concentration (DF) of Dacomitinib and Its Metabolite PF-05199265

Secondary: Fluctuation Coefficient Between Trough and Peak Plasma Concentration (DF) of Dacomitinib and Its Metabolite PF-05199265

Secondary: Apparent Clearance (CL) of Dacomitinib

Secondary: Apparent Clearance (CL) of Dacomitinib

Secondary: Pre-dose Plasma Concentrations (Ctrough) of Dacomitinib and Its Metabolite PF-05199265

Secondary: Pre-dose Plasma Concentrations (Ctrough) of Dacomitinib and Its Metabolite PF-05199265

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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