ARCHER1050: A Study of Dacomitinib vs. Gefitinib in 1st-Line Treatment Of Advanced NSCLC.

PFS: 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: \>=20% increase in sum of diameters of target lesions (TLs), referring smallest sum on study, sum must be an absolute increase of \>=5 mm, appearance of \>=1 new lesions; unequivocal progression of existing non TLs. 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.

Time frame: 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)

Population: Intent to treat (ITT) Population included all randomized participants, with study treatment assignment designated according to initial randomization, regardless of whether participants received study treatment or a different treatment from that to which they were randomized.

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).

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

Population: PK analysis set included all participants 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 outcome measure was planned to be analyzed in Chinese subgroup only.

AUCtau was defined as area under the plasma concentration-time curve over dosing interval tau and was determined by Linear/Log trapezoidal method.

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

Population: PK analysis set included all participants 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 outcome measure was planned to be analyzed in Chinese subgroup only.

Cavg was defined as averaged plasma concentration at steady state, and was calculated as AUCtau/tau.

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

Population: PK analysis set included all participants 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 outcome measure was planned to be analyzed in Chinese subgroup only.

DoR was defined as time from first documentation of objective response(CR or PR, whichever occurred first)to date of PD/death from any cause, whichever occurred first. CR: disappearance of all target lesions (TLs), non TLs; any pathological lymph nodes (LN) must reduce in short axis to \<10 mm; normalization of tumour marker level, for non TL all LN must be non-pathological in size (\<10 mm short axis); PR:\>=30% decrease in sum of diameters of TLs, referring baseline sum diameters. PD:\>=20% increase in sum of diameters of TLs, referring smallest sum on study, sum must be an absolute increase of \>=5 mm, appearance of \>=1 new lesions; unequivocal progression of existing non TLs. DoR was recorded based on IRC review and investigator's assessment and summarized for subgroup of participants with objective disease response.

Time frame: 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)

Population: ITT Population included all randomized participants, with study treatment assignment designated according to initial randomization, regardless of whether participants received study treatment or a different treatment from that to which they were randomized.

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.

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

Population: PK analysis set included all participants 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 outcome measure was planned to be analyzed in Chinese subgroup only.

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 baseline 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 participants completed an assessment for pain, dyspnea, fatigue or cough.

Time frame: Baseline until the end of treatment (up to 48 months)

Population: Patient reported outcomes (PRO) analysis set included all enrolled participants, who started treatment and completed a baseline PRO assessments and at least one post-baseline PRO assessment after the first dose.

Cmax was defined as maximum observed plasma concentration and can be observed directly from data.

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

Population: Pharmacokinetic (PK) analysis set included all participants 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 outcome measure was planned to be analyzed in Chinese subgroup only.

Cmin was defined as minimum observed plasma concentration and can be observed directly from data.

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

Population: PK analysis set included all participants 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 outcome measure was planned to be analyzed in Chinese subgroup only.

BOR for CR/PR:\>=1 objective status (OBS) of CR/PR documented before PD; SD:\>=1 OBS of stable documented \>=8 weeks (wks) post treatment & before PD, not qualifying as CR/PR; PD:OBS of PD within 12 wks treatment, not qualifying as CR/PR/SD; indeterminate:PD not documented within 12 wks post treatment & no other response category applies. RECIST v1.1, CR:disappearance of all target lesions (TLs), non TLs;any pathological lymph nodes (LN) must reduce in short axis to \<10 mm; normalization of tumour marker level, for non TL all LN must be non-pathological in size (\<10 mm short axis); PR:\>=30% decrease in sum of diameters of TLs, referring baseline sum diameters. SD:neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, referring smallest sum diameters on study. PD:\>=20% increase in sum of diameters of TLs, referring smallest sum on study, sum must be an absolute increase of \>=5 mm, appearance of \>=1 new lesions;unequivocal progression of existing non TLs.

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

Population: ITT Population included all randomized participants, with study treatment assignment designated according to initial randomization, regardless of whether participants received study treatment or a different treatment from that to which they were randomized.

BOR for CR/PR:\>=1 objective status (OBS) of CR/PR documented before PD; SD:\>=1 OBS of stable documented \>=8 weeks (wks) post treatment & before PD, not qualifying as CR/PR; PD:OBS of PD within 12 wks treatment, not qualifying as CR/PR/SD; indeterminate:PD not documented within 12 wks post treatment & no other response category applies. RECIST v1.1, CR:disappearance of all target lesions (TLs), non TLs;any pathological lymph nodes (LN) must reduce in short axis to \<10 mm; normalization of tumour marker level, for non TL all LN must be non-pathological in size (\<10 mm short axis); PR:\>=30% decrease in sum of diameters of TLs, referring baseline sum diameters. SD:neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, referring smallest sum diameters on study. PD:\>=20% increase in sum of diameters of TLs, referring smallest sum on study, sum must be an absolute increase of \>=5 mm, appearance of \>=1 new lesions;unequivocal progression of existing non TLs.

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

Population: ITT Population included all randomized participants, with study treatment assignment designated according to initial randomization, regardless of whether participants received study treatment or a different treatment from that to which they were randomized.

Criteria for vital signs abnormalities: postbaseline pulse rate less than (\<) 50 beats per minute (bpm) or greater than (\>)130 bpm and maximum increase from baseline in pulse rate \>=30 bpm and maximum decrease from baseline in pulse rate \<=30 bpm. Systolic blood pressure (BP) 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. And MDB in diastolic BP\<=-40 mmHg. Only categories with at least 1 participant with abnormality are reported in this outcome measure.

Time frame: From randomization until death or last date known as alive, up to 61 months

Population: Safety analysis set included all participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.

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, \>=500msec. The number of participants with potentially clinically significant ECG findings at any visit were reported.

Time frame: From randomization until death or last date known as alive, up to 61 months

Population: Safety analysis set included all participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received. Here, N (number of participants analyzed) signifies participants who were evaluable for this specified outcome measure.

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; Grade 4=life-threatening; Grade 5=death related to AE. Only categories with at least 1 participant with abnormality are reported in this outcome measure.

Time frame: From randomization until death or last date known as alive, up to 61 months

Population: Safety analysis set included all participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.

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 participants. Urine sediment abnormality was defined as the presence of any bacteria, casts, crystals, and epithelial cells. Only categories with at least 1 participant with abnormality are reported in this outcome measure.

Time frame: From randomization until death or last date known as alive, up to 61 months

Population: Safety analysis set included all participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.

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.

Time frame: From baseline up to 7 days of Cycle 4 (up to 91 days)

Population: Safety analysis set included all participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received. Here N signifies number of participants who were evaluable for this specified outcome measure.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.AEs included both serious and non- serious adverse events. An 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.

Time frame: From randomization until death or last date known as alive, up to 91 months

Population: Safety analysis set included all participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.

Percentage of participants with a BOR of either CR or PR based on investigator assessment recorded from the start of treatment until disease progression based on RECIST v1.1. CR: disappearance of all target lesions (TLs), non TLs; any pathological lymph nodes (LN) must reduce in short axis to \<10 mm; normalization of tumour marker level, for non TL all LN must be non-pathological in size (\<10 mm short axis); PR:\>=30% decrease in sum of diameters of TLs, referring baseline sum diameters. PD:\>=20% increase in sum of diameters of TLs, referring smallest sum on study, sum must be an absolute increase of \>=5 mm, appearance of \>=1 new lesions; unequivocal progression of existing non TLs.

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

Population: ITT Population included all randomized participants, with study treatment assignment designated according to initial randomization, regardless of whether participants received study treatment or a different treatment from that to which they were randomized.

Percentage of participants with a BOR of either CR or PR based on IRC review recorded from the start of treatment until disease progression based on RECIST v1.1. CR: disappearance of all target lesions (TLs), non TLs; any pathological lymph nodes (LN) must reduce in short axis to \<10 mm; normalization of tumour marker level, for non TL all LN must be non-pathological in size (\<10 mm short axis); PR:\>=30% decrease in sum of diameters of TLs, referring baseline sum diameters. PD:\>=20% increase in sum of diameters of TLs, referring smallest sum on study, sum must be an absolute increase of \>=5 mm, appearance of \>=1 new lesions; unequivocal progression of existing non TLs.

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

Population: ITT Population included all randomized participants, with study treatment assignment designated according to initial randomization, regardless of whether participants received study treatment or a different treatment from that to which they were randomized.

OS30m was defined as the probability of a participant being alive at 30 months from date of randomization.

Time frame: Up to 30 months from date of randomization

Population: ITT Population included all randomized participants, with study treatment assignment designated according to initial randomization, regardless of whether participants received study treatment or a different treatment from that to which they were randomized.

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 participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).

Time frame: From Cycle 1 Day 1 up to 48 months

Population: PRO analysis set included all enrolled participants, who started treatment and completed a baseline PRO assessments and at least one post-baseline PRO assessment after the first dose. Here N signifies number of participants who were evaluable for this specified outcome measure.

OS was defined as the time from randomization to the date of death for any cause. In the absence of confirmation of death, survival time was censored at the last date the participant was known to be alive. OS (month)=\[death date or last known alive date - randomization date + 1\]/30.4375.

Time frame: From randomization until death or last date known as alive, up to 45 months

Population: ITT Population included all randomized participants, with study treatment assignment designated according to initial randomization, regardless of whether participants received study treatment or a different treatment from that to which they were randomized.

Trough plasma concentration was defined as the measured concentration at the end of a dosing interval at steady state (taken directly before next administration).

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

Population: PK analysis set included all participants who were treated with dacomitinib with at least one measured plasma concentration and were dose-compliant. Dose-compliant participants 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, 'Number Analyzed' = participants evaluable for this outcome measure at specified time points.

PFS: time from randomization to date of PD as determined by investigator assessment 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.

Time frame: 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)

Population: ITT Population included all randomized participants, with study treatment assignment designated according to initial randomization, regardless of whether participants received study treatment or a different treatment from that to which they were randomized.

Tmax was defined as time to first occurrence of Cmax and can be observed directly from data as time of first occurrence.

Time frame: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose (sample collection time points had window of +/- 10% of nominal time) on Cycle 2 Day 1 (Day 29)

Population: PK analysis set included all participants 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 outcome measure was planned to be analyzed in Chinese subgroup only.