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

Study Overview
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Brief Summary
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This is a multinational, multicenter, randomized, open-label, Phase 3 study comparing the efficacy and safety of treatment with dacomitinib (PF-00299804) to treatment with gefitinib in patients with locally advanced or metastatic non-small cell lung cancer, with epidermal growth factor receptor EGFR-activating mutation (s). Analyses of primary objective (Progression Free Survival) will be done as defined in the protocol.

Detailed Description
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452 patients were randomized in a 1:1 ratio between dacomitinib (PF-00299804 ) vs. gefitinib.

Official Title
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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 IN SUBJECTS WITH EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) ACTIVATING MUTATION(S)

Conditions
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Non-small Cell Lung Cancer With EGFR-Activating Mutations

Intervention / Treatment
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* Drug: Dacomitinib (PF-00299804)
* Drug: Gefitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Evidence of histo or cytopathology confirmed, advanced NSCLC (with known histology) with the presence of EGFR-activating mutation (exon 19 deletion or the L858R mutation in exon 21). It is acceptable for subjects with the presence of the exon 20 T790M mutation together with either EGFR-activating mutation (exon 19 deletion or the L858R mutation in exon 21) to be included in this study No prior treatment with systemic therapy for locally advanced or metastatic NSCLC. Minimum of 12 months disease free interval between completion of neoadjuvant/adjuvant systemic therapy and recurrence of NSCLC Adequate tissue sample must be available for central analyses. Adequate renal, hematologic, liver function. ECOG PS of 0-1. Radiologically measurable disease. Exclusion Criteria: Any evidence of mixed histology that includes elements of small cell or carcinoid lung cancer. Any other mutation other than exon 19 deletion or L858R in exon 21, with or without the presence of the exon 20 T790M mutation. Any history of brain metastases or leptomeningeal metastases. Any previous anti-cancer systemic treatment of early, locally advanced, or metastatic NSCLC. Any surgery(not including minor procedures such as lymph node biopsy), palliative radiotherapy or pleurodesis within 2 weeks of baseline assessments Any clinically significant gastrointestinal abnormalities that may impair intake, transit or absorption of the study drug. Current enrollment in another therapeutic clinical study. History of, or currently suspected, diffuse non-infectious pneumonitis or interstitial lung disease Uncontrolled medical disorders. Prior malignancy and concurrent malignancy except for non melanoma skin cancer or in-situ cervical cancer with no evidence of active disease. Use of narrow therapeutic index drugs that are CYP2D6 substrates from screening to randomization.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dacomitinib (PF-00299804)<br>Dacomitinib (PF-00299804) is provided as 45 mg tablets, continuous oral daily dosing. | Drug: Dacomitinib (PF-00299804)<br>* Dacomitinib (PF-00299804) 45 mg tablets, continuous oral daily dosing.<br>* Other names: Dacomitinib;|
| Active Comparator: gefitinib<br>Gefitinib is provided as 250 mg tablets, continuous oral daily dosing. | Drug: Gefitinib<br>* Gefitinib 250 mg tablets, continuous oral daily dosing.<br>* Other names: Iressa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) Based on Independent Radiologic Central (IRC) Review | 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. | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | 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. | From randomization until death or last date known as alive, up to 45 months | 
| OS at 30 Months (OS30m) | OS30m was defined as the probability of a participant being alive at 30 months from date of randomization. | Up to 30 months from date of randomization | 
| Progression Free Survival (PFS) Based on Investigator Assessment | 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. | 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) | 
| Number of Participants With Best Overall Response (BOR) Based on IRC Review | 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. | Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months) | 
| Number of Participants With Best Overall Response (BOR) Based on Investigator Assessment | 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. | Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months) | 
| Duration of Response (DoR) | 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. | 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) | 
| Objective Response Rate (ORR) Based on IRC Review | 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. | Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months) | 
| Objective Response Rate (ORR) Based on Investigator Assessment | 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. | Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months) | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | From randomization until death or last date known as alive, up to 91 months | 
| Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03: Biochemistry and 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; 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. | From randomization until death or last date known as alive, up to 61 months | 
| Number of Participants With Laboratory Test Abnormalities: Urinalysis | 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. | From randomization until death or last date known as alive, up to 61 months | 
| Number of Participants With Clinically Significant Abnormalities in Vital Signs | 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. | From randomization until death or last date known as alive, up to 61 months | 
| Number of Participants With Clinically Significant Abnormality in Electrocardiogram (ECG) | 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. | From randomization until death or last date known as alive, up to 61 months | 
| Number of Participants With Maximum Relative Decrease From Baseline >20% in Left Ventricular Ejection Fraction (LVEF) | 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. | From baseline up to 7 days of Cycle 4 (up to 91 days) | 
| Health Related Quality of Life (HRQOL): Time to Deterioration (TTD) in Pain, Dyspnea, Fatigue or Cough | 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. | Baseline until the end of treatment (up to 48 months) | 
| Overall Mean Scores of Euro Quality of Life-5 Dimension Visual Analog Scale (EQ-5D VAS) | 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). | From Cycle 1 Day 1 up to 48 months | 
| Maximum Observed Plasma Concentration (Cmax) of Dacomitinib and Its Metabolite PF-05199265 | Cmax was defined as maximum observed plasma concentration and can be observed directly from data. | Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29) | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Dacomitinib and Its Metabolite PF-05199265 | Tmax was defined as time to first occurrence of Cmax and can be observed directly from data as time of first occurrence. | 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) | 
| Area Under the Plasma Concentration-Time Curve From Time Zero (0) to End of Dosing Interval (AUCtau) of Dacomitinib and Its Metabolite PF-05199265 | AUCtau was defined as area under the plasma concentration-time curve over dosing interval tau and was determined by Linear/Log trapezoidal method. | Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29) | 
| Averaged Plasma Concentration at Steady State (Cavg) of Dacomitinib and Its Metabolite PF-05199265 | Cavg was defined as averaged plasma concentration at steady state, and was calculated as AUCtau/tau. | Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29) | 
| Minimum Observed Plasma Concentration (Cmin) of Dacomitinib and Its Metabolite PF-05199265 | Cmin was defined as minimum observed plasma concentration and can be observed directly from data. | Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29) | 
| Fluctuation Coefficient Between Trough and Peak Plasma Concentration (DF) of Dacomitinib and Its Metabolite PF-05199265 | 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. | Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29) | 
| Apparent Clearance (CL) of Dacomitinib | 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). | Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29) | 
| Pre-dose Plasma Concentrations (Ctrough) of Dacomitinib and Its Metabolite PF-05199265 | Trough plasma concentration was defined as the measured concentration at the end of a dosing interval at steady state (taken directly before next administration). | Pre-dose on Day 1 of Cycle 2, 3, 4, 5 and 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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first-line, locally advanced or metastatic, non-small cell lung cancer, epidermal growth factor receptor, EGFR, ARCHER, mutation, dacomitinib, PF-00299804