Non-small Cell Lung Cancer
Conditions
Keywords
Non-small cell lung cancer, T790M mutation. dacomitinib
Brief summary
This is a Phase 2 study of oral dacomitinib given every 12 hours over days 1-4 of each two-week cycle to patients with Non-small cell lung cancer. The study includes two groups of patients, those whose tumor has a documented T790M mutation, and those without this mutation. All patients will receive repeated cycles of dacomitinib until disease progression, occurrence of unacceptable toxicity, or other withdrawal criteria are met.
Interventions
DRUGDacomitinib
Dacomitinib 45 mg every 12 hours Days 1-4 of the first week, and then 60 mg every 12 hours Days 1-4 of each 2-week cycle thereafter. The dose of dacomitinib for patients in Cohort A may be further escalated in increments of 15 mg.
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Evidence of histologically confirmed, advanced NSCLC (stage IIIB/IV). * Evidence of T790M mutation to enroll in Cohort A. * Evidence of measurable disease by radiographic technique. * Adequate organ function.
Exclusion criteria
* Patients with T790M mutation who stopped any prior EGFR-directed therapy without evidence of disease progression. * Symptomatic brain metastases. * Uncontrolled or significant cardiovascular disease. * Pregnant or breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response (BOR) in Participants With T790M Mutation | From baseline until disease progression, up to 61 weeks. | BOR was best response from start of treatment until disease progression, according to the RECIST,v1.1. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis \<10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. CR and PR were confirmed on a follow-up imaging assessment ≥4 weeks after the initial response documentation. Progression= ≥20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of any new unequivocal malignant lesions. Stable disease=not qualify for CR, PR or progression. BOR was analyzed only for participants with T790M mutation according to the primary study objective. |
| Objective Response Rate (ORR) in Participants With T790M Mutation | From baseline to disease progression, up to 61 weeks. | ORR was calculated as the percentage of participants with a confirmed CR or PR relative to the total number of participants enrolled. Response Evaluation Criteria in Solid Tumors (RECIST), version (v) 1.1 were used to define CR and PR. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis \<10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. CR and PR were confirmed on a follow-up imaging assessment ≥4 weeks after the initial response documentation. ORR was analyzed only for participants with T790M mutation according to the primary study objective. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | From baseline to disease progression or death, up to 61 weeks. | Progression-free survival was defined as the time from the date of first dosing of dacomitinib to the date of disease progression by RECIST v1.1, per the investigators' assessment, or death due to any cause, whichever occurred first. Objective progression= ≥20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of any new unequivocal malignant lesions. |
| Progression-free Survival at 4 Months | Month 4 | Progression-free survival at 4 months was defined as the percentage of participants who were alive without disease progression at 4 months relative to all participants enrolled. Disease progression was defined by RECIST v1.1. Objective progression= ≥20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of any new unequivocal malignant lesions. |
| Disease Control Rate (DCR) for Participants With T790M Mutation | From baseline to baseline to disease progression, up to 61 weeks. | DCR was calculated as the percentage of participants with an objective response (CR or PR) or stable disease, based on the RECIST, v1.1, relative to the total number of participants enrolled in the cohort. If baseline tumor assessment was inadequate for a participant, and the participant could not be assessed for RECIST responses and had no objective status of stable disease documented at least 6 weeks after the start date and before the progression, the participant was only counted in the denominator. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis \<10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. DCR was analyzed only for participants with T790M mutation according to the study objective. |
| Time to Maximum Plasma Concentration (Tmax) for Dacomitinib and PF-05199265 | Pre-dose (hour 0), 2, 4, 6, 8, and 10 hours post-dose on Day 4, Cycle 0. | Tmax was observed directly from data as time of first occurrence. Whole blood for pharmacokinetic analysis was collected immediately after completion of electrocardiograms, blood pressure, and pulse rate. |
| Changes From Time-matched Baseline in Adjusted Fridericia Corrected QT Interval (QTcF) on Echocardiogram (ECG) | From Baseline to Cycle 0, Day 4 | ECGs recorded on Day 1 of Cycle 0 were used as baseline. For the ECGs assessments, the following directions were followed by the ECG central laboratory: Blinding of ECG readers to treatment, time, and day identifiers. Review of ECGs from a particular participant was performed by a single reader. Prespecification of the lead for internal measurements. Baseline and on-treatment ECG assessments were based on the same lead. |
| Maximum Plasma Concentration (Cmax) for Dacomitinib and PF-05199265 | Pre-dose (hour 0), 2, 4, 6, 8, and 10 hours post-dose on Day 4, Cycle 0. | Cmax was observed directly from data. Whole blood for pharmacokinetic analysis was collected immediately after completion of electrocardiograms, blood pressure, and pulse rate. |
| Duration of Response in Participants With T790M Mutation | From baseline to date of disease progression or death, up to 61 weeks. | Duration of response was defined as the time from first documentation of response (CR or PR, whichever occurred first) to the date of disease progression or to death due to any cause, whichever occurred first. CR and PR were defined using RECIST, v1.1. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis \<10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. CR and PR were confirmed on a follow-up imaging assessment ≥4 weeks after the initial response documentation. DR was only calculated and summarized for the subgroup of participants with an objective tumor response in the cohort of participants with T790M mutation. |
Countries
South Korea, United States
Participant flow
Pre-assignment details
Of 41 participants enrolled in the study, 38 (16 with T790M mutation and 22 without T790M mutation) received study drug. Three of the enrolled participants without known T790M mutation did not receive treatment.
Participants by arm
| Arm | Count |
|---|---|
| Dacomitinib, 45/60 mg, With T790M Mutation Participants with documented T790M mutation in exon 20 of epidermal growth factor receptor received dacomitinib, 45 mg, every 12 hours for 6 doses over Days 1-4 of a 1-week lead-in cycle. Following the lead-in cycle, all participants received dacomitinib, 60 mg, every 12 hours for 6 doses over Days 1-4 of each subsequent 2-week cycle. Dose could be escalated beyond 60 mg after consultation with and approval of the sponsor. | 16 |
| Dacomitinib, 45/60 mg, Without T790M Mutation Participants with no known T790M mutation received dacomitinib, 45 mg, every 12 hours for 6 doses over Days 1-4 of a 1-week lead-in cycle. Following the lead-in cycle, all participants received dacomitinib, 60 mg, every 12 hours for 6 doses over Days 1-4 of each subsequent 2-week cycle. | 22 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Death | 1 | 3 |
| Overall Study | Did not receive treatment | 0 | 3 |
| Overall Study | Other | 2 | 4 |
| Overall Study | Progressive disease | 10 | 11 |
| Overall Study | Study terminated by sponsor | 0 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Dacomitinib, 45/60 mg, With T790M Mutation | Total | Dacomitinib, 45/60 mg, Without T790M Mutation |
|---|---|---|---|
| Age, Customized 65 years and older | 5 Participants | 14 Participants | 9 Participants |
| Age, Customized Between 18 and 44 years | 2 Participants | 2 Participants | 0 Participants |
| Age, Customized Between 45 and 64 years | 9 Participants | 22 Participants | 13 Participants |
| Age, Customized Younger than 18 years | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 7 Participants | 17 Participants | 10 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 4 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 6 Participants | 15 Participants | 9 Participants |
| Sex: Female, Male Female | 12 Participants | 24 Participants | 12 Participants |
| Sex: Female, Male Male | 4 Participants | 14 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 16 | 22 / 22 |
| serious Total, serious adverse events | 7 / 16 | 8 / 22 |
Outcome results
Primary
Best Overall Response (BOR) in Participants With T790M Mutation
BOR was best response from start of treatment until disease progression, according to the RECIST,v1.1. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis \<10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. CR and PR were confirmed on a follow-up imaging assessment ≥4 weeks after the initial response documentation. Progression= ≥20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of any new unequivocal malignant lesions. Stable disease=not qualify for CR, PR or progression. BOR was analyzed only for participants with T790M mutation according to the primary study objective.
Time frame: From baseline until disease progression, up to 61 weeks.
Population: All enrolled participants with T790M mutation
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dacomitinib, 45/60 mg, With T790M Mutation | Best Overall Response (BOR) in Participants With T790M Mutation | Complete response (CR) | 0 Participants |
| Dacomitinib, 45/60 mg, With T790M Mutation | Best Overall Response (BOR) in Participants With T790M Mutation | Partial response (PR) | 1 Participants |
| Dacomitinib, 45/60 mg, With T790M Mutation | Best Overall Response (BOR) in Participants With T790M Mutation | Stable disease/no response | 7 Participants |
| Dacomitinib, 45/60 mg, With T790M Mutation | Best Overall Response (BOR) in Participants With T790M Mutation | Objective progression | 6 Participants |
| Dacomitinib, 45/60 mg, With T790M Mutation | Best Overall Response (BOR) in Participants With T790M Mutation | Indeterminate | 2 Participants |
Primary
Objective Response Rate (ORR) in Participants With T790M Mutation
ORR was calculated as the percentage of participants with a confirmed CR or PR relative to the total number of participants enrolled. Response Evaluation Criteria in Solid Tumors (RECIST), version (v) 1.1 were used to define CR and PR. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis \<10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. CR and PR were confirmed on a follow-up imaging assessment ≥4 weeks after the initial response documentation. ORR was analyzed only for participants with T790M mutation according to the primary study objective.
Time frame: From baseline to disease progression, up to 61 weeks.
Population: All enrolled participants with T90M mutation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dacomitinib, 45/60 mg, With T790M Mutation | Objective Response Rate (ORR) in Participants With T790M Mutation | 6.3 Percentage of participants |
Secondary
Changes From Time-matched Baseline in Adjusted Fridericia Corrected QT Interval (QTcF) on Echocardiogram (ECG)
ECGs recorded on Day 1 of Cycle 0 were used as baseline. For the ECGs assessments, the following directions were followed by the ECG central laboratory: Blinding of ECG readers to treatment, time, and day identifiers. Review of ECGs from a particular participant was performed by a single reader. Prespecification of the lead for internal measurements. Baseline and on-treatment ECG assessments were based on the same lead.
Time frame: From Baseline to Cycle 0, Day 4
Population: All participants who received all scheduled doses of dacomitinib and had all ECGs performed on Days 1-4 of Cycle 0 (n=number evaluable)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Dacomitinib, 45/60 mg, With T790M Mutation | Changes From Time-matched Baseline in Adjusted Fridericia Corrected QT Interval (QTcF) on Echocardiogram (ECG) | QTcF Interval Cycle 0, Day 4: Hour 0 | 1.7 msecs |
| Dacomitinib, 45/60 mg, With T790M Mutation | Changes From Time-matched Baseline in Adjusted Fridericia Corrected QT Interval (QTcF) on Echocardiogram (ECG) | QTcF Interval Cycle 0, Day 4: Hour 2 | 4.4 msecs |
| Dacomitinib, 45/60 mg, With T790M Mutation | Changes From Time-matched Baseline in Adjusted Fridericia Corrected QT Interval (QTcF) on Echocardiogram (ECG) | QTcF Interval Cycle 0, Day 4: Hour 4 | 0.4 msecs |
| Dacomitinib, 45/60 mg, With T790M Mutation | Changes From Time-matched Baseline in Adjusted Fridericia Corrected QT Interval (QTcF) on Echocardiogram (ECG) | QTcF Interval Cycle 0, Day 4: Hour 6 (n=31) | -0.4 msecs |
| Dacomitinib, 45/60 mg, With T790M Mutation | Changes From Time-matched Baseline in Adjusted Fridericia Corrected QT Interval (QTcF) on Echocardiogram (ECG) | QTcF Interval Cycle 0, Day 4: Hour 8 (n=31) | 0.1 msecs |
| Dacomitinib, 45/60 mg, With T790M Mutation | Changes From Time-matched Baseline in Adjusted Fridericia Corrected QT Interval (QTcF) on Echocardiogram (ECG) | QTcF Interval Cycle 0, Day 4: Hour 10 (n=31) | 0.5 msecs |
Secondary
Disease Control Rate (DCR) for Participants With T790M Mutation
DCR was calculated as the percentage of participants with an objective response (CR or PR) or stable disease, based on the RECIST, v1.1, relative to the total number of participants enrolled in the cohort. If baseline tumor assessment was inadequate for a participant, and the participant could not be assessed for RECIST responses and had no objective status of stable disease documented at least 6 weeks after the start date and before the progression, the participant was only counted in the denominator. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis \<10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. DCR was analyzed only for participants with T790M mutation according to the study objective.
Time frame: From baseline to baseline to disease progression, up to 61 weeks.
Population: All enrolled participants with T790M mutation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dacomitinib, 45/60 mg, With T790M Mutation | Disease Control Rate (DCR) for Participants With T790M Mutation | 50 Percentage of participants |
Secondary
Duration of Response in Participants With T790M Mutation
Duration of response was defined as the time from first documentation of response (CR or PR, whichever occurred first) to the date of disease progression or to death due to any cause, whichever occurred first. CR and PR were defined using RECIST, v1.1. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis \<10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. CR and PR were confirmed on a follow-up imaging assessment ≥4 weeks after the initial response documentation. DR was only calculated and summarized for the subgroup of participants with an objective tumor response in the cohort of participants with T790M mutation.
Time frame: From baseline to date of disease progression or death, up to 61 weeks.
Population: All enrolled participants with T790M mutation status who had an objective tumor response (complete or partial response)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dacomitinib, 45/60 mg, With T790M Mutation | Duration of Response in Participants With T790M Mutation | 2.83 Months |
Secondary
Maximum Plasma Concentration (Cmax) for Dacomitinib and PF-05199265
Cmax was observed directly from data. Whole blood for pharmacokinetic analysis was collected immediately after completion of electrocardiograms, blood pressure, and pulse rate.
Time frame: Pre-dose (hour 0), 2, 4, 6, 8, and 10 hours post-dose on Day 4, Cycle 0.
Population: All participants who received at least 1 dose of study drug and who had at least 1 measured plasma concentration of dacomitinib or its major circulating metabolite PF 05199265.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dacomitinib, 45/60 mg, With T790M Mutation | Maximum Plasma Concentration (Cmax) for Dacomitinib and PF-05199265 | Dacomitnib | 96.76 ng/mL | Standard Deviation 37.51 |
| Dacomitinib, 45/60 mg, With T790M Mutation | Maximum Plasma Concentration (Cmax) for Dacomitinib and PF-05199265 | PF-05199265 (Dacomitnib metabolite) | 8.45 ng/mL | Standard Deviation 12.648 |
Secondary
Progression-free Survival
Progression-free survival was defined as the time from the date of first dosing of dacomitinib to the date of disease progression by RECIST v1.1, per the investigators' assessment, or death due to any cause, whichever occurred first. Objective progression= ≥20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of any new unequivocal malignant lesions.
Time frame: From baseline to disease progression or death, up to 61 weeks.
Population: All enrolled participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dacomitinib, 45/60 mg, With T790M Mutation | Progression-free Survival | 2.3 Months |
| Dacomitinib, 45/60 mg, Without T790M Mutation | Progression-free Survival | 1.6 Months |
Secondary
Progression-free Survival at 4 Months
Progression-free survival at 4 months was defined as the percentage of participants who were alive without disease progression at 4 months relative to all participants enrolled. Disease progression was defined by RECIST v1.1. Objective progression= ≥20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of any new unequivocal malignant lesions.
Time frame: Month 4
Population: All enrolled participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dacomitinib, 45/60 mg, With T790M Mutation | Progression-free Survival at 4 Months | 37.5 Percentage of participants |
| Dacomitinib, 45/60 mg, Without T790M Mutation | Progression-free Survival at 4 Months | 25.3 Percentage of participants |
Secondary
Time to Maximum Plasma Concentration (Tmax) for Dacomitinib and PF-05199265
Tmax was observed directly from data as time of first occurrence. Whole blood for pharmacokinetic analysis was collected immediately after completion of electrocardiograms, blood pressure, and pulse rate.
Time frame: Pre-dose (hour 0), 2, 4, 6, 8, and 10 hours post-dose on Day 4, Cycle 0.
Population: All participants who received at least 1 dose of study drug and who had at least 1 measured plasma concentration of dacomitinib or its major circulating metabolite PF 05199265.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dacomitinib, 45/60 mg, With T790M Mutation | Time to Maximum Plasma Concentration (Tmax) for Dacomitinib and PF-05199265 | Dacomitinib | 6.07 Hours |
| Dacomitinib, 45/60 mg, With T790M Mutation | Time to Maximum Plasma Concentration (Tmax) for Dacomitinib and PF-05199265 | PF-05199265 | 5.58 Hours |