Advanced Malignancies, Carcinoma, Lung Cancer, Non-small Cell Lung Cancer
Conditions
Keywords
Non-small cell lung cancer, Non-small cell lung carcinoma, Epithelial lung cancer, Squamous cell carcinoma, Large cell carcinoma, Adenocarcinoma, Carcinoma, Anaplastic Lymphoma Kinase (ALK), Advanced Cancers, Brigatinib, AP26113
Brief summary
The purpose of the study is to compare the efficacy of brigatinib to that of crizotinib in ALK+ locally advanced or metastatic non-small cell lung cancer (NSCLC) participants naive to ALK inhibitors, as evidenced by progression-free survival (PFS).
Detailed description
The purpose of this phase III, randomized, open-label, comparative, multicenter, international study is to compare the efficacy and safety of brigatinib to that of crizotinib in ALK+ locally advanced or metastatic NSCLC participants who have not previously been treated with an ALK inhibitor. Participants will be stratified by the presence of CNS metastases at baseline and prior chemotherapy used for locally advanced or metastatic disease. Participants will be randomized in a 1:1 ratio to receive either brigatinib, 90 mg orally once daily (QD) for 7 days, then a 180 mg orally QD, or crizotinib, 250 mg orally twice daily (BID). Participants will receive treatment until disease progression, intolerable toxicity, consent withdrawal, or death. Crossover from crizotinib to brigatinib is also permitted. The total estimated duration of the study is at least 4.5 years, including 1.5 years to accrue participants, with at least 3 years for treatment and follow-up.
Interventions
DRUGBrigatinib
Brigatinib tablets
DRUGCrizotinib
Crizotinib tablets
Sponsors
Ariad Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Have histologically or cytologically confirmed stage IIIB (and not a candidate for definitive multimodality therapy) or stage four (IV) NSCLC. 2. Must have documented ALK rearrangement. 3. Have sufficient tumor tissue available for central analysis. 4. Have at least 1 measurable (that is, target) lesion per RECIST v1.1. 5. Recovered from toxicities related to prior anticancer therapy to National Cancer Institute (of the United States) (NCI) Common Terminology Criteria for Adverse Events (version 4.0) (CTCAE v 4.0) grade be less than or equal to (\<=) 1. 6. Are a male or female participants greater than or equal to (\>=)18 years old. 7. Have adequate organ function, as defined by the study protocol. 8. Have Eastern Cooperative Oncology Group (ECOG) performance status \<=2. 9. Have normal QT interval on screening ECG evaluation, defined as QT interval corrected (Fridericia) (QTcF) of \<= 450 millisecond (msec) in males or \<=470 msec in females. 10. For female participants of childbearing potential, have a negative pregnancy test documented prior to randomization. 11. For female and male participants who are fertile, agree to use a highly effective form of contraception, as defined by the study protocol. 12. Provide signed and dated informed consent indicating that the participants has been informed of all pertinent aspects of the study, including the potential risks, and is willingly participating. 13. Have the willingness and ability to comply with scheduled visit and study procedures.
Exclusion criteria
1. Previously received an investigational antineoplastic agent for NSCLC. 2. Previously received any prior tyrosine kinase inhibitor (TKI), including ALK-targeted TKIs. 3. Previously received more than 1 regimen of systemic anticancer therapy for locally advanced or metastatic disease. 4. Received chemotherapy or radiation within 14 days of first dose of study drug, except stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT). 5. Received anti-neoplastic monoclonal antibodies within 30 days of the first dose of study drug. 6. Had major surgery within 30 days of the first dose of study drug, minor surgical procedures such as catheter placement or minimally invasive biopsies are allowed. 7. Have been diagnosed with another primary malignancy other than NSCLC, except for adequately treated non-melanoma skin cancer or cervical cancer in situ; definitively treated non-metastatic prostate cancer; or participants with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy. 8. Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening or asymptomatic disease requiring an increasing dose of corticosteroids to control symptoms within 7 days prior to randomization. 9. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Participants with leptomeningeal disease and without cord compression are allowed. 10. Be pregnant, planning a pregnancy, or breastfeeding. 11. Have significant, uncontrolled, or active cardiovascular disease, as defined by the study protocol. 12. Have uncontrolled hypertension. 13. Have a history or the presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis. 14. Have an ongoing or active infection. 15. Have a known history of human immunodeficiency virus (HIV) infection. 16. Have a known or suspected hypersensitivity to brigatinib or its excipients and/or crizotinib or its excipients. 17. Have malabsorption syndrome or other gastrointestinal (GI) illness or condition. 18. Have any condition or illness that, in the opinion of the investigator, would compromise participant's safety or interfere with the evaluation of the study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to end of study (Up to 56 months) | PFS as assessed by Blinded Independent Review Committee (BIRC), per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, was defined as the time interval from the date of randomization until the date of the first documented PD event. The data was censored for participants without a PFS event. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Intracranial ORR (iORR) | Baseline up to end of treatment (Up to 36 months) | ORR was defined as percentage of participants who achieved CR or PR in the central nervous system (CNS) in randomized participants with intracranial CNS metastasis at baseline. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. |
| Intracranial Progression Free Survival | Baseline up to end of study (Up to 56 months) | Intracranial PFS as assessed by BIRC, is defined as the time from randomization until first CNS PD is documented, or death due to any cause. PD is SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest), the SLD must also demonstrate an absolute increase of at least 5 mm, and unequivocal progression of existing non-target lesions. |
| Overall Survival (OS) | Baseline up to end of study (Up to 56 months) | Overall survival is defined as the time from randomization until death due to any cause. |
| Duration of Response (DOR) | Baseline up to end of study (Up to 56 months) | Duration of response as assessed by BIRC, is defined as the time interval from the date that the criteria are first met for CR/PR (whichever is first recorded) until the first date that progressive disease (PD) is objectively documented. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30 % decrease in the SLD of target lesions, taking as reference the baseline sum diameters. PD is SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest), the SLD must also demonstrate an absolute increase of at least 5 mm, and for non-target lesions, unequivocal progression of existing non-target lesions. |
| Confirmed Objective Response Rate (ORR) | Baseline up to end of treatment (Up to 36 months) | ORR was defined as percentage of participants who achieved Complete response (CR) or Partial responses (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v). 1.1 criteria. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to less than (\<) 10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in SLD of target lesions, taking as reference baseline sum diameters. |
| Disease Control Rate (DCR) | Baseline up to end of treatment (Up to 36 months) | Disease control as assessed by BIRC, defined as percentage of randomized participants who have achieved CR, PR, or stable disease (SD) after randomization. CR defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR: at least a 30% decrease in SLD of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: SLD increased by at least 20% from the smallest value on study, SLD must also demonstrate an absolute increase of at least 5 mm, and unequivocal progression of existing non-target lesions. |
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | From first dose up to 30 days after last dose of study drug (Up to approximately 37 months) | An AE is any untoward medical occurrence in a participant. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product whether or not considered related to the medicinal product. Any worsening of a preexisting condition which is temporally associated with the use of the study drug (i.e., occurs after the first dose of study drug) is also an AE. TEAEs are defined as AEs starting/worsening on or after the first dose of study treatment and no later than the earliest of 30 days after the last dose of the treatment to which the participant was assigned, or the day before start of brigatinib therapy in crossover participant. |
| Change From Baseline in Global Health Status/Quality of Life as Assessed by EORTC QLQ-C30 (Version 3.0) | Baseline and Month 36 | HRQoL: perceived quality of participant's life, includes self-reported multidimensional measures of physical and mental health. Patient-reported symptoms (PROs) and HRQoL will be collected by administering the european organisation for research and treatment of cancer (EORTC) quality of life (QLQ)-C30 questionnaire. EORTC-QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status/QOL scale. The 30 items have 4 response levels (not at all, a little, quite a bit, and very much), with 2 questions relying on a 7-point numeric rating scale. Raw scores are converted into overall score ranging from 0 to 100, where lower scores indicate better QOL. A negative change from Baseline indicates improvement. |
| Time to Response (TTR) | Baseline up to end of treatment (Up to 36 months) | Time to response as assessed by BIRC, assessment and is defined as the time interval from the date of randomization until the initial observation of CR or PR. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. |
Countries
Australia, Austria, Canada, Denmark, France, Germany, Hong Kong, Italy, Luxembourg, Netherlands, Norway, Singapore, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 92 investigative sites in Australia, Hong Kong, Singapore, South Korea, Taiwan, Austria, Denmark, France, Germany, Italy, Luxembourg, Netherlands, Norway, Spain, Sweden, Switzerland, United Kingdom, Canada, and the United States of America from 26 May 2016 to 29 January 2021.
Pre-assignment details
Participants with anaplastic lymphoma kinase and non-small-cell lung cancer (ALK+ NSCLC) who had not previously received an ALK-targeted tyrosine kinase inhibitor (TKI) were enrolled in 1:1 ratio to receive brigatinib 90 mg for 7 days followed by 180 mg or crizotinib 250 mg. Participants from crizotinib arm who experienced progressive disease (PD) or received radiotherapy to the brain in Randomized Phase were crossed over to receive brigatinib 90 mg/180 mg in the Crossover Phase.
Participants by arm
| Arm | Count |
|---|---|
| Randomized Phase: Brigatinib 90 mg QD/180 QD Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months). | 137 |
| Randomized Phase: Crizotinib 250 mg BID Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months). | 138 |
| Total | 275 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Crossover Phase | Died | 0 | 0 | 22 |
| Crossover Phase | Physician Decision | 0 | 0 | 1 |
| Crossover Phase | Site Terminated by Sponsor | 0 | 0 | 23 |
| Crossover Phase | Withdrew Consent | 0 | 0 | 9 |
| Randomized Phase | Died | 41 | 29 | 0 |
| Randomized Phase | Lost to Follow-up | 0 | 1 | 0 |
| Randomized Phase | Never Treated | 1 | 1 | 0 |
| Randomized Phase | Reason not Specified | 1 | 1 | 0 |
| Randomized Phase | Site Terminated by Sponsor | 58 | 16 | 0 |
| Randomized Phase | Withdrawal by Subject | 16 | 6 | 0 |
Baseline characteristics
| Characteristic | Randomized Phase: Brigatinib 90 mg QD/180 QD | Randomized Phase: Crizotinib 250 mg BID | Total |
|---|---|---|---|
| Age, Continuous | 57.9 years STANDARD_DEVIATION 13.46 | 58.6 years STANDARD_DEVIATION 11.42 | 58.2 years STANDARD_DEVIATION 12.46 |
| Global Health Status/Quality of Life (QoL) | 60.432 score on a scale | 59.160 score on a scale | 59.796 score on a scale |
| Race/Ethnicity, Customized Hispanic, Latino or Spanish | 6 Participants | 10 Participants | 16 Participants |
| Race/Ethnicity, Customized Not Hispanic, Latino or Spanish | 131 Participants | 128 Participants | 259 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 59 Participants | 49 Participants | 108 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 76 Participants | 86 Participants | 162 Participants |
| Region of Enrollment Australia | 2 Participants | 5 Participants | 7 Participants |
| Region of Enrollment Austria | 5 Participants | 4 Participants | 9 Participants |
| Region of Enrollment Canada | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Denmark | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment France | 7 Participants | 4 Participants | 11 Participants |
| Region of Enrollment Germany | 6 Participants | 11 Participants | 17 Participants |
| Region of Enrollment Hong Kong | 10 Participants | 6 Participants | 16 Participants |
| Region of Enrollment Italy | 19 Participants | 19 Participants | 38 Participants |
| Region of Enrollment Korea, Republic Of | 29 Participants | 28 Participants | 57 Participants |
| Region of Enrollment Luxembourg | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Netherlands | 5 Participants | 6 Participants | 11 Participants |
| Region of Enrollment Norway | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Singapore | 5 Participants | 1 Participants | 6 Participants |
| Region of Enrollment Spain | 14 Participants | 17 Participants | 31 Participants |
| Region of Enrollment Sweden | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Switzerland | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Taiwan, Province Of China | 12 Participants | 9 Participants | 21 Participants |
| Region of Enrollment United Kingdom | 10 Participants | 8 Participants | 18 Participants |
| Region of Enrollment United States | 10 Participants | 13 Participants | 23 Participants |
| Sex: Female, Male Female | 69 Participants | 81 Participants | 150 Participants |
| Sex: Female, Male Male | 68 Participants | 57 Participants | 125 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 41 / 137 | 29 / 138 | 22 / 65 |
| other Total, other adverse events | 132 / 136 | 135 / 137 | 63 / 65 |
| serious Total, serious adverse events | 56 / 136 | 53 / 137 | 24 / 65 |
Outcome results
Primary
Progression-free Survival (PFS)
PFS as assessed by Blinded Independent Review Committee (BIRC), per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, was defined as the time interval from the date of randomization until the date of the first documented PD event. The data was censored for participants without a PFS event.
Time frame: Up to end of study (Up to 56 months)
Population: ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized Phase: Brigatinib 90 mg QD/180 QD | Progression-free Survival (PFS) | 24.016 months |
| Randomized Phase: Crizotinib 250 mg BID | Progression-free Survival (PFS) | 11.072 months |
| Crossover Phase: Brigatinib 90 mg QD/180 mg QD | Progression-free Survival (PFS) | 16.821 months |
p-value: <0.000195% CI: [0.35, 0.66]Log Rank
Secondary
Change From Baseline in Global Health Status/Quality of Life as Assessed by EORTC QLQ-C30 (Version 3.0)
HRQoL: perceived quality of participant's life, includes self-reported multidimensional measures of physical and mental health. Patient-reported symptoms (PROs) and HRQoL will be collected by administering the european organisation for research and treatment of cancer (EORTC) quality of life (QLQ)-C30 questionnaire. EORTC-QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status/QOL scale. The 30 items have 4 response levels (not at all, a little, quite a bit, and very much), with 2 questions relying on a 7-point numeric rating scale. Raw scores are converted into overall score ranging from 0 to 100, where lower scores indicate better QOL. A negative change from Baseline indicates improvement.
Time frame: Baseline and Month 36
Population: ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose. Overall number of participants analyzed are the participants with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Phase: Brigatinib 90 mg QD/180 QD | Change From Baseline in Global Health Status/Quality of Life as Assessed by EORTC QLQ-C30 (Version 3.0) | 4.007 score on a scale | Standard Deviation 25.7563 |
| Randomized Phase: Crizotinib 250 mg BID | Change From Baseline in Global Health Status/Quality of Life as Assessed by EORTC QLQ-C30 (Version 3.0) | -4.088 score on a scale | Standard Deviation 27.4748 |
p-value: 0.029595% CI: [0.58, 11]Mixed Models Analysis
Secondary
Confirmed Intracranial ORR (iORR)
ORR was defined as percentage of participants who achieved CR or PR in the central nervous system (CNS) in randomized participants with intracranial CNS metastasis at baseline. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters.
Time frame: Baseline up to end of treatment (Up to 36 months)
Population: ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose. Overall number of participants analyzed are the participants with data available for analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Phase: Brigatinib 90 mg QD/180 QD | Confirmed Intracranial ORR (iORR) | 66.0 percentage of participants |
| Randomized Phase: Crizotinib 250 mg BID | Confirmed Intracranial ORR (iORR) | 14.3 percentage of participants |
| Crossover Phase: Brigatinib 90 mg QD/180 mg QD | Confirmed Intracranial ORR (iORR) | 35.7 percentage of participants |
p-value: <0.000195% CI: [4.7, 39.11]Cochran-Mantel-Haenszel
Secondary
Confirmed Objective Response Rate (ORR)
ORR was defined as percentage of participants who achieved Complete response (CR) or Partial responses (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v). 1.1 criteria. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to less than (\<) 10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in SLD of target lesions, taking as reference baseline sum diameters.
Time frame: Baseline up to end of treatment (Up to 36 months)
Population: ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Phase: Brigatinib 90 mg QD/180 QD | Confirmed Objective Response Rate (ORR) | 74.5 percentage of participants |
| Randomized Phase: Crizotinib 250 mg BID | Confirmed Objective Response Rate (ORR) | 62.3 percentage of participants |
| Crossover Phase: Brigatinib 90 mg QD/180 mg QD | Confirmed Objective Response Rate (ORR) | 56.9 percentage of participants |
p-value: 0.03395% CI: [1.04, 2.91]Cochran-Mantel-Haenszel
Secondary
Disease Control Rate (DCR)
Disease control as assessed by BIRC, defined as percentage of randomized participants who have achieved CR, PR, or stable disease (SD) after randomization. CR defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR: at least a 30% decrease in SLD of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: SLD increased by at least 20% from the smallest value on study, SLD must also demonstrate an absolute increase of at least 5 mm, and unequivocal progression of existing non-target lesions.
Time frame: Baseline up to end of treatment (Up to 36 months)
Population: ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Phase: Brigatinib 90 mg QD/180 QD | Disease Control Rate (DCR) | 85.4 percentage of participants |
| Randomized Phase: Crizotinib 250 mg BID | Disease Control Rate (DCR) | 86.2 percentage of participants |
| Crossover Phase: Brigatinib 90 mg QD/180 mg QD | Disease Control Rate (DCR) | 73.8 percentage of participants |
p-value: 0.82295% CI: [0.47, 1.82]Cochran-Mantel-Haenszel
Secondary
Duration of Response (DOR)
Duration of response as assessed by BIRC, is defined as the time interval from the date that the criteria are first met for CR/PR (whichever is first recorded) until the first date that progressive disease (PD) is objectively documented. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30 % decrease in the SLD of target lesions, taking as reference the baseline sum diameters. PD is SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest), the SLD must also demonstrate an absolute increase of at least 5 mm, and for non-target lesions, unequivocal progression of existing non-target lesions.
Time frame: Baseline up to end of study (Up to 56 months)
Population: ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose. Only responders were reported for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized Phase: Brigatinib 90 mg QD/180 QD | Duration of Response (DOR) | 33.150 months |
| Randomized Phase: Crizotinib 250 mg BID | Duration of Response (DOR) | 13.832 months |
| Crossover Phase: Brigatinib 90 mg QD/180 mg QD | Duration of Response (DOR) | 19.154 months |
Secondary
Intracranial Progression Free Survival
Intracranial PFS as assessed by BIRC, is defined as the time from randomization until first CNS PD is documented, or death due to any cause. PD is SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest), the SLD must also demonstrate an absolute increase of at least 5 mm, and unequivocal progression of existing non-target lesions.
Time frame: Baseline up to end of study (Up to 56 months)
Population: ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose. Overall number of participants analyzed are the participants with data available for analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized Phase: Brigatinib 90 mg QD/180 QD | Intracranial Progression Free Survival | 23.951 months |
| Randomized Phase: Crizotinib 250 mg BID | Intracranial Progression Free Survival | 5.520 months |
| Crossover Phase: Brigatinib 90 mg QD/180 mg QD | Intracranial Progression Free Survival | 24.542 months |
p-value: <0.000195% CI: [0.17, 0.51]Log Rank
Secondary
Overall Survival (OS)
Overall survival is defined as the time from randomization until death due to any cause.
Time frame: Baseline up to end of study (Up to 56 months)
Population: ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized Phase: Brigatinib 90 mg QD/180 QD | Overall Survival (OS) | NA months |
| Randomized Phase: Crizotinib 250 mg BID | Overall Survival (OS) | NA months |
| Crossover Phase: Brigatinib 90 mg QD/180 mg QD | Overall Survival (OS) | 35.023 months |
Secondary
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)
An AE is any untoward medical occurrence in a participant. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product whether or not considered related to the medicinal product. Any worsening of a preexisting condition which is temporally associated with the use of the study drug (i.e., occurs after the first dose of study drug) is also an AE. TEAEs are defined as AEs starting/worsening on or after the first dose of study treatment and no later than the earliest of 30 days after the last dose of the treatment to which the participant was assigned, or the day before start of brigatinib therapy in crossover participant.
Time frame: From first dose up to 30 days after last dose of study drug (Up to approximately 37 months)
Population: Treated Population included all participant who received at least 1 dose of study drug and served as basis of safety analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Phase: Brigatinib 90 mg QD/180 QD | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Randomized Phase: Crizotinib 250 mg BID | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Crossover Phase: Brigatinib 90 mg QD/180 mg QD | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | 98.5 percentage of participants |
Secondary
Time to Response (TTR)
Time to response as assessed by BIRC, assessment and is defined as the time interval from the date of randomization until the initial observation of CR or PR. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters.
Time frame: Baseline up to end of treatment (Up to 36 months)
Population: ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose. Only responders were reported for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized Phase: Brigatinib 90 mg QD/180 QD | Time to Response (TTR) | 1.840 months |
| Randomized Phase: Crizotinib 250 mg BID | Time to Response (TTR) | 1.873 months |
| Crossover Phase: Brigatinib 90 mg QD/180 mg QD | Time to Response (TTR) | 1.873 months |