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ALTA-1L Study: A Study of Brigatinib Versus Crizotinib in Anaplastic Lymphoma Kinase Positive (ALK+) Advanced Non-small Cell Lung Cancer (NSCLC) Participants (ALTA-1L)

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ClinicalTrials.gov Identifier: NCT02737501
Recruitment Status : Completed
First Posted : April 14, 2016
Results First Posted : August 20, 2021
Last Update Posted : August 20, 2021
Sponsor:
Information provided by (Responsible Party):
Takeda ( Ariad Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Non-small Cell Lung Cancer
Lung Cancer
Advanced Malignancies
Carcinoma
Interventions Drug: Brigatinib
Drug: Crizotinib
Enrollment 275
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.
Arm/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
Hide Arm/Group Description Brigatinib 90 mg, tablets, orally, once daily (QD) for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until disease progression (PD), intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months). Crizotinib 250 mg, tablets, twice daily (BID) in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months). Participants who experienced PD as assessed by the blinded Independent Review Committee (BIRC) or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Period Title: Randomized Phase
Started 137 138 0
Safety Analysis Set 136 137 0
Completed 20 84 0
Not Completed 117 54 0
Reason Not Completed
Died             41             29             0
Withdrawal by Subject             16             6             0
Lost to Follow-up             0             1             0
Site Terminated by Sponsor             58             16             0
Reason not Specified             1             1             0
Never Treated             1             1             0
Period Title: Crossover Phase
Started 0 0 65
Completed 0 0 10
Not Completed 0 0 55
Reason Not Completed
Died             0             0             22
Withdrew Consent             0             0             9
Physician Decision             0             0             1
Site Terminated by Sponsor             0             0             23
Arm/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Total
Hide Arm/Group Description 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). 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). Total of all reporting groups
Overall Number of Baseline Participants 137 138 275
Hide Baseline Analysis Population Description
Intent-to-treat (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.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 137 participants 138 participants 275 participants
57.9  (13.46) 58.6  (11.42) 58.2  (12.46)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 137 participants 138 participants 275 participants
Female
69
  50.4%
81
  58.7%
150
  54.5%
Male
68
  49.6%
57
  41.3%
125
  45.5%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 137 participants 138 participants 275 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
59
  43.1%
49
  35.5%
108
  39.3%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
2
   1.4%
2
   0.7%
White
76
  55.5%
86
  62.3%
162
  58.9%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
2
   1.5%
1
   0.7%
3
   1.1%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 137 participants 138 participants 275 participants
Hispanic, Latino or Spanish
6
   4.4%
10
   7.2%
16
   5.8%
Not Hispanic, Latino or Spanish
131
  95.6%
128
  92.8%
259
  94.2%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Australia Number Analyzed 137 participants 138 participants 275 participants
2
   1.5%
5
   3.6%
7
   2.5%
Hong Kong Number Analyzed 137 participants 138 participants 275 participants
10
   7.3%
6
   4.3%
16
   5.8%
Singapore Number Analyzed 137 participants 138 participants 275 participants
5
   3.6%
1
   0.7%
6
   2.2%
Korea, Republic Of Number Analyzed 137 participants 138 participants 275 participants
29
  21.2%
28
  20.3%
57
  20.7%
Taiwan, Province Of China Number Analyzed 137 participants 138 participants 275 participants
12
   8.8%
9
   6.5%
21
   7.6%
Austria Number Analyzed 137 participants 138 participants 275 participants
5
   3.6%
4
   2.9%
9
   3.3%
Denmark Number Analyzed 137 participants 138 participants 275 participants
2
   1.5%
1
   0.7%
3
   1.1%
France Number Analyzed 137 participants 138 participants 275 participants
7
   5.1%
4
   2.9%
11
   4.0%
Germany Number Analyzed 137 participants 138 participants 275 participants
6
   4.4%
11
   8.0%
17
   6.2%
Italy Number Analyzed 137 participants 138 participants 275 participants
19
  13.9%
19
  13.8%
38
  13.8%
Luxembourg Number Analyzed 137 participants 138 participants 275 participants
1
   0.7%
0
   0.0%
1
   0.4%
Netherlands Number Analyzed 137 participants 138 participants 275 participants
5
   3.6%
6
   4.3%
11
   4.0%
Norway Number Analyzed 137 participants 138 participants 275 participants
0
   0.0%
2
   1.4%
2
   0.7%
Spain Number Analyzed 137 participants 138 participants 275 participants
14
  10.2%
17
  12.3%
31
  11.3%
Sweden Number Analyzed 137 participants 138 participants 275 participants
0
   0.0%
1
   0.7%
1
   0.4%
Switzerland Number Analyzed 137 participants 138 participants 275 participants
0
   0.0%
1
   0.7%
1
   0.4%
United Kingdom Number Analyzed 137 participants 138 participants 275 participants
10
   7.3%
8
   5.8%
18
   6.5%
Canada Number Analyzed 137 participants 138 participants 275 participants
0
   0.0%
2
   1.4%
2
   0.7%
United States Number Analyzed 137 participants 138 participants 275 participants
10
   7.3%
13
   9.4%
23
   8.4%
Global Health Status/Quality of Life (QoL)   [1] [2] 
Mean (Full Range)
Unit of measure:  Score on a scale
Number Analyzed 131 participants 131 participants 262 participants
60.432
(0.00 to 100.00)
59.160
(0.00 to 100.00)
59.796
(0.00 to 100.00)
[1]
Measure Description: HRQoL:perceived quality of participant's life,includes self-reported multidimensional measures of physical,mental health.EORTC-QLQ-C30 contains 30 items across 5 functional scales(physical,role,cognitive,emotional,social),9 symptom scales(fatigue,nausea and vomiting,pain,dyspnea,sleep disturbance,appetite loss,constipation,diarrhea,financial difficulties),a global health status/QOL scale on 4 response levels(not at all,a little,quite a bit,very much),with 2 questions relying on a 7-point numeric rating scale.Raw scores converted into overall score of 0-100,lower scores indicate better QOL.
[2]
Measure Analysis Population Description: Number analyzed is number of participants with data available for global health status/QoL at Baseline.
1.Primary Outcome
Title Progression-free Survival (PFS)
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
Hide Arm/Group Description:
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).
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).
Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Overall Number of Participants Analyzed 137 138 65
Median (95% Confidence Interval)
Unit of Measure: months
24.016
(18.46 to 43.20)
11.072
(9.13 to 13.01)
16.821
(10.12 to 23.85)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Randomized Phase: Brigatinib 90 mg QD/180 QD, Randomized Phase: Crizotinib 250 mg BID
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments P-values are from a log-rank test stratified by randomization stratification factors (current; presence of intracranial central nervous system (iCNS) metastases at baseline and prior chemotherapy for locally advanced or metastatic disease).
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.481
Confidence Interval (2-Sided) 95%
0.35 to 0.66
Estimation Comments The hazard ratio was obtained using a Cox proportional hazards model with randomization stratification factors (current) as covariates.
2.Secondary Outcome
Title Confirmed Objective Response Rate (ORR)
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
Hide Arm/Group Description:
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).
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).
Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Overall Number of Participants Analyzed 137 138 65
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
74.5
(66.30 to 81.52)
62.3
(53.68 to 70.42)
56.9
(44.04 to 69.15)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Randomized Phase: Brigatinib 90 mg QD/180 QD, Randomized Phase: Crizotinib 250 mg BID
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0330
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.74
Confidence Interval (2-Sided) 95%
1.04 to 2.91
Estimation Comments Odds ratios and p-values were from a Cochran-Mantel-Haenszel test stratified by presence of intracranial central nervous system (iCNS) metastases at Baseline, and prior chemotherapy for locally advanced or metastatic disease (current strata).
3.Secondary Outcome
Title Confirmed Intracranial ORR (iORR)
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
Hide Arm/Group Description:
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).
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).
Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Overall Number of Participants Analyzed 47 49 42
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
66.0
(50.69 to 79.14)
14.3
(5.94 to 27.24)
35.7
(21.55 to 51.97)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Randomized Phase: Brigatinib 90 mg QD/180 QD, Randomized Phase: Crizotinib 250 mg BID
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 13.56
Confidence Interval (2-Sided) 95%
4.70 to 39.11
Estimation Comments Odds ratios and p-values were from a Cochran-Mantel-Haenszel test stratified by presence of prior chemotherapy for Locally advanced or metastatic disease at study entry (current strata).
4.Secondary Outcome
Title Intracranial Progression Free Survival
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
Hide Arm/Group Description:
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).
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).
Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Overall Number of Participants Analyzed 47 49 42
Median (95% Confidence Interval)
Unit of Measure: months
23.951
(12.91 to 30.78)
5.520
(3.71 to 7.52)
24.542 [1] 
(12.58 to NA)
[1]
Upper limit of 95% confidence interval (CI) was not estimable due to low number of participants with events.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Randomized Phase: Brigatinib 90 mg QD/180 QD, Randomized Phase: Crizotinib 250 mg BID
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments P-values are from a log-rank test stratified by randomization stratification factors (current; presence of iCNS metastases at baseline and prior chemotherapy for locally advanced or metastatic disease).
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.293
Confidence Interval (2-Sided) 95%
0.17 to 0.51
Estimation Comments The hazard ratio was obtained using a Cox proportional hazards model with prior chemotherapy for locally advanced or metastatic disease (current strata) as covariate.
5.Secondary Outcome
Title Overall Survival (OS)
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
Hide Arm/Group Description:
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).
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).
Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Overall Number of Participants Analyzed 137 138 65
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
35.023 [2] 
(30.42 to NA)
[1]
Median and 95% CI was not estimable due to fewer number of participants with events.
[2]
Upper limit of 95% CI was not estimable due to fewer number of participants with events.
6.Secondary Outcome
Title Duration of Response (DOR)
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
Hide Arm/Group Description:
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).
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).
Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Overall Number of Participants Analyzed 102 86 37
Median (Full Range)
Unit of Measure: months
33.150
(1.84 to 50.60)
13.832
(1.45 to 49.81)
19.154
(1.97 to 33.15)
7.Secondary Outcome
Title Time to Response (TTR)
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
Hide Arm/Group Description:
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).
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).
Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Overall Number of Participants Analyzed 137 138 65
Median (Full Range)
Unit of Measure: months
1.840
(1.02 to 29.47)
1.873
(0.79 to 7.43)
1.873
(0.20 to 18.33)
8.Secondary Outcome
Title Disease Control Rate (DCR)
Hide Description 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)
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Hide Analysis Population Description
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/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
Hide Arm/Group Description:
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).
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).
Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Overall Number of Participants Analyzed 137 138 65
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
85.4
(78.36 to 90.85)
86.2
(79.34 to 91.50)
73.8
(61.46 to 83.97)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Randomized Phase: Brigatinib 90 mg QD/180 QD, Randomized Phase: Crizotinib 250 mg BID
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8220
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.93
Confidence Interval (2-Sided) 95%
0.47 to 1.82
Estimation Comments Odds ratios and p-values were from a Cochran-Mantel-Haenszel test stratified by presence of iCNS metastases at Baseline, and prior chemotherapy for locally advanced or metastatic disease (current strata).
9.Secondary Outcome
Title Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)
Hide Description 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)
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Hide Analysis Population Description
Treated Population included all participant who received at least 1 dose of study drug and served as basis of safety analysis.
Arm/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
Hide Arm/Group Description:
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).
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).
Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Overall Number of Participants Analyzed 136 137 65
Measure Type: Number
Unit of Measure: percentage of participants
100 100 98.5
10.Secondary Outcome
Title Change From Baseline in Global Health Status/Quality of Life as Assessed by EORTC QLQ-C30 (Version 3.0)
Hide Description 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
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Hide Analysis Population Description
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/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID
Hide Arm/Group Description:
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).
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).
Overall Number of Participants Analyzed 104 53
Mean (Standard Deviation)
Unit of Measure: score on a scale
4.007  (25.7563) -4.088  (27.4748)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Randomized Phase: Brigatinib 90 mg QD/180 QD, Randomized Phase: Crizotinib 250 mg BID
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0295
Comments p-values were obtained using mixed effects models stratified by presence of iCNS metastases at study entry, prior chemotherapy at Baseline.
Method Mixed Models Analysis
Comments A mixed effect model is used with an unstructured covariance matrix.
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 5.79
Confidence Interval (2-Sided) 95%
0.58 to 11.00
Estimation Comments [Not Specified]
Time Frame All-Cause Mortality - Up to 56 months; Serious and other adverse events - From first dose up to 30 days after last dose of study drug (Up to approximately 37 months)
Adverse Event Reporting Description All Cause-mortality: 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. Serious and other (Non-serious): Treated Population included all participants who received ≥1 dose of study drug and served as basis of safety analysis. Crossover Population included participants from 'Crizotinib 250 mg BID' who crossed over to brigatinib following BIRC-assessed PD.
 
Arm/Group Title Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
Hide Arm/Group Description 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). 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). Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
All-Cause Mortality
Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   41/137 (29.93%)   29/138 (21.01%)   22/65 (33.85%) 
Hide Serious Adverse Events
Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   56/136 (41.18%)   53/137 (38.69%)   24/65 (36.92%) 
Blood and lymphatic system disorders       
Anaemia † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Disseminated Intravascular Coagulation † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Neutropenia † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Anaemia Macrocytic † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Cardiac disorders       
Atrial Fibrillation † 1  2/136 (1.47%)  0/137 (0.00%)  0/65 (0.00%) 
Pericardial Effusion † 1  1/136 (0.74%)  2/137 (1.46%)  0/65 (0.00%) 
Cardiac Tamponade † 1  1/136 (0.74%)  1/137 (0.73%)  0/65 (0.00%) 
Acute Myocardial Infarction † 1  1/136 (0.74%)  0/137 (0.00%)  1/65 (1.54%) 
Angina Pectoris † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Arrhythmia † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Bradycardia † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Myocardial Infarction † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Palpitations † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Cardiac Failure † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Ear and labyrinth disorders       
Vertigo Positional † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Gastrointestinal disorders       
Vomiting † 1  2/136 (1.47%)  2/137 (1.46%)  0/65 (0.00%) 
Diarrhoea † 1  2/136 (1.47%)  1/137 (0.73%)  2/65 (3.08%) 
Nausea † 1  2/136 (1.47%)  1/137 (0.73%)  1/65 (1.54%) 
Constipation † 1  1/136 (0.74%)  0/137 (0.00%)  1/65 (1.54%) 
Dysphagia † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Gastric Haemorrhage † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Inguinal Hernia † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Neutropenic Colitis † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Oesophageal Obstruction † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Abdominal Pain Lower † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Abdominal Pain Upper † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Ascites † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Large Intestine Perforation † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Oesophagitis Ulcerative † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Intestinal Obstruction † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Abdominal Pain † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
General disorders       
Pyrexia † 1  4/136 (2.94%)  0/137 (0.00%)  1/65 (1.54%) 
Asthenia † 1  2/136 (1.47%)  0/137 (0.00%)  0/65 (0.00%) 
Fatigue † 1  1/136 (0.74%)  1/137 (0.73%)  1/65 (1.54%) 
Mucosal Inflammation † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Multiple Organ Dysfunction Syndrome † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Sudden Death † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Non-Cardiac Chest Pain † 1  0/136 (0.00%)  3/137 (2.19%)  0/65 (0.00%) 
General Physical Health Deterioration † 1  0/136 (0.00%)  2/137 (1.46%)  2/65 (3.08%) 
Performance Status Decreased † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Hepatobiliary disorders       
Cholecystitis † 1  2/136 (1.47%)  0/137 (0.00%)  0/65 (0.00%) 
Bile Duct Stone † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Cholestasis † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Hepatocellular Injury † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Drug-Induced Liver Injury † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Infections and infestations       
Pneumonia † 1  6/136 (4.41%)  5/137 (3.65%)  4/65 (6.15%) 
Lower Respiratory Tract Infection † 1  2/136 (1.47%)  0/137 (0.00%)  1/65 (1.54%) 
Urinary Tract Infection † 1  1/136 (0.74%)  3/137 (2.19%)  0/65 (0.00%) 
Appendicitis † 1  1/136 (0.74%)  1/137 (0.73%)  0/65 (0.00%) 
Upper Respiratory Tract Infection † 1  1/136 (0.74%)  1/137 (0.73%)  0/65 (0.00%) 
Gastroenteritis † 1  1/136 (0.74%)  0/137 (0.00%)  1/65 (1.54%) 
Viral Infection † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Respiratory Tract Infection † 1  0/136 (0.00%)  3/137 (2.19%)  0/65 (0.00%) 
Cellulitis † 1  0/136 (0.00%)  2/137 (1.46%)  0/65 (0.00%) 
Cytomegalovirus Oesophagitis † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Herpes Zoster † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Listeriosis † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Pleural Infection † 1  0/136 (0.00%)  1/137 (0.73%)  1/65 (1.54%) 
Septic Shock † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Sinusitis Fungal † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Atypical Pneumonia † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Gastroenteritis Viral † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Pyelonephritis Acute † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Covid-19 † 1  0/136 (0.00%)  0/137 (0.00%)  2/65 (3.08%) 
Salmonella Sepsis † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Injury, poisoning and procedural complications       
Femoral Neck Fracture † 1  2/136 (1.47%)  1/137 (0.73%)  0/65 (0.00%) 
Fall † 1  1/136 (0.74%)  0/137 (0.00%)  1/65 (1.54%) 
Ligament Rupture † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Brain Herniation † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Spinal Fracture † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Tibia Fracture † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Toxicity To Various Agents † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Investigations       
Alanine Aminotransferase Increased † 1  1/136 (0.74%)  1/137 (0.73%)  0/65 (0.00%) 
Aspartate Aminotransferase Increased † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
C-Reactive Protein Increased † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Lipase Increased † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Transaminases Abnormal † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Neutrophil Count Decreased † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Platelet Count Decreased † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Metabolism and nutrition disorders       
Hyperkalaemia † 1  1/136 (0.74%)  1/137 (0.73%)  0/65 (0.00%) 
Gout † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Hypoglycaemia † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Hyperglycaemia † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Musculoskeletal and connective tissue disorders       
Back Pain † 1  1/136 (0.74%)  2/137 (1.46%)  1/65 (1.54%) 
Muscular Weakness † 1  1/136 (0.74%)  1/137 (0.73%)  0/65 (0.00%) 
Arthritis † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Bone Pain † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Rotator Cuff Syndrome † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Neoplasm Progression † 1  5/136 (3.68%)  4/137 (2.92%)  3/65 (4.62%) 
Metastases To Meninges † 1  2/136 (1.47%)  0/137 (0.00%)  0/65 (0.00%) 
Malignant Pleural Effusion † 1  1/136 (0.74%)  1/137 (0.73%)  0/65 (0.00%) 
Metastases To Central Nervous System † 1  1/136 (0.74%)  1/137 (0.73%)  1/65 (1.54%) 
Cancer Pain † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Diffuse Large B-Cell Lymphoma † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Invasive Breast Carcinoma † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Lung Adenocarcinoma † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Lung Neoplasm Malignant † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Ovarian Cancer Stage I † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Squamous Cell Carcinoma Of Skin † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Hodgkins Disease † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Tumour Haemorrhage † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Intracranial Tumour Haemorrhage † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Prostate Cancer † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Nervous system disorders       
Headache † 1  2/136 (1.47%)  0/137 (0.00%)  0/65 (0.00%) 
Syncope † 1  2/136 (1.47%)  0/137 (0.00%)  0/65 (0.00%) 
Dizziness † 1  1/136 (0.74%)  2/137 (1.46%)  1/65 (1.54%) 
Seizure † 1  1/136 (0.74%)  1/137 (0.73%)  2/65 (3.08%) 
Balance Disorder † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Cerebrovascular Accident † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Cognitive Disorder † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Dysarthria † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Encephalopathy † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Memory Impairment † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Paraesthesia † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Partial Seizures † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Peripheral Sensory Neuropathy † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Vocal Cord Paralysis † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Ischaemic Stroke † 1  0/136 (0.00%)  2/137 (1.46%)  0/65 (0.00%) 
Central Nervous System Lesion † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Aphasia † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Depressed Level Of Consciousness † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Generalised Tonic-Clonic Seizure † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Hemiparesis † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Intraventricular Haemorrhage † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Psychiatric disorders       
Confusional State † 1  2/136 (1.47%)  0/137 (0.00%)  0/65 (0.00%) 
Delirium † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Disorientation † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Renal and urinary disorders       
Acute Kidney Injury † 1  1/136 (0.74%)  1/137 (0.73%)  0/65 (0.00%) 
Urinary Retention † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Haematuria † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Reproductive system and breast disorders       
Menorrhagia † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Dyspnoea † 1  3/136 (2.21%)  6/137 (4.38%)  1/65 (1.54%) 
Pulmonary Embolism † 1  3/136 (2.21%)  5/137 (3.65%)  0/65 (0.00%) 
Pleural Effusion † 1  3/136 (2.21%)  3/137 (2.19%)  1/65 (1.54%) 
Interstitial Lung Disease † 1  3/136 (2.21%)  0/137 (0.00%)  0/65 (0.00%) 
Pneumonitis † 1  2/136 (1.47%)  2/137 (1.46%)  2/65 (3.08%) 
Pneumonia Aspiration † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Pneumothorax † 1  1/136 (0.74%)  0/137 (0.00%)  1/65 (1.54%) 
Pulmonary Oedema † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Respiratory Distress † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
Acute Respiratory Failure † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Respiratory Failure † 1  0/136 (0.00%)  1/137 (0.73%)  0/65 (0.00%) 
Respiratory Arrest † 1  0/136 (0.00%)  0/137 (0.00%)  1/65 (1.54%) 
Skin and subcutaneous tissue disorders       
Rash † 1  1/136 (0.74%)  0/137 (0.00%)  0/65 (0.00%) 
1
Term from vocabulary, MedDRA 23.0
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Randomized Phase: Brigatinib 90 mg QD/180 QD Randomized Phase: Crizotinib 250 mg BID Crossover Phase: Brigatinib 90 mg QD/180 mg QD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   132/136 (97.06%)   135/137 (98.54%)   63/65 (96.92%) 
Blood and lymphatic system disorders       
Anaemia † 1  12/136 (8.82%)  8/137 (5.84%)  5/65 (7.69%) 
Cardiac disorders       
Bradycardia † 1  10/136 (7.35%)  22/137 (16.06%)  0/65 (0.00%) 
Sinus Bradycardia † 1  7/136 (5.15%)  11/137 (8.03%)  0/65 (0.00%) 
Eye disorders       
Vision Blurred † 1  7/136 (5.15%)  14/137 (10.22%)  0/65 (0.00%) 
Photopsia † 1  1/136 (0.74%)  29/137 (21.17%)  0/65 (0.00%) 
Visual Impairment † 1  1/136 (0.74%)  23/137 (16.79%)  0/65 (0.00%) 
Gastrointestinal disorders       
Diarrhoea † 1  78/136 (57.35%)  77/137 (56.20%)  17/65 (26.15%) 
Nausea † 1  44/136 (32.35%)  81/137 (59.12%)  11/65 (16.92%) 
Vomiting † 1  30/136 (22.06%)  59/137 (43.07%)  9/65 (13.85%) 
Constipation † 1  26/136 (19.12%)  57/137 (41.61%)  10/65 (15.38%) 
Abdominal Pain † 1  18/136 (13.24%)  20/137 (14.60%)  0/65 (0.00%) 
Dyspepsia † 1  15/136 (11.03%)  23/137 (16.79%)  0/65 (0.00%) 
Stomatitis † 1  12/136 (8.82%)  9/137 (6.57%)  5/65 (7.69%) 
Abdominal Pain Upper † 1  11/136 (8.09%)  26/137 (18.98%)  0/65 (0.00%) 
Dry Mouth † 1  8/136 (5.88%)  6/137 (4.38%)  0/65 (0.00%) 
Dysphagia † 1  2/136 (1.47%)  12/137 (8.76%)  0/65 (0.00%) 
Gastrooesophageal Reflux Disease † 1  1/136 (0.74%)  16/137 (11.68%)  0/65 (0.00%) 
General disorders       
Fatigue † 1  28/136 (20.59%)  31/137 (22.63%)  9/65 (13.85%) 
Pyrexia † 1  20/136 (14.71%)  22/137 (16.06%)  9/65 (13.85%) 
Asthenia † 1  18/136 (13.24%)  26/137 (18.98%)  8/65 (12.31%) 
Oedema Peripheral † 1  13/136 (9.56%)  63/137 (45.99%)  6/65 (9.23%) 
Non-Cardiac Chest Pain † 1  11/136 (8.09%)  10/137 (7.30%)  0/65 (0.00%) 
Malaise † 1  7/136 (5.15%)  3/137 (2.19%)  0/65 (0.00%) 
Influenza Like Illness † 1  6/136 (4.41%)  11/137 (8.03%)  10/65 (15.38%) 
Peripheral Swelling † 1  5/136 (3.68%)  8/137 (5.84%)  0/65 (0.00%) 
Infections and infestations       
Upper Respiratory Tract Infection † 1  18/136 (13.24%)  12/137 (8.76%)  6/65 (9.23%) 
Nasopharyngitis † 1  12/136 (8.82%)  15/137 (10.95%)  5/65 (7.69%) 
Urinary Tract Infection † 1  10/136 (7.35%)  11/137 (8.03%)  5/65 (7.69%) 
Pneumonia † 1  10/136 (7.35%)  5/137 (3.65%)  6/65 (9.23%) 
Respiratory Tract Infection † 1  7/136 (5.15%)  3/137 (2.19%)  0/65 (0.00%) 
Investigations       
Blood Creatine Phosphokinase Increased † 1  68/136 (50.00%)  23/137 (16.79%)  31/65 (47.69%) 
Aspartate Aminotransferase Increased † 1  35/136 (25.74%)  36/137 (26.28%)  17/65 (26.15%) 
Alanine Aminotransferase Increased † 1  31/136 (22.79%)  49/137 (35.77%)  11/65 (16.92%) 
Lipase Increased † 1  31/136 (22.79%)  23/137 (16.79%)  18/65 (27.69%) 
Amylase Increased † 1  25/136 (18.38%)  13/137 (9.49%)  14/65 (21.54%) 
Blood Alkaline Phosphatase Increased † 1  17/136 (12.50%)  18/137 (13.14%)  4/65 (6.15%) 
Blood Cholesterol Increased † 1  13/136 (9.56%)  1/137 (0.73%)  5/65 (7.69%) 
Blood Creatinine Increased † 1  8/136 (5.88%)  20/137 (14.60%)  0/65 (0.00%) 
Electrocardiogram Qt Prolonged † 1  8/136 (5.88%)  8/137 (5.84%)  5/65 (7.69%) 
Blood Lactate Dehydrogenase Increased † 1  7/136 (5.15%)  5/137 (3.65%)  0/65 (0.00%) 
Gamma-Glutamyltransferase Increased † 1  5/136 (3.68%)  8/137 (5.84%)  0/65 (0.00%) 
Neutrophil Count Decreased † 1  3/136 (2.21%)  14/137 (10.22%)  0/65 (0.00%) 
Amylase Increased † 1  0/136 (0.00%)  0/137 (0.00%)  14/65 (21.54%) 
Blood Insulin Increased † 1  0/136 (0.00%)  0/137 (0.00%)  4/65 (6.15%) 
Metabolism and nutrition disorders       
Decreased Appetite † 1  16/136 (11.76%)  28/137 (20.44%)  7/65 (10.77%) 
Hyperglycaemia † 1  7/136 (5.15%)  6/137 (4.38%)  0/65 (0.00%) 
Hypophosphataemia † 1  7/136 (5.15%)  5/137 (3.65%)  0/65 (0.00%) 
Hypokalaemia † 1  7/136 (5.15%)  1/137 (0.73%)  0/65 (0.00%) 
Hypercholesterolaemia † 1  7/136 (5.15%)  0/137 (0.00%)  0/65 (0.00%) 
Hypocalcaemia † 1  3/136 (2.21%)  11/137 (8.03%)  0/65 (0.00%) 
Hypoalbuminaemia † 1  1/136 (0.74%)  11/137 (8.03%)  0/65 (0.00%) 
Musculoskeletal and connective tissue disorders       
Back Pain † 1  35/136 (25.74%)  22/137 (16.06%)  11/65 (16.92%) 
Arthralgia † 1  27/136 (19.85%)  17/137 (12.41%)  9/65 (13.85%) 
Muscle Spasms † 1  20/136 (14.71%)  15/137 (10.95%)  17/65 (26.15%) 
Musculoskeletal Pain † 1  15/136 (11.03%)  11/137 (8.03%)  10/65 (15.38%) 
Myalgia † 1  14/136 (10.29%)  11/137 (8.03%)  11/65 (16.92%) 
Musculoskeletal Chest Pain † 1  12/136 (8.82%)  10/137 (7.30%)  0/65 (0.00%) 
Pain In Extremity † 1  9/136 (6.62%)  19/137 (13.87%)  9/65 (13.85%) 
Muscular Weakness † 1  0/136 (0.00%)  0/137 (0.00%)  5/65 (7.69%) 
Nervous system disorders       
Headache † 1  31/136 (22.79%)  25/137 (18.25%)  16/65 (24.62%) 
Dizziness † 1  23/136 (16.91%)  29/137 (21.17%)  12/65 (18.46%) 
Paraesthesia † 1  12/136 (8.82%)  9/137 (6.57%)  5/65 (7.69%) 
Dysgeusia † 1  5/136 (3.68%)  20/137 (14.60%)  0/65 (0.00%) 
Hypoaesthesia † 1  3/136 (2.21%)  9/137 (6.57%)  0/65 (0.00%) 
Taste Disorder † 1  3/136 (2.21%)  8/137 (5.84%)  0/65 (0.00%) 
Psychiatric disorders       
Insomnia † 1  14/136 (10.29%)  12/137 (8.76%)  7/65 (10.77%) 
Depression † 1  5/136 (3.68%)  8/137 (5.84%)  0/65 (0.00%) 
Anxiety † 1  0/136 (0.00%)  0/137 (0.00%)  4/65 (6.15%) 
Respiratory, thoracic and mediastinal disorders       
Cough † 1  49/136 (36.03%)  29/137 (21.17%)  16/65 (24.62%) 
Dyspnoea † 1  31/136 (22.79%)  26/137 (18.98%)  8/65 (12.31%) 
Oropharyngeal Pain † 1  13/136 (9.56%)  7/137 (5.11%)  8/65 (12.31%) 
Productive Cough † 1  12/136 (8.82%)  10/137 (7.30%)  8/65 (12.31%) 
Epistaxis † 1  9/136 (6.62%)  0/137 (0.00%)  0/65 (0.00%) 
Dysphonia † 1  8/136 (5.88%)  6/137 (4.38%)  0/65 (0.00%) 
Rhinorrhoea † 1  7/136 (5.15%)  5/137 (3.65%)  0/65 (0.00%) 
Pleural Effusion † 1  2/136 (1.47%)  9/137 (6.57%)  0/65 (0.00%) 
Haemoptysis † 1  0/136 (0.00%)  0/137 (0.00%)  4/65 (6.15%) 
Skin and subcutaneous tissue disorders       
Pruritus † 1  28/136 (20.59%)  8/137 (5.84%)  6/65 (9.23%) 
Rash † 1  25/136 (18.38%)  4/137 (2.92%)  6/65 (9.23%) 
Dermatitis Acneiform † 1  13/136 (9.56%)  3/137 (2.19%)  5/65 (7.69%) 
Rash Erythematous † 1  9/136 (6.62%)  1/137 (0.73%)  0/65 (0.00%) 
Dry Skin † 1  8/136 (5.88%)  6/137 (4.38%)  0/65 (0.00%) 
Rash Maculo-Papular † 1  8/136 (5.88%)  5/137 (3.65%)  9/65 (13.85%) 
Eczema † 1  8/136 (5.88%)  3/137 (2.19%)  6/65 (9.23%) 
Vascular disorders       
Hypertension † 1  44/136 (32.35%)  12/137 (8.76%)  15/65 (23.08%) 
Hypotension † 1  3/136 (2.21%)  10/137 (7.30%)  0/65 (0.00%) 
Deep Vein Thrombosis † 1  0/136 (0.00%)  9/137 (6.57%)  0/65 (0.00%) 
1
Term from vocabulary, MedDRA 23.0
†
Indicates events were collected by systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Director
Organization: Takeda
Phone: +1-877-825-3327
EMail: TrialDisclosures@takeda.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Takeda ( Ariad Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT02737501    
Other Study ID Numbers: AP26113-13-301
U1111-1210-4363 ( Other Identifier: WHO )
2015-003447-19 ( EudraCT Number )
First Submitted: March 30, 2016
First Posted: April 14, 2016
Results First Submitted: July 27, 2021
Results First Posted: August 20, 2021
Last Update Posted: August 20, 2021