A Study to Evaluate the Efficacy of Brigatinib (AP26113) in Participants With Anaplastic Lymphoma Kinase (ALK)-Positive, Non-small Cell Lung Cancer (NSCLC) Previously Treated With Crizotinib

• Sponsor: Ariad Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02094573
• Collaborator: (none)
• Enrollment: 222
• Arms: 2
• Actual Duration (Months): 68.8

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of two different dosing regimens of brigatinib (AP26113) in participants with ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on therapy with crizotinib.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small-Cell Lung	Drug: Brigatinib	Phase 2

Detailed Description

The drug being tested in this study is called brigatinib (AP26113). Brigatinib was tested to treat people with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or were intolerant to crizotinib. This study looked at the efficacy of brigatinib.

The study enrolled 222 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:

• Brigatinib 90 mg

• Brigatinib 90 mg -180 mg

All participants were asked to take a tablet, orally once daily until disease progression or intolerable toxicity. Participants in Brigatinib 90 mg - 180 mg received 180 mg with a 7-day lead-in at 90 mg.

This multi-center trial was conducted worldwide. The overall time to participate in this study is up to 3 years. Participants will make multiple visits to the clinic, and 3 months after the End-of-Treatment visit. Follow-up is intended to continue for 2 years after the last participants was enrolled into the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 222 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase 2 Study of AP26113 in Patients With ALK-positive, Non-small Cell Lung Cancer (NSCLC) Previously Treated With Crizotinib
• Actual Study Start Date: Jun 4, 2014
• Actual Primary Completion Date: Feb 29, 2016
• Actual Study Completion Date: Feb 27, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Brigatinib 90 mg Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).	Drug: Brigatinib; Brigatinib tablets; Other Names: AP26113 ALUNBRIG™
Experimental: Brigatinib 90 mg - 180 mg Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).	Drug: Brigatinib; Brigatinib tablets; Other Names: AP26113 ALUNBRIG™

Outcome Measures

Primary Outcome Measures

1. Confirmed Objective Response Rate (ORR) as Assessed by Investigator [Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or up to end of the study (approximately up to 69 months)]

   ORR assessed by the investigator, was defined as percentage of the participants with confirmed complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumors (RECIST) v1.1 (confirmed ≥4 weeks after initial response), after initiation of study treatment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters. The exact 2-sided 97.5% confidence interval was calculated. The treatment regimen was considered to have achieved the primary objective when lower bound of the 97.5% confidence interval for ORR assessed by investigator is greater than 20%.

Secondary Outcome Measures

1. Confirmed Objective Response Rate (ORR) as Assessed by Independent Review Committee (IRC) [Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or up to end of the study (approximately up to 69 months)]

   ORR assessed by the IRC, was defined as the percentage of the participants with CR or PR according to RECIST v1.1 (confirmed ≥4 weeks after initial response), after the initiation of study treatment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in theSLD of target lesions, taking as reference the baseline sum diameters. The exact 2-sided 95% confidence interval was calculated.

2. Confirmed Intracranial Central Nervous System Objective Response Rate (CNS ORR) in Participants With Measurable Active Brain Metastases [Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or approximately up to 29 months]

   Confirmed intracranial CNS ORR was defined as the percentage of the participants with CR or PR in the intracranial CNS per modification of RECIST v1.1 as evaluated by IRC after the initiation of study drug. Confirmed responses were those that persisted on repeat imaging 4 weeks or more after initial response. CR for target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis). CR for non-target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the Baseline sum diameters.

3. Confirmed Intracranial Central Nervous System Objective Response Rate (CNS ORR) in Participants With Only Non-measurable Active Brain Metastases [Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or approximately up to 29 months]

   Confirmed intracranial CNS ORR is defined as the percentage of the participants with CR or PR in the intracranial CNS per modification of RECIST v1.1 as evaluated by IRC after the initiation of study drug. Confirmed responses were those that persisted on repeat imaging 4 weeks or more after initial response. CR for target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis). CR for non-target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the Baseline sum diameters.

4. Intracranial CNS Progression Free Survival (PFS) in Participants With Active Brain Metastases [Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or approximately up to 29 months]

   Intracranial CNS PFS as evaluated by IRC is defined as the time interval from the date of the first dose of the study drug until the first date at which intracranial CNS disease progression, an increase of 20% or more in the sum of diameters of intracranial CNS target lesions, unequivocal progression of non-target lesions, or the appearance of new lesions in the intracranial CNS, was objectively documented by a scan, or death due to any cause, whichever occurred first. The analysis was based on the Kaplan-Meier (KM) Estimates.

5. Time to Response [Up to approximately 69 months]

   Time to response was defined as the time interval from the date of the first dose of the study drug until the initial observation of CR or PR for participants with confirmed CR/PR. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the Baseline sum diameters.

6. Duration of Response [Up to approximately 69 months]

   Duration of response was defined as the time interval from the time that the measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that the progressive disease is objectively documented or death. Patients without progressive disease or death were censored at the last valid response assessment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. The analysis was based on the Kaplan-Meier (KM) Estimates.

7. Time on Treatment [Up to approximately 69 months]

   Time on treatment was defined as the time from the first to the last dose of study drug. For participants who have not discontinued, time on treatment was censored as of the last dose of the study drug.

8. Disease Control Rate (DCR) [Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or up to end of the study (approximately up to 69 months)]

   DCR was defined as the percentage of randomized participants who were confirmed to have achieved CR or PR or have a best overall response as stable disease (SD) for 6 weeks or more after initiation of the study drug. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD was defined as at least a 20% increase in the sum of diameters of target lesions.

9. Progression Free Survival (PFS) [Up to approximately 69 months]

   PFS was defined as the time interval from the date of the first dose of the study treatment until the first date at which disease progression is objectively documented, or death due to any cause, whichever occurs first. Disease progression for target lesion: SLD increased by at least 20% from the smallest value on study (including Baseline, if that is the smallest) and SLD must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. Disease progression for non-target lesion: Unequivocal progression of existing non-target lesions. (Subjective judgment by experienced reader). The analysis was based on the Kaplan-Meier (KM) Estimates.

10. Overall Survival (OS) [Up to approximately 69 months]

    OS is defined as the time interval from the date of the first dose of the study treatment until death due to any cause. Intracranial OS was calculated by Kaplan-Meier estimation.

11. Number of Participants Who Had at Least One Treatment-Emergent Adverse Event (TEAE) [From first dose of study drug up to 30 days following the last dose of study drug (approximately up to 69 months)]

    An Adverse Event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE was defined as an adverse event with an onset that occurs after receiving study drug.

12. Pre-dose Brigatinib Plasma Concentration [Day 1 Cycles 2, 3, 4 and 5 (each Cycle of 28-days) pre-dose]

13. Patient-reported Symptoms Global Health Status/Quality of Life (QoL) Scores [Baseline and at each 28-day cycle up to end of the study (up to approximately 69 months)]

    Patient-reported symptoms global health status/quality of life (QoL) scores were based on questions 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30 (QLQ-C30). The first 28 questions used 4-point scale (1=not at all,2=a little,3=quite a bit,4=very much) for evaluating 5 functional scales (physical, role, cognitive, emotional, and social functioning); 3 symptom scales (fatigue, pain, and nausea/vomiting); and last 2 questions on global health status/QoL scale are coded on 7-point scale (1=very poor to 7=excellent). Six single-item scales also are included (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Raw scores for multi-item scales and single-item measures was linearly transformed to obtain the score ranging from 0 to 100, where higher score represents a higher ("better") level of functioning.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Have histologically or cytologically confirmed locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) that is anaplastic lymphoma kinase (ALK+).

2. Must meet one of the following two criteria:

3. Have documented ALK rearrangement by a positive result from the Vysis® ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit; or

4. Have documented ALK positivity by a different test and tissue available for the Vysis® FISH test. Tissue should be derived preferably from a biopsy taken after progression with crizotinib. If such a sample is not available, testing may be performed with archived tumor tissue.

5. Had progressive disease while on crizotinib, as assessed by the investigator or treating physician.

6. Have at least 1 measurable lesion per RECIST v1.1. Note: Previously irradiated lesions may not be used for target lesions, unless there is unambiguous radiological progression after radiotherapy. Brain lesions may not be used as target lesions if they were: 1) previously treated with whole brain radiation therapy (WBRT) within 3 months, or 2) previously treated by stereotactic radiosurgery (SRS) or surgical resection.

7. Recovered from toxicities related to prior anticancer therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, v4.0) grade ≤2.

8. Are a male or female participants ≥18 years old.

9. Have a life expectancy ≥3 months.

10. Have adequate organ and hematologic function, as determined by:

11. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN; ≤5 x ULN is acceptable if liver metastases are present)

12. Total serum bilirubin ≤1.5 x ULN (<3.0 x ULN for participants with Gilbert syndrome)

13. Serum creatinine ≤1.5 x ULN

14. Serum lipase/amylase ≤1.5 x ULN

15. Absolute neutrophil count (ANC) ≥1500/µL

16. Platelets ≥75000/µL

17. Hemoglobin ≥10 g/dL

18. Have Eastern Cooperative Oncology Group (ECOG) performance status ≤2.

19. Have normal QT interval on screening electrocardiogram (ECG) evaluation, defined as QT interval corrected (Fridericia) (QTcF) of ≤450 ms in males or ≤470 ms in females.

20. For female participants of childbearing potential, a negative pregnancy test must be documented prior to enrollment.

21. Female and male participants who are fertile must agree to use a highly effective form of contraception with their sexual partners throughout study participation.

22. Must provide a 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.

23. Have the willingness and ability to comply with scheduled visits and study procedures.

Exclusion Criteria:

1. Received any prior ALK-targeted TKI other than crizotinib.

2. Received crizotinib within 3 days of the first dose of brigatinib (Day 1, Cycle 1).

3. Received cytotoxic chemotherapy, investigational agents, or radiation within 14 days, except SRS or stereotactic body radiosurgery.

4. Received monoclonal antibodies or had major surgery within 30 days of the first dose of brigatinib (Day 1, Cycle 1).

5. Have been diagnosed with another primary malignancy within the past 3 years (except for adequately treated non-melanoma skin cancer, cervical cancer in situ, or prostate cancer, which are allowed within 3 years).

6. Have symptomatic CNS metastases that are neurologically unstable or require an increasing dose of corticosteroids.

7. Have current spinal cord compression.

8. Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:

9. Myocardial infarction (MI) within 6 months prior to the first dose of brigatinib

10. Unstable angina within 6 months prior to first dose

11. Congestive heart failure (CHF) within 6 months prior to first dose

12. History of clinically significant (as determined by the treating physician) atrial arrhythmia

13. Any history of ventricular arrhythmia

14. Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose

15. Have a history or the presence of pulmonary interstitial disease or drug-related pneumonitis.

16. Have an ongoing or active infection. The requirement for intravenous (IV) antibiotics is considered active infection.

17. Have a known history of human immunodeficiency virus (HIV). Testing is not required in the absence of history.

18. Have a history of or active significant gastrointestinal (GI) bleeding within 3 months of the first dose of brigatinib.

19. Have a known or suspected hypersensitivity to brigatinib or its excipients.

20. Have malabsorption syndrome or other GI illness that could affect oral absorption of the study drug.

21. Have any condition or illness that, in the opinion of the investigator, would compromise participants safety or interfere with evaluation of the drug study.

22. Be pregnant or breastfeeding.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Ariad Pharmaceuticals

Investigators

• Study Director: Medical Director Clinical Science, Takeda

Study Documents (Full-Text)

• Study Protocol - Aug 24, 2015
• Statistical Analysis Plan - Feb 25, 2016

More Information

Publications

None provided.

• Responsible Party: Ariad Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02094573
• Other Study ID Numbers: AP26113-13-201; 2013-002134-21; U1111-1196-8246
• First Posted: Mar 24, 2014
• Last Update Posted: Mar 15, 2021
• Last Verified: Feb 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Ariad Pharmaceuticals: Drug Therapy
• Additional relevant MeSH terms: Carcinoma, Non-Small-Cell Lung

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 71 investigative sites in the United States, Canada, Europe, Australia, and Asia from 04 Jun 2014 to 27 February 2020.
Pre-assignment Detail	Participants with diagnosis of anaplastic lymphoma kinase (ALK)-positive, non-small cell lung cancer (NSCLC) who had progressed on crizotinib were enrolled to receive brigatinib 90 mg, once daily or brigatinib 90-180 mg, once daily.

Arm/Group Title	Brigatinib 90 mg	Brigatinib 90 mg - 180 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).	Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
Period Title: Overall Study
STARTED	112	110
Treated	109	110
COMPLETED	0	0
NOT COMPLETED	112	110

Baseline Characteristics

Arm/Group Title	Brigatinib 90 mg	Brigatinib 90 mg - 180 mg	Total
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).	Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).	Total of all reporting groups
Overall Participants	112	110	222
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.5 (13.03)	55.4 (12.98)	53.4 (13.13)
Sex: Female, Male (Count of Participants)
Female	62 55.4%	64 58.2%	126 56.8%
Male	50 44.6%	46 41.8%	96 43.2%
Race/Ethnicity, Customized (Count of Participants)
White	72 64.3%	76 69.1%	148 66.7%
Black or African American	1 0.9%	2 1.8%	3 1.4%
Asian	39 34.8%	30 27.3%	69 31.1%
Unknown	0 0%	2 1.8%	2 0.9%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	5 4.5%	8 7.3%	13 5.9%
Not Hispanic or Latino	107 95.5%	102 92.7%	209 94.1%
Region of Enrollment (Count of Participants)
Australia	3 2.7%	6 5.5%	9 4.1%
Austria	3 2.7%	6 5.5%	9 4.1%
Belgium	3 2.7%	2 1.8%	5 2.3%
Canada	2 1.8%	1 0.9%	3 1.4%
Denmark	2 1.8%	6 5.5%	8 3.6%
France	4 3.6%	2 1.8%	6 2.7%
Germany	7 6.3%	7 6.4%	14 6.3%
Hong Kong	6 5.4%	0 0%	6 2.7%
Italy	15 13.4%	14 12.7%	29 13.1%
Netherlands	6 5.4%	6 5.5%	12 5.4%
Norway	1 0.9%	1 0.9%	2 0.9%
Singapore	4 3.6%	3 2.7%	7 3.2%
Spain	5 4.5%	7 6.4%	12 5.4%
Sweden	2 1.8%	2 1.8%	4 1.8%
Switzerland	0 0%	1 0.9%	1 0.5%
United Kingdom	2 1.8%	1 0.9%	3 1.4%
United States	21 18.8%	25 22.7%	46 20.7%
Korea, Republic Of	26 23.2%	20 18.2%	46 20.7%

Outcome Measures

1. Primary Outcome

Title	Confirmed Objective Response Rate (ORR) as Assessed by Investigator
Description	ORR assessed by the investigator, was defined as percentage of the participants with confirmed complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumors (RECIST) v1.1 (confirmed ≥4 weeks after initial response), after initiation of study treatment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters. The exact 2-sided 97.5% confidence interval was calculated. The treatment regimen was considered to have achieved the primary objective when lower bound of the 97.5% confidence interval for ORR assessed by investigator is greater than 20%.
Time Frame	Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or up to end of the study (approximately up to 69 months)

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose.

Arm/Group Title	Brigatinib 90 mg	Brigatinib 90 mg - 180 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).	Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
Measure Participants	112	110
Number (97.5% Confidence Interval) [percentage of participants]	45.5 40.6%	57.3 52.1%

2. Secondary Outcome

Title	Confirmed Objective Response Rate (ORR) as Assessed by Independent Review Committee (IRC)
Description	ORR assessed by the IRC, was defined as the percentage of the participants with CR or PR according to RECIST v1.1 (confirmed ≥4 weeks after initial response), after the initiation of study treatment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in theSLD of target lesions, taking as reference the baseline sum diameters. The exact 2-sided 95% confidence interval was calculated.
Time Frame	Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or up to end of the study (approximately up to 69 months)

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose.

Arm/Group Title	Brigatinib 90 mg	Brigatinib 90 mg - 180 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).	Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
Measure Participants	112	110
Number (95% Confidence Interval) [percentage of participants]	51.8 46.3%	56.4 51.3%

3. Secondary Outcome

Title	Confirmed Intracranial Central Nervous System Objective Response Rate (CNS ORR) in Participants With Measurable Active Brain Metastases
Description	Confirmed intracranial CNS ORR was defined as the percentage of the participants with CR or PR in the intracranial CNS per modification of RECIST v1.1 as evaluated by IRC after the initiation of study drug. Confirmed responses were those that persisted on repeat imaging 4 weeks or more after initial response. CR for target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis). CR for non-target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the Baseline sum diameters.
Time Frame	Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or approximately up to 29 months

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Participants with measurable active brain metastases at Baseline were evaluated for this outcome measure.

Arm/Group Title	Brigatinib 90 mg	Brigatinib 90 mg - 180 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).	Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
Measure Participants	19	15
Number (95% Confidence Interval) [percentage of participants]	47.4 42.3%	73.3 66.6%

4. Secondary Outcome

Title	Confirmed Intracranial Central Nervous System Objective Response Rate (CNS ORR) in Participants With Only Non-measurable Active Brain Metastases
Description	Confirmed intracranial CNS ORR is defined as the percentage of the participants with CR or PR in the intracranial CNS per modification of RECIST v1.1 as evaluated by IRC after the initiation of study drug. Confirmed responses were those that persisted on repeat imaging 4 weeks or more after initial response. CR for target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis). CR for non-target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the Baseline sum diameters.
Time Frame	Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or approximately up to 29 months

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Participants with only non-measurable active brain metastases at Baseline were evaluated for this outcome measure.

Arm/Group Title	Brigatinib 90 mg	Brigatinib 90 mg - 180 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).	Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
Measure Participants	33	36
Number (95% Confidence Interval) [percentage of participants]	12.1 10.8%	16.7 15.2%

5. Secondary Outcome

Title	Intracranial CNS Progression Free Survival (PFS) in Participants With Active Brain Metastases
Description	Intracranial CNS PFS as evaluated by IRC is defined as the time interval from the date of the first dose of the study drug until the first date at which intracranial CNS disease progression, an increase of 20% or more in the sum of diameters of intracranial CNS target lesions, unequivocal progression of non-target lesions, or the appearance of new lesions in the intracranial CNS, was objectively documented by a scan, or death due to any cause, whichever occurred first. The analysis was based on the Kaplan-Meier (KM) Estimates.
Time Frame	Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or approximately up to 29 months

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Participants with active brain metastases whether it was measurable or non-measurable at baseline were evaluated for this outcome measure.

Arm/Group Title	Brigatinib 90 mg	Brigatinib 90 mg - 180 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).	Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
Measure Participants	52	51
Median (95% Confidence Interval) [months]	12.8	12.8

6. Secondary Outcome

Title	Time to Response
Description	Time to response was defined as the time interval from the date of the first dose of the study drug until the initial observation of CR or PR for participants with confirmed CR/PR. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the Baseline sum diameters.
Time Frame	Up to approximately 69 months

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Participants who had confirmed CR or PR were evaluable for this outcome measure.

Arm/Group Title	Brigatinib 90 mg	Brigatinib 90 mg - 180 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).	Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
Measure Participants	51	63
Median (Full Range) [months]	1.8	1.9

7. Secondary Outcome

Title	Duration of Response
Description	Duration of response was defined as the time interval from the time that the measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that the progressive disease is objectively documented or death. Patients without progressive disease or death were censored at the last valid response assessment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. The analysis was based on the Kaplan-Meier (KM) Estimates.
Time Frame	Up to approximately 69 months

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Participants who had confirmed CR or PR were evaluable for this outcome measure.

Arm/Group Title	Brigatinib 90 mg	Brigatinib 90 mg - 180 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).	Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
Measure Participants	51	63
Median (95% Confidence Interval) [months]	12.0	13.8

8. Secondary Outcome

Title	Time on Treatment
Description	Time on treatment was defined as the time from the first to the last dose of study drug. For participants who have not discontinued, time on treatment was censored as of the last dose of the study drug.
Time Frame	Up to approximately 69 months

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who received at least one dose of study drug.

Arm/Group Title	Brigatinib 90 mg	Brigatinib 90 mg - 180 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).	Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
Measure Participants	109	110
Median (Full Range) [days]	402.0	522.0

9. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	DCR was defined as the percentage of randomized participants who were confirmed to have achieved CR or PR or have a best overall response as stable disease (SD) for 6 weeks or more after initiation of the study drug. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD was defined as at least a 20% increase in the sum of diameters of target lesions.
Time Frame	Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or up to end of the study (approximately up to 69 months)

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose.

Arm/Group Title	Brigatinib 90 mg	Brigatinib 90 mg - 180 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).	Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
Measure Participants	112	110
Number (95% Confidence Interval) [percentage of participants]	81.3 72.6%	86.4 78.5%

10. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as the time interval from the date of the first dose of the study treatment until the first date at which disease progression is objectively documented, or death due to any cause, whichever occurs first. Disease progression for target lesion: SLD increased by at least 20% from the smallest value on study (including Baseline, if that is the smallest) and SLD must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. Disease progression for non-target lesion: Unequivocal progression of existing non-target lesions. (Subjective judgment by experienced reader). The analysis was based on the Kaplan-Meier (KM) Estimates.
Time Frame	Up to approximately 69 months

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose.

Arm/Group Title	Brigatinib 90 mg	Brigatinib 90 mg - 180 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).	Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
Measure Participants	112	110
Median (95% Confidence Interval) [months]	9.2	15.6

11. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time interval from the date of the first dose of the study treatment until death due to any cause. Intracranial OS was calculated by Kaplan-Meier estimation.
Time Frame	Up to approximately 69 months

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose.

Arm/Group Title	Brigatinib 90 mg	Brigatinib 90 mg - 180 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).	Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
Measure Participants	112	110
Median (95% Confidence Interval) [months]	25.9	40.6

12. Secondary Outcome

Title	Number of Participants Who Had at Least One Treatment-Emergent Adverse Event (TEAE)
Description	An Adverse Event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE was defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame	From first dose of study drug up to 30 days following the last dose of study drug (approximately up to 69 months)

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who received at least one dose of study drug.

Arm/Group Title	Brigatinib 90 mg	Brigatinib 90 mg - 180 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).	Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
Measure Participants	109	110
Number [participants]	109 97.3%	110 100%

13. Secondary Outcome

Title	Pre-dose Brigatinib Plasma Concentration
Time Frame	Day 1 Cycles 2, 3, 4 and 5 (each Cycle of 28-days) pre-dose

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Here, number of participants analyzed is the participants who were evaluable for this outcome measure.

Arm/Group Title	Brigatinib 90 mg	Brigatinib 90 mg - 180 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).	Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
Measure Participants	112	110
Cycle 2	295.2 (252.0)	520.0 (321.9)
Cycle 3	263.9 (238.9)	537.0 (360.3)
Cycle 4	236.1 (188.0)	564.7 (415.0)
Cycle 5	256.4 (282.3)	579.7 (396.7)

14. Secondary Outcome

Title	Patient-reported Symptoms Global Health Status/Quality of Life (QoL) Scores
Description	Patient-reported symptoms global health status/quality of life (QoL) scores were based on questions 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30 (QLQ-C30). The first 28 questions used 4-point scale (1=not at all,2=a little,3=quite a bit,4=very much) for evaluating 5 functional scales (physical, role, cognitive, emotional, and social functioning); 3 symptom scales (fatigue, pain, and nausea/vomiting); and last 2 questions on global health status/QoL scale are coded on 7-point scale (1=very poor to 7=excellent). Six single-item scales also are included (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Raw scores for multi-item scales and single-item measures was linearly transformed to obtain the score ranging from 0 to 100, where higher score represents a higher ("better") level of functioning.
Time Frame	Baseline and at each 28-day cycle up to end of the study (up to approximately 69 months)

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Here, number of participants analyzed is the participants who were evaluable for this outcome measure.

Arm/Group Title	Brigatinib 90 mg	Brigatinib 90 mg - 180 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).	Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
Measure Participants	112	110
Baseline	52.39 (27.42)	58.49 (23.40)
Cycle 2	64.19 (20.73)	65.72 (19.54)
Cycle 3	65.57 (24.06)	68.50 (20.52)
Cycle 4	69.44 (20.59)	66.95 (20.89)
Cycle 5	70.12 (20.28)	71.86 (17.63)
Cycle 6	70.15 (20.18)	71.24 (18.66)
Cycle 7	67.42 (20.29)	70.21 (21.66)
Cycle 8	67.24 (22.79)	69.87 (20.42)
Cycle 9	68.45 (22.61)	68.67 (21.35)
Cycle 10	71.79 (20.61)	67.98 (23.25)
Cycle 11	72.54 (19.56)	68.45 (21.37)
Cycle 12	68.03 (23.08)	70.51 (21.35)
Cycle 13	70.11 (19.93)	72.79 (19.20)
Cycle 14	69.55 (20.04)	70.76 (19.42)
Cycle 15	70.06 (21.08)	70.83 (20.66)
Cycle 16	68.17 (22.94)	72.27 (18.36)
Cycle 17	73.61 (18.78)	69.81 (20.36)
Cycle 18	67.64 (22.80)	71.55 (17.94)
Cycle 19	69.57 (23.14)	72.12 (20.49)
Cycle 20	66.04 (24.05)	72.76 (18.53)
Cycle 21	69.23 (22.87)	69.83 (19.04)
Cycle 22	72.69 (21.70)	71.20 (18.90)
Cycle 23	72.38 (21.93)	71.10 (20.10)
Cycle 24	72.66 (19.66)	71.43 (15.74)
Cycle 25	71.57 (21.72)	70.09 (19.38)
Cycle 26	71.88 (22.28)	69.68 (20.43)
Cycle 27	71.46 (20.94)	70.83 (21.96)
Cycle 28	71.24 (22.24)	69.59 (20.24)
Cycle 29	70.00 (21.73)	71.17 (22.27)
Cycle 30	69.25 (21.72)	70.83 (18.03)
Cycle 31	75.64 (17.63)	69.95 (18.15)
Cycle 32	73.00 (20.02)	70.97 (20.28)
Cycle 33	71.67 (20.41)	70.31 (20.84)
Cycle 34	72.62 (20.61)	69.62 (20.70)
Cycle 35	72.22 (18.88)	66.67 (22.97)
Cycle 36	68.33 (22.72)	71.67 (19.89)
Cycle 37	73.33 (19.42)	72.50 (19.47)
Cycle 38	68.98 (22.10)	72.99 (17.49)
Cycle 39	68.63 (25.09)	73.72 (19.96)
Cycle 40	71.57 (24.13)	69.87 (23.10)
Cycle 41	72.55 (21.20)	68.27 (22.98)
Cycle 42	72.06 (21.84)	72.57 (20.78)
Cycle 43	67.65 (24.63)	71.01 (22.17)
Cycle 44	72.55 (20.57)	73.48 (19.35)
Cycle 45	66.67 (19.88)	72.35 (22.03)
Cycle 46	70.56 (19.12)	71.59 (20.52)
Cycle 47	60.12 (25.36)	73.02 (19.88)
Cycle 48	65.38 (20.93)	74.60 (19.80)
Cycle 49	57.69 (24.88)	71.67 (22.69)
Cycle 50	61.54 (26.47)	70.00 (24.54)
Cycle 51	63.19 (23.96)	69.05 (22.69)
Cycle 52	56.94 (22.71)	72.22 (22.26)
Cycle 53	61.11 (21.42)	70.83 (23.02)
Cycle 54	61.81 (25.24)	71.49 (20.47)
Cycle 55	63.33 (26.12)	72.37 (20.42)
Cycle 56	63.89 (23.94)	73.61 (19.23)
Cycle 57	65.00 (19.95)	73.53 (19.37)
Cycle 58	65.00 (25.09)	70.83 (20.61)
Cycle 59	64.81 (25.27)	71.43 (19.81)
Cycle 60	70.83 (27.82)	73.15 (19.44)
Cycle 61	71.43 (28.41)	78.13 (19.89)
Cycle 62	66.67 (23.57)	79.76 (15.85)
Cycle 63	58.33 (31.91)	78.57 (17.91)
Cycle 64	61.11 (34.69)	77.38 (20.81)
Cycle 65	75.00 (35.36)	76.39 (22.62)
Cycle 66	75.00 (35.36)	77.08 (31.46)
Cycle 67	75.00 (35.36)	41.67 (NA)
Cycle 68	41.67 (NA)
Cycle 69	58.33 (NA)
Cycle 70	41.67 (NA)
Cycle 71	41.67 (NA)
Cycle 72	75.00 (NA)
End of Treatment	52.29 (28.25)	61.15 (23.15)
Follow-Up 30 Days After Last Dose	61.05 (30.58)	61.67 (23.33)

Adverse Events

Time Frame	All-cause Mortality: From first dose of study drug up to end of the study (approximately up to 69 months); Serious and Other Adverse Events: From first dose of study drug up to 30 days following the last dose of study drug (approximately up to 69 months)
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Brigatinib 90 mg		Brigatinib 90 mg - 180 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).		Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
All Cause Mortality
	Brigatinib 90 mg		Brigatinib 90 mg - 180 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	64/109 (58.7%)		54/110 (49.1%)
Serious Adverse Events
	Brigatinib 90 mg		Brigatinib 90 mg - 180 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	58/109 (53.2%)		69/110 (62.7%)
Blood and lymphatic system disorders
Lymph node pain	1/109 (0.9%)		0/110 (0%)
Anaemia	1/109 (0.9%)		1/110 (0.9%)
Cardiac disorders
Atrial fibrillation	1/109 (0.9%)		1/110 (0.9%)
Angina pectoris	0/109 (0%)		1/110 (0.9%)
Supraventricular tachycardia	0/109 (0%)		1/110 (0.9%)
Ear and labyrinth disorders
Vertigo positional	2/109 (1.8%)		0/110 (0%)
Eye disorders
Macular oedema	0/109 (0%)		1/110 (0.9%)
Gastrointestinal disorders
Abdominal pain	1/109 (0.9%)		1/110 (0.9%)
Diarrhoea	1/109 (0.9%)		0/110 (0%)
Food poisoning	0/109 (0%)		1/110 (0.9%)
Gastrointestinal haemorrhage	1/109 (0.9%)		0/110 (0%)
Small intestinal obstruction	1/109 (0.9%)		0/110 (0%)
Abdominal pain upper†	2/109 (1.8%)		0/110 (0%)
Dysphagia	1/109 (0.9%)		0/110 (0%)
Haematemesis	1/109 (0.9%)		0/110 (0%)
Haematochezia	0/109 (0%)		1/110 (0.9%)
Tooth socket haemorrhage	0/109 (0%)		1/110 (0.9%)
General disorders
Asthenia	1/109 (0.9%)		0/110 (0%)
Infusion site thrombosis	0/109 (0%)		1/110 (0.9%)
Sudden death	0/109 (0%)		1/110 (0.9%)
Euthanasia	0/109 (0%)		1/110 (0.9%)
Non-cardiac chest pain	1/109 (0.9%)		0/110 (0%)
Oedema peripheral	1/109 (0.9%)		0/110 (0%)
Pyrexia	0/109 (0%)		1/110 (0.9%)
General physical health deterioration	1/109 (0.9%)		1/110 (0.9%)
Hepatobiliary disorders
Cholangitis acute	1/109 (0.9%)		0/110 (0%)
Jaundice cholestatic	0/109 (0%)		1/110 (0.9%)
Hepatic function abnormal†	0/109 (0%)		2/110 (1.8%)
Infections and infestations
Pneumonia	4/109 (3.7%)		13/110 (11.8%)
Appendicitis	1/109 (0.9%)		2/110 (1.8%)
Bronchitis	2/109 (1.8%)		1/110 (0.9%)
Atypical pneumonia	1/109 (0.9%)		0/110 (0%)
Cellulitis	0/109 (0%)		1/110 (0.9%)
Meningitis bacterial	1/109 (0.9%)		1/110 (0.9%)
Tuberculous pleurisy	0/109 (0%)		1/110 (0.9%)
Urosepsis	1/109 (0.9%)		1/110 (0.9%)
Bronchopulmonary aspergillosis	0/109 (0%)		1/110 (0.9%)
Clostridium difficile colitis	0/109 (0%)		1/110 (0.9%)
Diverticulitis	0/109 (0%)		1/110 (0.9%)
Escherichia urinary tract infection	0/109 (0%)		1/110 (0.9%)
Haematoma infection	1/109 (0.9%)		0/110 (0%)
Peritonitis	1/109 (0.9%)		0/110 (0%)
Pyelonephritis	0/109 (0%)		1/110 (0.9%)
Skin infection	0/109 (0%)		1/110 (0.9%)
Injury, poisoning and procedural complications
Head injury	0/109 (0%)		1/110 (0.9%)
Radiation necrosis	0/109 (0%)		1/110 (0.9%)
Radiation pneumonitis	0/109 (0%)		1/110 (0.9%)
Fall	1/109 (0.9%)		0/110 (0%)
Hip fracture	0/109 (0%)		1/110 (0.9%)
Skin laceration	1/109 (0.9%)		0/110 (0%)
Investigations
Neutrophil count decreased	0/109 (0%)		1/110 (0.9%)
Platelet count decreased	1/109 (0.9%)		0/110 (0%)
Metabolism and nutrition disorders
Dehydration	2/109 (1.8%)		0/110 (0%)
Hyponatraemia	0/109 (0%)		1/110 (0.9%)
Decreased appetite	0/109 (0%)		1/110 (0.9%)
Hyperglycaemia	0/109 (0%)		1/110 (0.9%)
Musculoskeletal and connective tissue disorders
Back pain	1/109 (0.9%)		1/110 (0.9%)
Arthralgia	1/109 (0.9%)		0/110 (0%)
Neck pain	1/109 (0.9%)		0/110 (0%)
Pathological fracture	1/109 (0.9%)		0/110 (0%)
Osteoarthritis	1/109 (0.9%)		1/110 (0.9%)
Pain in extremity	1/109 (0.9%)		1/110 (0.9%)
Muscular weakness	1/109 (0.9%)		0/110 (0%)
Musculoskeletal pain	0/109 (0%)		1/110 (0.9%)
Osteonecrosis	0/109 (0%)		1/110 (0.9%)
Soft tissue necrosis	1/109 (0.9%)		0/110 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm progression	15/109 (13.8%)		8/110 (7.3%)
Malignant pleural effusion	2/109 (1.8%)		4/110 (3.6%)
Metastases to central nervous system	0/109 (0%)		3/110 (2.7%)
Metastases to meninges	1/109 (0.9%)		0/110 (0%)
Squamous cell carcinoma of skin	1/109 (0.9%)		1/110 (0.9%)
Bowens disease	0/109 (0%)		1/110 (0.9%)
Metastases to peritoneum	1/109 (0.9%)		0/110 (0%)
Metastatic malignant melanoma	1/109 (0.9%)		0/110 (0%)
Thyroid cancer	1/109 (0.9%)		0/110 (0%)
Tumour associated fever	1/109 (0.9%)		0/110 (0%)
Metastases to liver	1/109 (0.9%)		0/110 (0%)
Nervous system disorders
Epilepsy	3/109 (2.8%)		1/110 (0.9%)
Cerebrovascular accident	1/109 (0.9%)		0/110 (0%)
Generalised tonic-clonic seizure	1/109 (0.9%)		0/110 (0%)
Headache	1/109 (0.9%)		0/110 (0%)
Nervous system disorder	0/109 (0%)		1/110 (0.9%)
Seizure	4/109 (3.7%)		1/110 (0.9%)
Simple partial seizures	0/109 (0%)		1/110 (0.9%)
Spinal cord compression	1/109 (0.9%)		0/110 (0%)
Syncope	1/109 (0.9%)		2/110 (1.8%)
Transient ischaemic attack	1/109 (0.9%)		1/110 (0.9%)
Hemiparesis	1/109 (0.9%)		1/110 (0.9%)
Aphasia	1/109 (0.9%)		0/110 (0%)
Cognitive disorder	0/109 (0%)		1/110 (0.9%)
Dizziness	1/109 (0.9%)		0/110 (0%)
Hyperaesthesia	1/109 (0.9%)		0/110 (0%)
Intracranial pressure increased	1/109 (0.9%)		0/110 (0%)
Paraesthesia	0/109 (0%)		1/110 (0.9%)
Tonic clonic movements	1/109 (0.9%)		0/110 (0%)
Product Issues
Device occlusion	1/109 (0.9%)		1/110 (0.9%)
Psychiatric disorders
Confusional state	2/109 (1.8%)		2/110 (1.8%)
Renal and urinary disorders
Hydronephrosis	2/109 (1.8%)		0/110 (0%)
Renal impairment	1/109 (0.9%)		0/110 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis	3/109 (2.8%)		10/110 (9.1%)
Dyspnoea	3/109 (2.8%)		5/110 (4.5%)
Pulmonary embolism	1/109 (0.9%)		2/110 (1.8%)
Dyspnoea exertional	1/109 (0.9%)		0/110 (0%)
Haemoptysis	0/109 (0%)		2/110 (1.8%)
Respiratory failure	1/109 (0.9%)		0/110 (0%)
Oesophagobronchial fistula	1/109 (0.9%)		0/110 (0%)
Pleural effusion	1/109 (0.9%)		0/110 (0%)
Pneumonia aspiration	1/109 (0.9%)		0/110 (0%)
Pneumothorax	1/109 (0.9%)		0/110 (0%)
Skin and subcutaneous tissue disorders
Angioedema	0/109 (0%)		1/110 (0.9%)
Dermatitis allergic	0/109 (0%)		1/110 (0.9%)
Paraneoplastic dermatomyositis	0/109 (0%)		1/110 (0.9%)
Rash erythematous	1/109 (0.9%)		0/110 (0%)
Vascular disorders
Behcets syndrome	0/109 (0%)		1/110 (0.9%)
Hypertension	0/109 (0%)		1/110 (0.9%)
Iliac artery stenosis	0/109 (0%)		1/110 (0.9%)
Other (Not Including Serious) Adverse Events
	Brigatinib 90 mg		Brigatinib 90 mg - 180 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	108/109 (99.1%)		105/110 (95.5%)
Blood and lymphatic system disorders
Anaemia	8/109 (7.3%)		8/110 (7.3%)
Cardiac disorders
Palpitations	1/109 (0.9%)		6/110 (5.5%)
Ear and labyrinth disorders
Vertigo	3/109 (2.8%)		13/110 (11.8%)
Eye disorders
Vision blurred	7/109 (6.4%)		9/110 (8.2%)
Gastrointestinal disorders
Nausea	47/109 (43.1%)		55/110 (50%)
Diarrhoea	34/109 (31.2%)		51/110 (46.4%)
Vomiting	44/109 (40.4%)		39/110 (35.5%)
Constipation	29/109 (26.6%)		28/110 (25.5%)
Abdominal pain	13/109 (11.9%)		10/110 (9.1%)
Dyspepsia	8/109 (7.3%)		8/110 (7.3%)
Stomatitis	5/109 (4.6%)		10/110 (9.1%)
Dry mouth	4/109 (3.7%)		11/110 (10%)
Abdominal pain upper	11/109 (10.1%)		13/110 (11.8%)
General disorders
Pyrexia	23/109 (21.1%)		11/110 (10%)
Asthenia	16/109 (14.7%)		19/110 (17.3%)
Oedema peripheral	13/109 (11.9%)		14/110 (12.7%)
Fatigue	34/109 (31.2%)		41/110 (37.3%)
Influenza like illness	8/109 (7.3%)		9/110 (8.2%)
Non-cardiac chest pain	6/109 (5.5%)		5/110 (4.5%)
Infections and infestations
Nasopharyngitis	15/109 (13.8%)		15/110 (13.6%)
Upper respiratory tract infection	13/109 (11.9%)		10/110 (9.1%)
Urinary tract infection	9/109 (8.3%)		13/110 (11.8%)
Pneumonia	3/109 (2.8%)		15/110 (13.6%)
Bronchitis	5/109 (4.6%)		6/110 (5.5%)
Sinusitis	3/109 (2.8%)		8/110 (7.3%)
Herpes zoster	1/109 (0.9%)		6/110 (5.5%)
Injury, poisoning and procedural complications
Fall	2/109 (1.8%)		7/110 (6.4%)
Investigations
Blood creatine phosphokinase increased	24/109 (22%)		41/110 (37.3%)
Amylase increased	16/109 (14.7%)		20/110 (18.2%)
Aspartate aminotransferase increased	15/109 (13.8%)		22/110 (20%)
Lipase increased	15/109 (13.8%)		23/110 (20.9%)
Alanine aminotransferase increased	15/109 (13.8%)		18/110 (16.4%)
Blood lactate dehydrogenase increased	3/109 (2.8%)		10/110 (9.1%)
Weight decreased	8/109 (7.3%)		7/110 (6.4%)
Blood alkaline phosphatase increased	7/109 (6.4%)		6/110 (5.5%)
Blood creatinine increased	5/109 (4.6%)		8/110 (7.3%)
Electrocardiogram QT prolonged	4/109 (3.7%)		8/110 (7.3%)
Metabolism and nutrition disorders
Decreased appetite	32/109 (29.4%)		27/110 (24.5%)
Hyperglycaemia	6/109 (5.5%)		9/110 (8.2%)
Hypokalaemia	7/109 (6.4%)		6/110 (5.5%)
Hyponatraemia	5/109 (4.6%)		8/110 (7.3%)
Musculoskeletal and connective tissue disorders
Muscle spasms	17/109 (15.6%)		28/110 (25.5%)
Arthralgia	19/109 (17.4%)		21/110 (19.1%)
Back pain	16/109 (14.7%)		30/110 (27.3%)
Pain in extremity	17/109 (15.6%)		15/110 (13.6%)
Myalgia	7/109 (6.4%)		17/110 (15.5%)
Musculoskeletal chest pain	7/109 (6.4%)		10/110 (9.1%)
Neck pain	4/109 (3.7%)		13/110 (11.8%)
Musculoskeletal pain	9/109 (8.3%)		15/110 (13.6%)
Muscular weakness	6/109 (5.5%)		4/110 (3.6%)
Nervous system disorders
Headache	39/109 (35.8%)		44/110 (40%)
Dizziness	18/109 (16.5%)		22/110 (20%)
Paraesthesia	13/109 (11.9%)		12/110 (10.9%)
Peripheral sensory neuropathy	8/109 (7.3%)		10/110 (9.1%)
Memory impairment	4/109 (3.7%)		11/110 (10%)
Seizure	4/109 (3.7%)		11/110 (10%)
Hypoaesthesia	5/109 (4.6%)		6/110 (5.5%)
Cognitive disorder	3/109 (2.8%)		6/110 (5.5%)
Tremor	2/109 (1.8%)		6/110 (5.5%)
Psychiatric disorders
Insomnia	20/109 (18.3%)		15/110 (13.6%)
Anxiety	3/109 (2.8%)		11/110 (10%)
Renal and urinary disorders
Haematuria	3/109 (2.8%)		9/110 (8.2%)
Respiratory, thoracic and mediastinal disorders
Cough	35/109 (32.1%)		45/110 (40.9%)
Dyspnoea	28/109 (25.7%)		31/110 (28.2%)
Oropharyngeal pain	12/109 (11%)		11/110 (10%)
Dysphonia	8/109 (7.3%)		7/110 (6.4%)
Productive cough	10/109 (9.2%)		9/110 (8.2%)
Dyspnoea exertional	6/109 (5.5%)		2/110 (1.8%)
Haemoptysis	4/109 (3.7%)		8/110 (7.3%)
Epistaxis	4/109 (3.7%)		8/110 (7.3%)
Skin and subcutaneous tissue disorders
Rash	6/109 (5.5%)		4/110 (3.6%)
Pruritus	12/109 (11%)		15/110 (13.6%)
Dermatitis acneiform	7/109 (6.4%)		4/110 (3.6%)
Rash erythematous	9/109 (8.3%)		14/110 (12.7%)
Dry skin	8/109 (7.3%)		3/110 (2.7%)
Rash maculo-papular	3/109 (2.8%)		7/110 (6.4%)
Rash pruritic	2/109 (1.8%)		8/110 (7.3%)
Vascular disorders
Hypertension	21/109 (19.3%)		35/110 (31.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.