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Neoplasms by Histologic Type

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Respiratory Tract Diseases

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Crizotinib

Tyrosine Kinase Inhibitors

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Tyrosine

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).

Brigatinib

Medical Director

The purpose of the study is to compare the efficacy of brigatinib to that of crizotinib in ALK+ locally advanced or metastatic non-small cell lung cancer (NSCLC) participants naive to ALK inhibitors, as evidenced by progression-free survival (PFS).

The purpose of this phase III, randomized, open-label, comparative, multicenter, international study is to compare the efficacy and safety of brigatinib to that of crizotinib in ALK+ locally advanced or metastatic NSCLC participants who have not previously been treated with an ALK inhibitor. Participants will be stratified by the presence of CNS metastases at baseline and prior chemotherapy used for locally advanced or metastatic disease. Participants will be randomized in a 1:1 ratio to receive either brigatinib, 90 mg orally once daily (QD) for 7 days, then a 180 mg orally QD, or crizotinib, 250 mg orally twice daily (BID). Participants will receive treatment until disease progression, intolerable toxicity, consent withdrawal, or death. Crossover from crizotinib to brigatinib is also permitted.

The total estimated duration of the study is at least 4.5 years, including 1.5 years to accrue participants, with at least 3 years for treatment and follow-up.

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

A Phase 3 Multicenter Open-label Study of Brigatinib (AP26113) Versus Crizotinib in Patients With ALK-positive Advanced Lung Cancer

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

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.

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.

ORR was defined as percentage of participants who achieved CR or PR in the central nervous system (CNS) in randomized participants with intracranial CNS metastasis at baseline. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters.

Intracranial PFS as assessed by BIRC, is defined as the time from randomization until first CNS PD is documented, or death due to any cause. PD is SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest), the SLD must also demonstrate an absolute increase of at least 5 mm, and unequivocal progression of existing non-target lesions.

Overall survival is defined as the time from randomization until death due to any cause.

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 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.

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.

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.

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.

Ariad Pharmaceuticals

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.

Randomized Phase: Brigatinib 90 mg QD/180 QD

Randomized Phase: Crizotinib 250 mg BID

Crossover Phase: Brigatinib 90 mg QD/180 mg QD

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Race/Ethnicity, Customized

Australia

Hong Kong

Singapore

Korea, Republic Of

Taiwan, Province Of China

Austria

Denmark

France

Germany

Italy

Luxembourg

Netherlands

Norway

Spain

Sweden

Switzerland

United Kingdom

Canada

United States

Region of Enrollment

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.

Number analyzed is number of participants with data available for global health status/QoL at Baseline.

Global Health Status/Quality of Life (QoL)

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.

Study Director

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.

Progression-free Survival (PFS)

Confirmed Objective Response Rate (ORR)

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.

Confirmed Intracranial ORR (iORR)

Intracranial Progression Free Survival

Overall Survival (OS)

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.

Duration of Response (DOR)

Time to Response (TTR)

Disease Control Rate (DCR)

Treated Population included all participant who received at least 1 dose of study drug and served as basis of safety analysis.

Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)

Change From Baseline in Global Health Status/Quality of Life as Assessed by EORTC QLQ-C30 (Version 3.0)

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).

Randomized Phase

Crossover Phase

Brigatinib will be administered orally to eligible patients with locally advanced or metastatic ALK+ NSCLC who are resistant or intolerant to a prior ALK inhibitor at a dose of 180 mg QD with a 7 day lead-in at 90 mg QD, continuously, with or without food.

The purpose of this study is to provide brigatinib for those patients with locally advanced and/or metastatic patients with ALK+ NSCLC on an expanded access basis due to their inability to meet eligibility criteria for on-going recruiting trials, inability to participate in other clinical trials (e.g., poor performance status, lack of geographic proximity), or because other medical interventions are not considered appropriate or acceptable.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
ALTA-1L Study: A Study of Brigatinib Versus Crizotinib in Anaplastic Lymphoma Kinase Positive (ALK+) Advanced Non-small Cell Lung Cancer (NSCLC) Participants	NCT02737501	Non-small Cell ... Lung Cancer Advanced Malign... Carcinoma	Brigatinib Crizotinib	18 Years -	Takeda
ALTA-1L Study: A Study of Brigatinib Versus Crizotinib in Anaplastic Lymphoma Kinase Positive (ALK+) Advanced Non-small Cell Lung Cancer (NSCLC) Participants	NCT02737501	Non-small Cell ... Lung Cancer Advanced Malign... Carcinoma	Brigatinib Crizotinib	18 Years -	Takeda
ALTA-1L Study: A Study of Brigatinib Versus Crizotinib in Anaplastic Lymphoma Kinase Positive (ALK+) Advanced Non-small Cell Lung Cancer (NSCLC) Participants	NCT02737501	Non-small Cell ... Lung Cancer Advanced Malign... Carcinoma	Brigatinib Crizotinib	18 Years -	Takeda
An Expanded Access Study of Brigatinib for Patients With ALK-positive Advanced Non-Small Cell Lung Cancer	NCT02784158	Non-small Cell ... Lung Cancer Advanced Malign... Carcinoma	Brigatinib	18 Years -	Takeda
An Expanded Access Study of Brigatinib for Patients With ALK-positive Advanced Non-Small Cell Lung Cancer	NCT02784158	Non-small Cell ... Lung Cancer Advanced Malign... Carcinoma	Brigatinib	18 Years -	Takeda

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