Trial Outcomes & Findings for Phase 2 Study of Brigatinib in Japanese Participants With Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer (NSCLC) (NCT NCT03410108)

Participants with non-small cell lung cancer (NSCLC) based on prior anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) treatment or naïve (with no prior treatment with TKIs) took part in the study at 32 investigative sites in Japan from 29 January 2018 to data cut-off date: 29 September 2020. The study is ongoing.

Participants enrolled in single arm in this study to receive brigatinib 90/180 mg. The first 9 participants were assessed for initial safety in 'Safety Evaluation Lead-in Part'. Once safety was confirmed, participants were further enrolled in same arm. Data for outcome measures were assessed based on treatment taken before screening: Main Cohort(at least 1 line of prior treatment); Sub-Cohort(with 2 prior ALK-TKIs treatment); TKI-Naive Expansion Cohort(no prior treatment).

Race and Ethnicity were not collected from any participant.

Confirmed ORR: Percentage of participants confirmed to have achieved complete response(CR) or partial response(PR) per Independent Review Committee(IRC) using Response Evaluation Criteria in Solid Tumors(RECIST) version 1.1 after the initiation of study treatment(confirmed ≥4 weeks after initial response). CR(target lesion response): disappearance of all extranodal target lesions, all pathological lymph nodes must have decreased to \<10 mm in short axis. CR(non-target lesion response): disappearance of all extranodal nontarget lesions, all lymph nodes must be nonpathological in size(\<10 mm short axis) and normalization of tumor marker level. PR(target lesions): at least 30% decrease in sum of the longest diameters(SLD) of target lesions, taking as reference Baseline sum diameters. As pre-specified in the protocol, this outcome measure was assessed and reported data only in the participants with at least 1 line of prior treatment(called as Main Cohort) of the Refractory Expansion Part.

12 months PFS rate was defined as the percentage of the participants who did not have PFS events (PD per IRC using RECIST version 1.1, or death by any cause) at 12 months after the start of study treatment. PD for target lesion: 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. PD for non-target lesion: unequivocal progression of existing nontarget lesions. Kaplan-Meier method was used for analysis of percentage of participants who achieved PFS of 12 months. As pre-specified in the protocol, this outcome measure was assessed and reported data only in the TKI-Naïve Expansion Cohort (participants with no prior treatment).

Confirmed ORR was defined as percentage of participants who were confirmed to have achieved CR or PR per an IRC using RECIST version 1.1 after initiation of study treatment (confirmed ≥4 weeks after initial response). CR for target lesion response: disappearance of all extranodal target lesions, all pathological lymph nodes must have decreased to \<10 mm in short axis. CR for non-target lesion response: disappearance of all extranodal nontarget lesions, all lymph nodes must be nonpathological in size (\<10 mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in SLD of target lesions, taking as reference baseline sum diameters. As pre-specified in the protocol, the data for this outcome measure is reported based on previous treatment as: All Refractory Participants, and TKI-Naive Expansion Cohort.

Confirmed ORR was defined as the percentage of the participants who were confirmed to have achieved CR or PR per the investigator using RECIST version 1.1 after the initiation of study treatment (confirmed ≥4 weeks after initial response). CR for target lesion response: disappearance of all extranodal target lesions, all pathological lymph nodes must have decreased to \<10 mm in short axis. CR for non-target lesion response: disappearance of all extranodal nontarget lesions, all lymph nodes must be nonpathological in size (\<10 mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort: Main Cohort of the Refractory Expansion Part and TKI-Naive Expansion Cohort. The Safety Evaluation Lead-in Part was excluded from the analysis.

DOR was assessed by an IRC, per RECIST version 1.1. DOR was defined as the time between the first documentation of objective tumor response (CR or PR) and the first subsequent documentation of objective PD or death due to any cause, whichever occurs first. PD for target lesion: 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. PD for non-target lesion: unequivocal progression of existing nontarget lesions. Only responders were analyzed for this outcome measure. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort: Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort.

PFS was assessed by an IRC, per RECIST version 1.1. PFS was defined as the time from the start of study treatment to the first documentation of objective PD or to death due to any cause, whichever occurs first. PD for target lesion: 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. PD for non-target lesion: unequivocal progression of existing nontarget lesions. This outcome measure reports the data in refractory participants only and data is reported per cohort separately for Main Cohort of the Refractory Expansion Part, and for All Refractory Participants.

PFS was assessed by an IRC, per RECIST version 1.1. PFS was defined as the time from the start of study treatment to the first documentation of objective PD or to death due to any cause, whichever occurs first. PD for target lesion: 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. PD for non-target lesion: unequivocal progression of existing nontarget lesions. This outcome measure reports data only in the TKI-Naive Expansion Cohort.

DCR was assessed by an IRC, per RECIST version 1.1. DCR: percentage of participants confirmed to have achieved CR or PR or have best overall response of stable disease (SD), for 6 weeks or more after initiation of study drug. CR (target lesion): disappearance of all target lesions. CR (non-target lesions): the nontarget lesion(s) has fully resolved. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. SD (target lesion): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD (target lesion): SLD increased by at least 20% from the smallest value on study, the SLD must also demonstrate an absolute increase of at least 5 mm. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort: Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort.

Time to response was assessed by an IRC, per RECIST version 1.1. and was defined as the time interval from the date of the first dose of study treatment until the initial observation of CR or PR for participants with confirmed CR/PR. CR(target lesion response):disappearance of all extranodal target lesions, all pathological lymph nodes must have decreased to \<10 mm in short axis. CR(non-target lesion response):disappearance of all extranodal nontarget lesions, all lymph nodes must be nonpathological in size (\<10 mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort: Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort.

OS is defined as the time interval from the date of the first dose of the study treatment until death due to any cause. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort: Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort.

Confirmed iORR was defined as the percentage of the participants who had achieved confirmed CR or PR in the intracranial CNS per modified RECIST version 1.1 as evaluated by an IRC after the initiation of study treatment. CR for target lesion: disappearance of all target lesions. CR for non-target lesions: the nontarget lesion(s) has fully resolved. PR for target lesion: at least a 30% decrease in SLD of target lesions, taking as reference the Baseline SLD. Additionally, progression of target lesions must not be present. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort: Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort.

iDOR was assessed by an IRC, per modified RECIST version 1.1 and was defined as the time between first documentation of objective intracranial tumor response (CR or PR) and first subsequent documentation of objective intracranial PD or death due to any cause. Participants who had systemic PD without intracranial PD were censored. CR (target lesion): disappearance of all target lesions. CR (non-target lesions):the nontarget lesion(s) has fully resolved. PR (target lesion):at least a 30% decrease in SLD of target lesions, taking as reference Baseline SLD. Progression of target lesions must not be present. CNS PD (target lesions):at least a 20% increase in SLD of target lesions, taking as reference the nadir SLD (or the baseline) and SLD must also demonstrate an absolute increase of ≥5 mm. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort: Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort.

iPFS was assessed by an IRC, per modified RECIST version 1.1 and was defined as the time from the start of study treatment to the first documentation of objective intracranial PD or death due to any cause, whichever occurred first. The participant who had systemic PD and withdrawn from study without intracranial PD was censored. CNS PD for target lesions: at least a 20% increase in the SLD of target lesions, taking as reference the nadir SLD (or the baseline, if the baseline is the nadir value) and the SLD must also demonstrate an absolute increase of ≥5 mm. PD for non-target lesions: the nontarget site of disease has shown unequivocal progression. As pre-specified in the protocol, this outcome measure was assessed and reports data per cohort in all participants with measurable or not measurable intracranial metastases at Baseline: Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort.

Time on treatment was defined as the time interval from the first dose to the last dose of brigatinib. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort: Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort.

EORTC QLQ-C30 contains 30 items - 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 QOL scale. Out of 30, 28 questions had 4 response levels (not at all, a little, quite a bit, and very much); 2 questions for global health status had score of 1 to 7 (very poor to excellent) to evaluate overall health and QOL. Each subscale raw score including global health status was transformed to a total score of 0 to 100. For functional scales, global health status scale, higher scores=better QOL (positive change from Baseline=improvement). For symptom scales, lower scores=better QOL (negative change from Baseline=improvement). As pre-specified in protocol, this outcome measure was assessed and reports data per cohort: Refractory Expansion Participants (including Main Cohort and Sub-Cohort), and TKI-Naive Expansion Cohort.

HRQOL scores was assessed with EORTC, its lung cancer module QLQ-LC13. QLQ-LC13 contains 13 questions (4-point scale where 1=Not at all \[best\] to 4=Very much \[worst\]) assessing lung cancer-associated symptoms \[cough, hemoptysis, dyspnea, and site-specific pain (chest, arm or shoulder, other parts)\], treatment-related side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and use of pain medication. Subscale score range: 0 to 100. Higher symptom score = greater degree of symptom severity. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort only in the Refractory Expansion Participants (including Main Cohort and Sub-cohort), and TKI-Naive Expansion Cohort.

EQ-5D-5L comprises of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each rated on 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, 5= extremely severe problems. Higher scores indicated greater levels of problems across the five dimensions. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort only in the Refractory Expansion Participants (including Main Cohort and Sub-cohort), and TKI-Naive Expansion Cohort. Number of participants with a particular score at the given timepoint is reported. Only categories with data are reported.

The EQ VAS records the respondent's self-rated health on a 20 centimeter (cm), vertical, visual analogue scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). As pre-specified in the protocol, this outcome measure assessed and reports data per cohort only in the Refractory Expansion Participants (including Main Cohort and Sub-cohort), and TKI-Naive Expansion Cohort.

As pre-specified in the protocol, this outcome measure was assessed only in the participants with or without prior ALK-TKI treatment called as the Safety Evaluation Lead-in Part.

As pre-specified in the protocol, this outcome measure was assessed only in the participants with or without prior ALK-TKI treatment called as the Safety Evaluation Lead-in Part.

As pre-specified in the protocol, this outcome measure was assessed only in the participants with or without prior ALK-TKI treatment called as the Safety Evaluation Lead-in Part.