ALTA-2: A Study of Brigatinib in Participants With Anaplastic Lymphoma Kinase-Positive (ALK+), Advanced Non-Small-Cell Lung Cancer (NSCLC) Progressed on Alectinib or Ceritinib

• Sponsor: Ariad Pharmaceuticals (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03535740
• Collaborator: Takeda (Industry)
• Enrollment: 103
• Locations: 80
• Arm: 1
• Anticipated Duration (Months): 44.9
• Patients Per Site: 1.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The primary purpose of this study is to determine the efficacy of brigatinib by confirmed objective response rate (ORR) by response evaluation criteria in solid tumors (Response Evaluation Criteria in Solid Tumors [RECIST]), in participants with ALK+ locally advanced or metastatic NSCLC whose disease has progressed on therapy with alectinib or ceritinib.

Condition or Disease	Intervention/Treatment	Phase
ALK-positive Advanced NSCLC	Drug: Brigatinib	Phase 2

Detailed Description

The drug being tested in this study is called brigatinib (AP26113). Brigatinib is being tested to treat people who have anaplastic lymphoma kinase-positive (ALK+), advanced non-small-cell lung cancer (NSCLC).

The study will enroll approximately 103 patients. Participants will be assigned to the treatment group:

• Brigatinib

All participants will be asked to take brigatinib 90 mg tablet in lead-in period for 7 days, followed by brigatinib 180 mg at the same time each day throughout the study. Participants with progressive disease had an option to receive an escalated dose of brigatinib 240 mg as per investigator's discretion in case no toxicities (greater than grade 2) are experienced.

This multicenter trial will be conducted worldwide. The overall time to participate in this study is approximately 3 years. Participants will make multiple visits to the clinic, and 30 days after last dose of study drug for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 103 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Brigatinib in Patients With Anaplastic Lymphoma Kinase-Positive (ALK+), Advanced Non-Small-Cell Lung Cancer (NSCLC) Progressed on Alectinib or Ceritinib
• Actual Study Start Date: Jan 31, 2019
• Actual Primary Completion Date: Sep 30, 2020
• Anticipated Study Completion Date: Oct 30, 2022

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Brigatinib 90 mg/180 mg with Optional Dose Escalation to 240 mg Brigatinib 90 mg, tablets, orally, once daily for 7 days, followed by Brigatinib 180 mg, tablets, orally, once daily for until objective disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by the investigator, or intolerable toxicity. Participants who experienced progression on the 180 mg dose and had not experienced toxicities greater than Grade 2 had the option to receive brigatinib 240 mg QD based on investigator's discretion, up to 20 months from start of enrollment until data cut-off: 30 September 2020. Participants who experienced progression on any doses but judged as still benefiting from the study treatment by the investigator may continue to use the current dose, up to study end.

Drug: Brigatinib; Brigatinib Tablets; Other Names: AP26113

Outcome Measures

Primary Outcome Measures

1. Confirmed Objective Response Rate (ORR) Using RECIST v1.1 as Assessed by the Independent Review Committee (IRC) [Up to approximately 20 months from start of enrollment till data cut-off: 30 September 2020]

   Confirmed ORR is defined as the percentage of the participants who are confirmed to have achieved complete response (CR) or partial response (PR), per RECIST version 1.1 (confirmed ≥4 weeks after initial response), after the initiation of study treatment. CR: disappearance of all extranodal target lesions and all pathological lymph nodes must have decreased to <10 mm in short axis and PR: at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions taking as reference the Baseline sum diameters.

Secondary Outcome Measures

1. Confirmed ORR Using RECIST v1.1 as Assessed by the Investigator [Until the radiological disease progression or study end (approximately 3 years)]

   Confirmed ORR is defined as the percentage of the participants who are confirmed to have achieved CR or PR, per RECIST version 1.1 (confirmed ≥4 weeks after initial response), after the initiation of study treatment. CR: disappearance of all extranodal target lesions and all pathological lymph nodes must have decreased to <10 mm in short axis and PR: at least a 30% decrease in the SLD of target lesions taking as reference the baseline sum diameters.

2. Duration of Response (DOR) as Assessed by the Investigator and IRC [Until the radiological disease progression or study end (approximately 3 years)]

   DOR is defined as the time interval from the time that the measurement criteria are first met for CR or PR until the first date that the progressive disease (PD) is objectively documented, or death. CR: disappearance of all extranodal target lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. PR: at least a 30% decrease in the SLD of target lesions taking as reference the Baseline sum diameters. PD: SLD increased by at least 20% from the smallest value on study (including Baseline, if that is the smallest). SLD must also demonstrate an absolute increase of at least 5 mm (2 lesions increasing from, for example, 2 mm to 3 mm, does not qualify).

3. Progression-Free Survival (PFS) as Assessed by the Investigator and IRC [Until the radiological disease progression or study end (approximately 3 years)]

   PFS is 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. PFS will be censored for participants without documented disease progression or death.

4. Disease Control Rate (DCR) as Assessed by the Investigator and IRC [Until the radiological disease progression or study end (approximately 3 years)]

   DCR is defined as the percentage of participants who have achieved CR, PR or stable disease (SD) (in the case of SD, measurements must have met the SD criteria at least once after study entry at a minimum interval of 6 weeks) after the initiation of study treatment. CR: disappearance of all extranodal target lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. 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 PD.

5. Time to Response as Assessed by the Investigator and IRC [Until the radiological disease progression or study end (approximately 3 years)]

   Time to response is defined as the time interval from the date of the first dose of the study treatment until the initial observation of CR or PR. CR: disappearance of all extranodal target lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. PR: at least a 30% decrease in the SLD of target lesions taking as reference the baseline sum diameters.

6. Confirmed Intracranial Objective Response Rate (iORR) in Participants With Brain Metastases at Baseline, as Assessed by the IRC [Until the radiological disease progression or study end (approximately 3 years)]

   Confirmed iORR is defined as the proportion of the participants who have achieved CR or PR in the brain per a modification of RECIST version 1.1, after the initiation of study treatment, in participants with intracranial brain metastases at baseline. CR: disappearance of all extranodal target lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. or partial response or PR: at least a 30% decrease in the SLD of target lesions taking as reference the baseline sum diameters.

7. Duration of Intracranial Response in Participants With Brain Metastases at Baseline, as Assessed by the IRC [Until the radiological disease progression or study end (approximately 3 years)]

   Duration of intracranial response is defined as the time interval from the time that the measurement criteria are first met for CR or PR until the first date that PD (including baseline, if that is the smallest). SLD must also demonstrate an absolute increase of at least 5 mm. (2 lesions increasing from, for example, 2 mm to 3 mm, does not qualify) in the brain is objectively documented or death, in participants with intracranial metastases at baseline. CR: disappearance of all extranodal target lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. or partial response or PR: at least a 30% decrease in the SLD of target lesions taking as reference the baseline sum diameters in the brain. PD: SLD increased by at least 20% from the smallest value on study.

8. Intracranial Progression-Free Survival (iPFS) in Participants With Brain Metastases at Baseline, as Assessed by the IRC [Until the radiological disease progression or study end (approximately 3 years)]

   iPFS is defined as the time interval from the date of the first dose of the study treatment until the first date at which intracranial brain disease progression is objectively documented, or death due to any cause, whichever occurs first, in participants with intracranial metastases at enrollment. iPFS will be censored for participants without documented intracranial disease progression or death.

9. Overall Survival (OS) [Until the radiological disease progression or study end (approximately 3 years)]

   OS is defined as the time interval from the date of the first dose of the study treatment until death due to any cause. It will be censored on the date of last contact for those participants who are alive.

10. Number of Participants With One or More Treatment-emergent Adverse Event (TEAE) [First dose of study drug up to 30 days after last dose (approximately 3 years)]

    An adverse event (AE) means any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. This includes any newly occurring event, or a previous condition that has increased in severity or frequency since the administration of study drug.

11. Health-Related Quality of Life (HRQOL) From European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Score [First dose of study drug up to 30 days after last dose (approximately 3 years)]

    EORTC QLQ-C30 incorporates 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). EORTC QLQ-C30 contains 28 questions (4-point scale where 1=Not at all [best] to 4=Very Much [worst]) and 2 questions (7-point scale where 1=Very poor [worst] to 7= Excellent [best]). Raw scores are converted into scale scores ranging from 0 to 100. For the functional scales and the global health status scale, higher scores represent better quality of life (QOL); for the symptom scales, lower scores represent better QOL.

12. HRQOL From EORTC QLQ- Lung Cancer (LC) 13 [First dose of study drug up to 30 days after last dose (approximately 3 years)]

    HRQOL scores will be assessed with EORTC, its lung cancer module QLQ-LC13. QLQ-LC13 contains 13 questions assessing lung cancer-associated symptoms (cough, hemoptysis, dyspnea, and site-specific pain), treatment-related side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and use of pain medication. Scale score range: 0 to 100. Higher symptom score = greater degree of symptom severity.

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 stage IIIB (locally advanced or recurrent and not a participant for curative therapy) or stage IV non-small-cell lung cancer (NSCLC).

2. Must meet both of the following 2 criteria:

3. Have documentation of anaplastic lymphoma kinase (ALK) rearrangement by a positive result from any laboratory test® approved by the food and drug administration (FDA) or Have documented ALK rearrangement by a different test (non-FDA-approved local lab tests) and have provided tumor sample to the central laboratory. (Note: Central laboratory ALK rearrangement testing results are not required to be obtained before randomization.)

4. Had been on any one of the ALK tyrosine kinase inhibitor (TKIs) (alectinib, ceritinib, crizotinib) for at least 12 weeks before progression.

5. Had progressive disease (PD) while on alectinib or ceritinib

6. Had alectinib or ceritinib as the most recent ALK inhibitor therapy.

7. Have at least 1 measurable lesion per response evaluation criteria in solid tumors (RECIST) version 1.1 as assessed by the investigator.

8. Had recovered from toxicities related to prior anticancer therapy to national cancer institute common terminology criteria for adverse events (NCI CTCAE), version 4.03, Grade <=1. (Note: Treatment-related alopecia or peripheral neuropathy that are Grade

1 are allowed if deemed irreversible.) and have adequate major organ functions.

1. Have a life expectancy of ≥3 months.

Exclusion Criteria:

1. Had received any prior ALK-targeted TKI other than crizotinib, alectinib, or ceritinib.

2. Had received both alectinib and ceritinib.

3. Had previously received more than 3 regimens of systemic anticancer therapy for locally advanced or metastatic disease.

4. Had symptomatic brain metastasis (parenchymal or leptomeningeal). Participants with asymptomatic brain metastasis or who have stable symptoms that did not require an increased dose of corticosteroids to control symptoms in the past 7 days before the first dose of brigatinib may be enrolled.

5. Had current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Participants with leptomeningeal disease and without cord compression are allowed.

6. Had a cerebrovascular accident or transient ischemic attack within 6 months before first dose of brigatinib.

7. Had an ongoing or active infection, including, but not limited to, the requirement for intravenous antibiotics.

8. Had malabsorption syndrome or other gastrointestinal (GI) illness that could affect oral absorption of brigatinib.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Irvine Health Chao Family Comprehensive Cancer Center	Orange	California	United States	92868
2	The Oncology Institute of Hope and Innovation	Whittier	California	United States	90602
3	USOR - Rocky Mountain Cancer Centers - Pueblo	Pueblo	Colorado	United States	81008
4	Florida Hospital Medical Group	Orlando	Florida	United States	32804
5	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201
6	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
7	Levine Cancer Institute - Southpark	Charlotte	North Carolina	United States	28211
8	Providence Portland Medical Center	Portland	Oregon	United States	97213
9	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
10	USOR - Virginia Cancer Specialists - Fairfax Office	Fairfax	Virginia	United States	22031
11	Saint Vincent's Hospital Melbourne	Fitzroy	Victoria	Australia	3065
12	Peninsula & South Eastern Haematology and Oncology Group	Frankston	Victoria	Australia	3199
13	Sir Charles Gairdner Hospital	Nedlands	Western Australia	Australia	6009
14	Klinikum Klagenfurt Am Worthersee	Klagenfurt	Carinthia	Austria	9020
15	Krankenhaus Elisabethinen Linz	Linz	Upper Austria	Austria	4020
16	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
17	Tom Baker Cancer Center	Calgary	British Columbia	Canada	T2N 2T9
18	Toronto University Health Network	Toronto	Ontario	Canada	M5G 2M9
19	McGill University Health Centre	Montreal	Quebec	Canada	H4A 3J1
20	Beijing Cancer Hospital	Beijing	Beijing	China	100000
21	The First Affiliated Hospital of Guangzhou Medical University	Guangzhou	Guangdong	China	510000
22	Jilin Provincial Cancer Hospital (Changchun Cancer Hospital)	Changchun	Jilin	China	130000
23	Shanghai Pulmonary Hospital	Shanghai	Shanghai	China	200001
24	The First Affiliated Hospital of Zhejiang University School of Medicine	Hangzhou	Zhejiang	China	310000
25	Zhejiang Cancer Hospital	Hangzhou	Zhejiang	China	310000
26	Hopital Haut-Leveque	Pessac	Aquitaine	France	33604
27	Centre Hospitalier Intercommunal de Creteil	Creteil	Ile-de-france	France	94010
28	Hopital Larrey, CHU de Toulouse, Service de Pneumologie	Toulouse Cedex 9	Midi-pyrenees	France	31059
29	Assistance Publique-Hopitaux de Marseille Hopital Nord	Marseille	Provence Alpes COTE D'azur	France	13915
30	Centre de Lutte Contre le Cancer Centre Leon Berard	Lyon	Rhone-alpes	France	69008
31	Thoraxklinik Heidelberg gGmbH	Heidelberg	Baden-wuerttemberg	Germany	69126
32	Universitatsklinikum Ulm	Ulm	Baden-wuerttemberg	Germany	89081
33	Klinikum Kempten-Oberallgau	Kempten	Bavaria	Germany	87439
34	Ludwig-Maximilians-Universitat Munchen	Munchen	Bayern	Germany	80336
35	Pius Hospital Oldenburg	Oldenburg	Niedersachsen	Germany	26121
36	Evangelisches Krankenhaus Hamm	Hamm	Nordrhein-westfalen	Germany	59063
37	HELIOS Klinikum Emil von Behring	Berlin		Germany	14165
38	Prince of Wales Hospital	Shatin	New Territories	Hong Kong
39	Queen Mary Hospital	Hong Kong		Hong Kong	00852
40	Queen Mary Hospital	Hong Kong		Hong Kong
41	Queen Elizabeth Hospital	Kowloon		Hong Kong	1076
42	Princess Margaret Hospital - Hong Kong	Kowloon		Hong Kong
43	Azienda Ospedaliera San Camillo Forlanini	Roma	Lazio	Italy	00152
44	Centro di Riferimento Oncologico di Aviano	Aviano	Pordenone	Italy	33081
45	Azienda Ospedaliero - Universitaria San Luigi Gonzaga	Orbassano	Torino	Italy	10043
46	Istituto Europeo di Oncologia	Milano		Italy	20141
47	Istituto Nazionale Tumori IRCCS Fondazione Pascale	Napoli		Italy	80131
48	Azienda Ospedaliero Universitaria di Parma	Parma		Italy	43126
49	Azienda USL della Romagna	Ravenna		Italy	48121
50	Fujita Health University Hospital	Toyoake	Aichi	Japan	470-1192
51	Kanagawa Cancer Center	Yokohama	Kanagawa	Japan	241-8515
52	Sendai Kousei Hospital	Sendai	Miyagi	Japan	980-0873
53	Okayama University Hospital	Okayama-city	Okayama	Japan	700-8558
54	Kansai Medical University Hirakata Hospital	Hirakata-shi	Osaka	Japan	573-1191
55	The Cancer Institute Hospital of Japanese Foundation for Cancer Research	Koto-ku	Tokyo	Japan	135-8550
56	National Cancer Center	Goyang-si	Gyeonggi-do	Korea, Republic of	411-769
57	Gachon University Gil Medical Center	Incheon	Gyeonggi-do	Korea, Republic of	21565
58	Korea University Anam Hospital	Seoul	Gyeonggi-do	Korea, Republic of	02841
59	Chungbuk National University Hospital	Cheongju-si	Gyeongsangbuk-do	Korea, Republic of	28644
60	Keimyung University Dongsan Medical Center	Daegu		Korea, Republic of	41931
61	Seoul National University Hospital	Seoul		Korea, Republic of	03080
62	Severance Hospital	Seoul		Korea, Republic of	03722
63	Asan Medical Center	Seoul		Korea, Republic of	05505
64	Samsung Medical Center	Seoul		Korea, Republic of	135-710
65	Maastricht University Medical Centre	Maastricht	Limburg	Netherlands	6229 HX
66	Vrije Universiteit Medisch Centrum	Amsterdam	Noord-holland	Netherlands	1081 HV
67	Erasmus University Medical Center	Rotterdam	Zuid-holland	Netherlands	3015 CE
68	Institut Catala d'Oncologia Badalona - Hospital Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
69	Complejo Hospitalario Universitario A Coruna	A Coruna	LA Coruna	Spain	15006
70	Hospital Universitario Vall d'Hebron	Barcelona		Spain	08035
71	Hospital Universitario Ramon Y Cajal	Madrid		Spain	28034
72	Hospital Universitario La Paz	Madrid		Spain	28046
73	Hospital Universitario Puerta de Hierro - Majadahonda	Madrid		Spain	28222
74	Skanes Universitetssjukhus i Lund	Lund	Skane	Sweden	214 01
75	Karolinska Universitetssjukhuset	Stockholm		Sweden	171 76
76	Uppsala Akademiska Sjukhus	Uppsala		Sweden	751 85
77	Changhua Christian Hospital	Changhua City	Changhwa	Taiwan	500
78	National Cheng Kung University	Tainan	Tainan CITY	Taiwan	70403
79	China Medical University Hospital	Taichung		Taiwan	404
80	Taichung Veterans General Hospital	Taichung		Taiwan	40705

Sponsors and Collaborators

• Ariad Pharmaceuticals
• Takeda

Investigators

• Study Director: Medical Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Sep 24, 2020
• Statistical Analysis Plan - Jun 5, 2020

More Information

Publications

None provided.

• Responsible Party: Ariad Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03535740
• Other Study ID Numbers: Brigatinib-2002; 2018-000635-27; NL66462.078.18; JapicCTI-194915
• First Posted: May 24, 2018
• Last Update Posted: Jan 5, 2022
• Last Verified: Dec 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• 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 54 investigative sites in Canada, United States, Austria, France, Germany, Italy, Netherlands, Spain, Sweden, China, Hong Kong, Japan, Korea, Taiwan, and Australia from 31 January 2019 to data cut-off date: 30 September 2020. This study is ongoing.
Pre-assignment Detail	Participants with a diagnosis of anaplastic lymphoma kinase-positive (ALK+), advanced non-small-cell lung cancer (NSCLC) were enrolled in single arm to receive brigatinib 90 mg followed by 180 mg up to disease progression.

Arm/Group Title	Brigatinib 90 mg/180 mg With Optional Dose Escalation to 240 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily for 7 days, followed by Brigatinib 180 mg, tablets, orally, once daily for until objective disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by the investigator, or intolerable toxicity. Participants who experienced progression on the 180 mg dose and had not experienced toxicities greater than Grade 2 had the option to receive brigatinib 240 mg QD based on investigator's discretion, up to 20 months from start of enrollment until data cut-off: 30 September 2020. Participants who experienced progression on any doses but judged as still benefiting from the study treatment by the investigator may continue to use the current dose, up to study end.
Period Title: Overall Study
STARTED	103
Participants Who Received Escalated Dose of Brigatinib 240 mg	13
COMPLETED	0
NOT COMPLETED	103

Baseline Characteristics

Arm/Group Title	Brigatinib 90 mg/180 mg With Optional Dose Escalation to 240 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily for 7 days, followed by Brigatinib 180 mg, tablets, orally, once daily for until objective disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by the investigator, or intolerable toxicity. Participants who experienced progression on the 180 mg dose and had not experienced toxicities greater than Grade 2 had the option to receive brigatinib 240 mg QD based on investigator's discretion, up to 20 months from start of enrollment until data cut-off: 30 September 2020. Participants who experienced progression on any doses but judged as still benefiting from the study treatment by the investigator may continue to use the current dose, up to study end.
Overall Participants	103
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.7 (11.94)
Sex: Female, Male (Count of Participants)
Female	52 50.5%
Male	51 49.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 1.9%
Not Hispanic or Latino	92 89.3%
Unknown or Not Reported	9 8.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	49 47.6%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 1%
White	44 42.7%
More than one race	0 0%
Unknown or Not Reported	9 8.7%
Region of Enrollment (Count of Participants)
Canada	6 5.8%
United States	7 6.8%
Austria	1 1%
France	7 6.8%
Germany	3 2.9%
Italy	16 15.5%
Netherlands	2 1.9%
Spain	11 10.7%
Sweden	2 1.9%
China	14 13.6%
Hong Kong	6 5.8%
Japan	3 2.9%
South Korea	20 19.4%
Taiwan	4 3.9%
Australia	1 1%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	69.23 (15.409)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	165.86 (10.172)

Outcome Measures

1. Primary Outcome

Title	Confirmed Objective Response Rate (ORR) Using RECIST v1.1 as Assessed by the Independent Review Committee (IRC)
Description	Confirmed ORR is defined as the percentage of the participants who are confirmed to have achieved complete response (CR) or partial response (PR), per RECIST version 1.1 (confirmed ≥4 weeks after initial response), after the initiation of study treatment. CR: disappearance of all extranodal target lesions and all pathological lymph nodes must have decreased to <10 mm in short axis and PR: at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions taking as reference the Baseline sum diameters.
Time Frame	Up to approximately 20 months from start of enrollment till data cut-off: 30 September 2020

Outcome Measure Data

Analysis Population Description

FAS included all participants who received at least 1 dose of brigatinib.

Arm/Group Title	Brigatinib 90 mg/180 mg With Optional Dose Escalation to 240 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily for 7 days, followed by Brigatinib 180 mg, tablets, orally, once daily for until objective disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by the investigator, or intolerable toxicity. Participants who experienced progression on the 180 mg dose and had not experienced toxicities greater than Grade 2 had the option to receive brigatinib 240 mg QD based on investigator's discretion, up to 20 months from start of enrollment until data cut-off: 30 September 2020. Participants who experienced progression on any doses but judged as still benefiting from the study treatment by the investigator may continue to use the current dose, up to study end.
Measure Participants	103
Number (95% Confidence Interval) [percentage of participants]	26.2 25.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brigatinib 90 mg/180 mg With Optional Dose Escalation to 240 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0763
	Comments
	Method	Exact Binomial Test
	Comments	The calculation was based on an exact binomial test with a total 1-sided alpha level of 0.025 at primary analysis.

2. Secondary Outcome

Title	Confirmed ORR Using RECIST v1.1 as Assessed by the Investigator
Description	Confirmed ORR is defined as the percentage of the participants who are confirmed to have achieved CR or PR, per RECIST version 1.1 (confirmed ≥4 weeks after initial response), after the initiation of study treatment. CR: disappearance of all extranodal target lesions and all pathological lymph nodes must have decreased to <10 mm in short axis and PR: at least a 30% decrease in the SLD of target lesions taking as reference the baseline sum diameters.
Time Frame	Until the radiological disease progression or study end (approximately 3 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Duration of Response (DOR) as Assessed by the Investigator and IRC
Description	DOR is defined as the time interval from the time that the measurement criteria are first met for CR or PR until the first date that the progressive disease (PD) is objectively documented, or death. CR: disappearance of all extranodal target lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. PR: at least a 30% decrease in the SLD of target lesions taking as reference the Baseline sum diameters. PD: SLD increased by at least 20% from the smallest value on study (including Baseline, if that is the smallest). SLD must also demonstrate an absolute increase of at least 5 mm (2 lesions increasing from, for example, 2 mm to 3 mm, does not qualify).
Time Frame	Until the radiological disease progression or study end (approximately 3 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Progression-Free Survival (PFS) as Assessed by the Investigator and IRC
Description	PFS is 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. PFS will be censored for participants without documented disease progression or death.
Time Frame	Until the radiological disease progression or study end (approximately 3 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Disease Control Rate (DCR) as Assessed by the Investigator and IRC
Description	DCR is defined as the percentage of participants who have achieved CR, PR or stable disease (SD) (in the case of SD, measurements must have met the SD criteria at least once after study entry at a minimum interval of 6 weeks) after the initiation of study treatment. CR: disappearance of all extranodal target lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. 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 PD.
Time Frame	Until the radiological disease progression or study end (approximately 3 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Time to Response as Assessed by the Investigator and IRC
Description	Time to response is defined as the time interval from the date of the first dose of the study treatment until the initial observation of CR or PR. CR: disappearance of all extranodal target lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. PR: at least a 30% decrease in the SLD of target lesions taking as reference the baseline sum diameters.
Time Frame	Until the radiological disease progression or study end (approximately 3 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Confirmed Intracranial Objective Response Rate (iORR) in Participants With Brain Metastases at Baseline, as Assessed by the IRC
Description	Confirmed iORR is defined as the proportion of the participants who have achieved CR or PR in the brain per a modification of RECIST version 1.1, after the initiation of study treatment, in participants with intracranial brain metastases at baseline. CR: disappearance of all extranodal target lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. or partial response or PR: at least a 30% decrease in the SLD of target lesions taking as reference the baseline sum diameters.
Time Frame	Until the radiological disease progression or study end (approximately 3 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Duration of Intracranial Response in Participants With Brain Metastases at Baseline, as Assessed by the IRC
Description	Duration of intracranial response is defined as the time interval from the time that the measurement criteria are first met for CR or PR until the first date that PD (including baseline, if that is the smallest). SLD must also demonstrate an absolute increase of at least 5 mm. (2 lesions increasing from, for example, 2 mm to 3 mm, does not qualify) in the brain is objectively documented or death, in participants with intracranial metastases at baseline. CR: disappearance of all extranodal target lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. or partial response or PR: at least a 30% decrease in the SLD of target lesions taking as reference the baseline sum diameters in the brain. PD: SLD increased by at least 20% from the smallest value on study.
Time Frame	Until the radiological disease progression or study end (approximately 3 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Intracranial Progression-Free Survival (iPFS) in Participants With Brain Metastases at Baseline, as Assessed by the IRC
Description	iPFS is defined as the time interval from the date of the first dose of the study treatment until the first date at which intracranial brain disease progression is objectively documented, or death due to any cause, whichever occurs first, in participants with intracranial metastases at enrollment. iPFS will be censored for participants without documented intracranial disease progression or death.
Time Frame	Until the radiological disease progression or study end (approximately 3 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. 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. It will be censored on the date of last contact for those participants who are alive.
Time Frame	Until the radiological disease progression or study end (approximately 3 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Number of Participants With One or More Treatment-emergent Adverse Event (TEAE)
Description	An adverse event (AE) means any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. This includes any newly occurring event, or a previous condition that has increased in severity or frequency since the administration of study drug.
Time Frame	First dose of study drug up to 30 days after last dose (approximately 3 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	Health-Related Quality of Life (HRQOL) From European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Score
Description	EORTC QLQ-C30 incorporates 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). EORTC QLQ-C30 contains 28 questions (4-point scale where 1=Not at all [best] to 4=Very Much [worst]) and 2 questions (7-point scale where 1=Very poor [worst] to 7= Excellent [best]). Raw scores are converted into scale scores ranging from 0 to 100. For the functional scales and the global health status scale, higher scores represent better quality of life (QOL); for the symptom scales, lower scores represent better QOL.
Time Frame	First dose of study drug up to 30 days after last dose (approximately 3 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	HRQOL From EORTC QLQ- Lung Cancer (LC) 13
Description	HRQOL scores will be assessed with EORTC, its lung cancer module QLQ-LC13. QLQ-LC13 contains 13 questions assessing lung cancer-associated symptoms (cough, hemoptysis, dyspnea, and site-specific pain), treatment-related side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and use of pain medication. Scale score range: 0 to 100. Higher symptom score = greater degree of symptom severity.
Time Frame	First dose of study drug up to 30 days after last dose (approximately 3 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Up to data cut-off date: 30 September 2020 (approximately 20 months from first dose of study treatment (Brigatinib 90/180 mg or Brigatinib 240 mg))
Adverse Event Reporting Description	As pre-specified in protocol, AEs are reported for 2 sets/arms. Arm 1 (Brigatinib 90/180 mg) has AEs in participants who received brigatinib 90/180 mg from first dose of study treatment for all participants till 30 days after last dose, if participant discontinues/do not escalate to 240 mg dose. Arm 2 (brigatinib 240 mg) has AEs in participants who had brigatinib dose-escalated to 240 mg from date of escalation to 240 mg QD up to 30 days post last dose until data cut-off date: 30 September 2020.
Arm/Group Title	Brigatinib 90 mg/180 mg		Brigatinib 240 mg
Arm/Group Description	Brigatinib 90 mg, tablets, orally, once daily for 7 days, followed by Brigatinib 180 mg, tablets, orally, once daily for until objective disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by the investigator, or intolerable toxicity Up to approximately 20 months from start of enrollment till data cut-off: 30 September 2020. Participants who experienced progression on any doses but judged as still benefiting from the study treatment by the investigator may continue to use the current dose, up to study end.		Participants who experienced progression on the 180 mg dose and had not experienced toxicities greater than Grade 2 had the option from start of enrollment to receive brigatinib 240 mg QD based on investigator's discretion up to data-cut off: 30 September 2020 (approximately 20 months). Participants who experienced progression on any doses but judged as still benefiting from the study treatment by the investigator may continue to use the current dose, up to study end.
All Cause Mortality
	Brigatinib 90 mg/180 mg		Brigatinib 240 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/103 (30.1%)		3/13 (23.1%)
Serious Adverse Events
	Brigatinib 90 mg/180 mg		Brigatinib 240 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	47/103 (45.6%)		2/13 (15.4%)
Blood and lymphatic system disorders
Neutropenia	1/103 (1%)		0/13 (0%)
Thrombocytopenia	1/103 (1%)		0/13 (0%)
Cardiac disorders
Atrial flutter	1/103 (1%)		0/13 (0%)
Cardiac arrest	1/103 (1%)		0/13 (0%)
Cardiac failure	1/103 (1%)		0/13 (0%)
Gastrointestinal disorders
Duodenal obstruction	1/103 (1%)		0/13 (0%)
Intestinal obstruction	1/103 (1%)		0/13 (0%)
General disorders
Pyrexia	2/103 (1.9%)		0/13 (0%)
Death	1/103 (1%)		0/13 (0%)
Fatigue	1/103 (1%)		0/13 (0%)
General physical health deterioration	1/103 (1%)		0/13 (0%)
Pain	1/103 (1%)		0/13 (0%)
Peripheral swelling	1/103 (1%)		0/13 (0%)
Infections and infestations
Pneumonia	4/103 (3.9%)		0/13 (0%)
Abdominal sepsis	1/103 (1%)		0/13 (0%)
Appendicitis	1/103 (1%)		0/13 (0%)
Cellulitis	1/103 (1%)		0/13 (0%)
Infectious pleural effusion	1/103 (1%)		0/13 (0%)
Meningitis	1/103 (1%)		0/13 (0%)
Respiratory tract infection	1/103 (1%)		0/13 (0%)
Sepsis	1/103 (1%)		0/13 (0%)
Injury, poisoning and procedural complications
Facial bones fracture	1/103 (1%)		0/13 (0%)
Investigations
Liver function test abnormal	1/103 (1%)		0/13 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/103 (1%)		0/13 (0%)
Gout	1/103 (1%)		0/13 (0%)
Hypercalcaemia	1/103 (1%)		0/13 (0%)
Hyperglycaemia	1/103 (1%)		0/13 (0%)
Hyperkalaemia	1/103 (1%)		0/13 (0%)
Hyponatraemia	1/103 (1%)		0/13 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/103 (1%)		0/13 (0%)
Back pain	1/103 (1%)		0/13 (0%)
Intervertebral disc protrusion	1/103 (1%)		0/13 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm malignant	2/103 (1.9%)		0/13 (0%)
Malignant pleural effusion	2/103 (1.9%)		0/13 (0%)
Non-small cell lung cancer	2/103 (1.9%)		0/13 (0%)
Cancer pain	1/103 (1%)		0/13 (0%)
Metastases to central nervous system	1/103 (1%)		0/13 (0%)
Metastases to meninges	1/103 (1%)		0/13 (0%)
Neoplasm progression	1/103 (1%)		0/13 (0%)
Tumour associated fever	1/103 (1%)		0/13 (0%)
Nervous system disorders
Cerebral haemorrhage	2/103 (1.9%)		0/13 (0%)
Epilepsy	2/103 (1.9%)		0/13 (0%)
Seizure	2/103 (1.9%)		0/13 (0%)
Ischaemic stroke	1/103 (1%)		0/13 (0%)
Moyamoya disease	1/103 (1%)		0/13 (0%)
Sciatica	1/103 (1%)		0/13 (0%)
Spinal cord compression	1/103 (1%)		0/13 (0%)
Paraesthesia	0/103 (0%)		1/13 (7.7%)
Renal and urinary disorders
Dysuria	0/103 (0%)		1/13 (7.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	4/103 (3.9%)		0/13 (0%)
Pneumonitis	2/103 (1.9%)		0/13 (0%)
Bronchial haemorrhage	1/103 (1%)		0/13 (0%)
Pleural effusion	1/103 (1%)		0/13 (0%)
Pulmonary artery thrombosis	1/103 (1%)		0/13 (0%)
Pulmonary embolism	1/103 (1%)		0/13 (0%)
Pulmonary oedema	1/103 (1%)		0/13 (0%)
Respiratory failure	1/103 (1%)		0/13 (0%)
Surgical and medical procedures
Hospitalisation	1/103 (1%)		0/13 (0%)
Vascular disorders
Hypertension	2/103 (1.9%)		0/13 (0%)
Deep vein thrombosis	1/103 (1%)		0/13 (0%)
Hypovolaemic shock	1/103 (1%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Brigatinib 90 mg/180 mg		Brigatinib 240 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	98/103 (95.1%)		10/13 (76.9%)
Blood and lymphatic system disorders
Anaemia	9/103 (8.7%)		0/13 (0%)
Cardiac disorders
Ventricular extrasystoles	0/103 (0%)		1/13 (7.7%)
Congenital, familial and genetic disorders
Hypertrophic cardiomyopathy	0/103 (0%)		1/13 (7.7%)
Gastrointestinal disorders
Diarrhoea	40/103 (38.8%)		6/13 (46.2%)
Nausea	29/103 (28.2%)		1/13 (7.7%)
Vomiting	18/103 (17.5%)		1/13 (7.7%)
Constipation	10/103 (9.7%)		1/13 (7.7%)
Anal haemorrhage	0/103 (0%)		1/13 (7.7%)
General disorders
Asthenia	12/103 (11.7%)		3/13 (23.1%)
Pyrexia	12/103 (11.7%)		1/13 (7.7%)
Oedema peripheral	8/103 (7.8%)		0/13 (0%)
Non-cardiac chest pain	7/103 (6.8%)		0/13 (0%)
Chest pain	4/103 (3.9%)		1/13 (7.7%)
Fatigue	4/103 (3.9%)		1/13 (7.7%)
Mucosal inflammation	2/103 (1.9%)		1/13 (7.7%)
Swelling face	0/103 (0%)		1/13 (7.7%)
Infections and infestations
Pneumonia	8/103 (7.8%)		0/13 (0%)
Tonsillitis	0/103 (0%)		1/13 (7.7%)
Investigations
Blood creatine phosphokinase increased	35/103 (34%)		4/13 (30.8%)
Aspartate aminotransferase increased	21/103 (20.4%)		1/13 (7.7%)
Alanine aminotransferase increased	18/103 (17.5%)		1/13 (7.7%)
Lipase increased	18/103 (17.5%)		1/13 (7.7%)
Amylase increased	15/103 (14.6%)		1/13 (7.7%)
Weight decreased	13/103 (12.6%)		0/13 (0%)
Blood alkaline phosphatase increased	9/103 (8.7%)		0/13 (0%)
Gamma-glutamyltransferase increased	8/103 (7.8%)		0/13 (0%)
Blood cholesterol increased	5/103 (4.9%)		1/13 (7.7%)
Blood calcium increased	2/103 (1.9%)		1/13 (7.7%)
Blood bilirubin increased	0/103 (0%)		1/13 (7.7%)
Metabolism and nutrition disorders
Decreased appetite	11/103 (10.7%)		0/13 (0%)
Hyperglycaemia	9/103 (8.7%)		1/13 (7.7%)
Hypokalaemia	7/103 (6.8%)		0/13 (0%)
Hyponatraemia	7/103 (6.8%)		0/13 (0%)
Hypertriglyceridaemia	3/103 (2.9%)		1/13 (7.7%)
Hypophosphataemia	2/103 (1.9%)		1/13 (7.7%)
Musculoskeletal and connective tissue disorders
Pain in extremity	13/103 (12.6%)		0/13 (0%)
Back pain	11/103 (10.7%)		0/13 (0%)
Myalgia	7/103 (6.8%)		0/13 (0%)
Musculoskeletal pain	6/103 (5.8%)		1/13 (7.7%)
Musculoskeletal chest pain	6/103 (5.8%)		0/13 (0%)
Bone pain	1/103 (1%)		1/13 (7.7%)
Nervous system disorders
Headache	14/103 (13.6%)		1/13 (7.7%)
Dizziness	10/103 (9.7%)		0/13 (0%)
Paraesthesia	4/103 (3.9%)		1/13 (7.7%)
Dysgeusia	2/103 (1.9%)		1/13 (7.7%)
Tunnel vision	0/103 (0%)		1/13 (7.7%)
Psychiatric disorders
Anxiety	6/103 (5.8%)		1/13 (7.7%)
Insomnia	3/103 (2.9%)		1/13 (7.7%)
Respiratory, thoracic and mediastinal disorders
Cough	24/103 (23.3%)		3/13 (23.1%)
Dyspnoea	12/103 (11.7%)		1/13 (7.7%)
Skin and subcutaneous tissue disorders
Rash	8/103 (7.8%)		1/13 (7.7%)
Skin exfoliation	0/103 (0%)		1/13 (7.7%)
Vascular disorders
Hypertension	20/103 (19.4%)		2/13 (15.4%)

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.