Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication ALUNBRIG is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test [see Dosage and Administration (2.1) ] . FDA label
Also known as AP26113, Alunbrig
Brigatinib · 8 trials · 12 indications
PFS is defined as the time interval from the date of randomization until the first date at which disease progression is objectively documented via RECIST v1.1 by BIRC, or death due to any cause, whichever occurs first, in the full analysis set. PFS was censored for participants without documented disease progression or death at the last valid tumor response assessment.
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.
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. Percentages were rounded off to the nearest single decimal place.
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).
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%.
Phase 1: • To assess the MTD/RP2D regimen of brigatinib monotherapy when administered in pediatric and AYA patients with ALK+ ALCL or ALK+ solid tumors. Dose-limiting toxicities (DLTs) during the first course of therapy. The RP2D is defined as the dose that results in equivalent (approximately ±20% of the adult values) PK exposure to 180 mg QD with a 7 day lead in of 90 mg QD in adults and with 0 or 1 DLT in 6 patients.
Phase 1: • To characterize the PK of brigatinib administered as monotherapy in pediatric and AYA patients with ALK+ ALCL or ALK+ solid tumors: o maximum observed concentration (Cmax),
• B1, ALK+ IMT: To establish the activity (ORR by RECIST 1.1, best response) of single agent brigatinib when administered to children with ALK+ IMT: Best response, defined as the percentage of patients with CR or PR according to RECIST 1.1 as best response during brigatinib treatment.
• B2, ALK+ ALCL: To establish the efficacy (EFS) of single agent brigatinib when administered to children with ALK+ ALCL for a duration of 2 years, without SCT in consolidation. EFS, defined as the time between start of study treatment and first event being progressive disease (according to IPNHL criteria), relapse, death of any cause and second malignancies.
The statistical analysis was calculated via a mixed-effects analysis of variance (ANOVA) fitting terms for treatment (midazolam with or without brigatinib coadministration).
The statistical analysis was calculated via a mixed-effects ANOVA fitting terms for treatment (midazolam with or without brigatinib coadministration).
The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of Cycle 1).
ORR assessed by the investigator, is defined as the percentage of the participants with complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid tumors (RECIST) v1.1 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 normalization of tumor marker level. PR: at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters. Crzb=Crizotinib.
| Arm | Type | Description |
|---|---|---|
| Brigatinib | EXPERIMENTAL | Participants were administered brigatinib 90 milligrams (mg), tablets, orally, once daily (QD) for 7 days, followed by brigatinib 180 mg, tablets, orally, QD until objective disease progression per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), as assessed by the investigator, or intolerable toxicity, or up to 63.47 months. |
| Alectinib | ACTIVE_COMPARATOR | Participants were administered alectinib 600 mg, capsules, orally, twice daily (BID) until objective disease progression per RECIST v1.1, as assessed by the investigator, or intolerable toxicity, or up to 59.83 months. |
| Randomized Phase: Brigatinib 90 mg QD/180 QD | EXPERIMENTAL | 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). |
| Randomized Phase: Crizotinib 250 mg BID | ACTIVE_COMPARATOR | 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). |
| Crossover Phase: Brigatinib 90 mg QD/180 mg QD | EXPERIMENTAL | 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 90 mg/180 mg With Optional Dose Escalation to 240 mg | EXPERIMENTAL | Brigatinib 90 mg, tablets, orally, once daily (QD) for 7 days, followed by brigatinib 180 mg, tablets, orally, QD 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 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. |
| Brigatinib 90 mg + Brigatinib 180 mg | EXPERIMENTAL | Brigatinib 90 milligram (mg), tablets, orally, once daily (QD) for first 7 days followed by brigatinib, 180 mg, tablets, orally, QD in Cycle 1 of 28 days followed by brigatinib 180 mg, tablets, orally, QD in Cycle 2 and onward cycles of 28 days until investigator-assessed progressive disease (PD) or intolerable toxicity, withdrawal of consent, or discontinuation for any other reason, whichever comes first up to Cycle 34 of 28-day cycle, until data cut-off date 29 September 2020. |
| Brigatinib 90 mg | EXPERIMENTAL | 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 - 180 mg | EXPERIMENTAL | 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). |
| Phase 1 | OTHER | Phase 1: * To estimate the MTD/RP2D regimen of brigatinib monotherapy when administered in pediatric and AYA patients with ALK+ ALCL or ALK+ solid tumors. * To characterize the PK of brigatinib administered as monotherapy in pediatric and AYA patients with ALK+ ALCL or ALK+ solid tumors. Note that: * If the MTD is not reached at the highest proposed test dose, no further dose-escalation will be performed. * Pediatric PK data, compared to exposure in adults, and cumulative toxicity, will be taken into consideration to determine the RP2D regimen. |
| Phase 2 | OTHER | Phase 2: • B1, ALK+ IMT: To establish the activity (ORR by RECIST 1.1) of single agent brigatinib when administered to children with ALK+ IMT. • B2, ALK+ ALCL: To establish the efficacy (EFS) of single agent brigatinib when administered to children with ALK+ ALCL for a duration of 2 years, without SCT in consolidation. |
| Midazolam 3 mg + Brigatinib 90 mg | EXPERIMENTAL | Midazolam 3 mg, orally, once on Day 1, followed by brigatinib 90 mg, orally, once daily on Days 2 to 8, further followed by brigatinib 180 mg, orally, once daily on Days 9 to 28 in Part A Cycle 1 (28 days treatment cycle). Participants escalating to brigatinib 180 mg once daily will also receive midazolam 3 mg, orally, once on Day 21 of Part A Cycle 1. After completion of Part A, participants will continue into Part B. Participants in Part B will receive brigatinib up to 180 mg (or at the highest tolerated dose in Part A), orally, once daily in a 28 day treatment cycle, up to a maximum of 23 cycles or until progression of disease, unacceptable toxicity, or another discontinuation criterion is met. |
| Brigatinib 30 mg QD/60 mg QD | EXPERIMENTAL | Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). |
| Brigatinib 90 mg QD | EXPERIMENTAL | Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). |
| Brigatinib 120 mg QD/60 mg BID | EXPERIMENTAL | Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). |
| Brigatinib 90 mg QD-180 mg QD | EXPERIMENTAL | 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. |
| Brigatinib 180 mg QD/90 mg BID | EXPERIMENTAL | Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years). |
| Brigatinib 240 mg QD/120 mg BID/300 mg QD | EXPERIMENTAL | Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). |
| Name | Type | Description |
|---|---|---|
| Brigatinib | DRUG | Brigatinib Tablets. |
| Alectinib | DRUG | Alectinib Capsules. |
| Crizotinib | DRUG | Crizotinib tablets |
| Midazolam | DRUG | Midazolam syrup. |
Inclusion Criteria: 1. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 2. Have histologically or cytologically confirmed stage IIIB (locally advanced or recurrent) or stage IV NSCLC. 3. Must meet one of the following criteria: * Have documentation of ALK rearrangeme...
Brigatinib is used to treat ALK-positive advanced non-small cell lung cancer (NSCLC), including disease that has progressed on prior ALK inhibitors such as alectinib or ceritinib. It is also being studied in anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, and other ALK-positive or ROS1-positive solid tumors. It is an oncology small molecule developed by Takeda.
Brigatinib targets ALK and EGFR. It is an inhibitor of these kinases, which means it blocks their signaling activity. ALK rearrangements drive the growth of certain lung cancers and lymphomas, and EGFR is a related receptor tyrosine kinase. This dual inhibitory profile underlies its use in ALK-positive malignancies.
Brigatinib is developed by Takeda Pharmaceutical Company Limited, which trades under the ticker TAK. Takeda is the sponsor responsible for the clinical development program across lung cancer and lymphoma indications.
Brigatinib is in Phase 3 development. A completed Phase 3 trial compared it with alectinib in adults with ALK-positive advanced non-small cell lung cancer. Additional completed Phase 1 and Phase 2 studies have evaluated it in ALK-positive NSCLC and in drug interaction settings, and a Phase 1 pediatric and young adult study is recruiting.
Brigatinib trials include NCT04925609, a recruiting Phase 1 study in pediatric and young adult patients with ALK-positive anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, or other solid tumors. Completed studies include NCT03596866, a Phase 3 comparison with alectinib in ALK-positive advanced NSCLC, NCT03535740, a Phase 2 study in patients progressed on alectinib or ceritinib, and NCT03420742, a Phase 1 drug interaction study.
Yes. Brigatinib development is biomarker selected, meaning trials enroll patients whose tumors carry specific molecular alterations. The studies focus on ALK-positive disease, including ALK-positive advanced non-small cell lung cancer and ALK-positive anaplastic large cell lymphoma, with some trials also including ROS1-positive solid tumors.