Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
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).
| 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). |
| Sequence AB | EXPERIMENTAL | Participants received single dose of brigatinib 90 milligram (mg) as an oral solution in a fasted state on Day 1 of Period 1 (Treatment A) followed by single dose of brigatinib 90 mg as an immediate-release tablet in a fasted state on Day 1 of Period 2 (Treatment B). A washout period of at least 14 days was maintained between brigatinib administration in Period 1 and 2. |
| Sequence BA | EXPERIMENTAL | Participants received single dose of brigatinib 90 mg as an immediate-release tablet in a fasted state on Day 1 of Period 1 (Treatment B) followed by single dose of brigatinib 90 mg as an oral solution in a fasted state on Day 1 of Period 2 (Treatment A). A washout period of at least 14 days was maintained between brigatinib administration in Period 1 and 2. |
| 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. |
| 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 an investigational small molecule being studied for the treatment of several cancers, including non-small cell lung cancer (NSCLC), advanced ALK+ or ROS1+ solid tumors, and ALK-positive anaplastic large cell lymphoma. It is also being evaluated in healthy volunteers for drug interaction studies.
Brigatinib is a kinase inhibitor, belonging to the -tinib class of drugs. It targets anaplastic lymphoma kinase (ALK) and ROS1, which are implicated in certain cancers such as non-small cell lung cancer. By inhibiting these kinases, it aims to block cancer cell growth.
Brigatinib is being developed by Takeda Pharmaceutical Company Limited, which is publicly traded under the ticker symbol TAK. The company is conducting clinical trials to evaluate the drug's safety and efficacy across multiple cancer indications.
Brigatinib is in Phase 3 clinical development for non-small cell lung cancer. It has completed Phase 3 trials comparing it to crizotinib and alectinib, and is also being studied in earlier-phase trials for other indications. It remains investigational and is not yet approved.
Brigatinib has been studied in several clinical trials, including NCT02737501 (ALTA-1L, Phase 3 vs crizotinib in ALK+ NSCLC), NCT03596866 (Phase 3 vs alectinib in ALK+ NSCLC), NCT03420742 (Phase 1 drug interaction study), and NCT04925609 (Phase 1 in pediatric ALK+ tumors).
Brigatinib is the generic name for the drug marketed as Alunbrig. In clinical trials, it is referred to as brigatinib, and it is being developed by Takeda for the treatment of ALK-positive non-small cell lung cancer and other ALK or ROS1 positive tumors.