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brigatinib
Brigatinib is an inhibitor of multiple tyrosine kinases including anaplastic lymphoma kinase (ALK), ROS-1 and insulin-like growth factor receptor-1 (IGFR-1). Brigatinib has activity against cells expressing EML4-ALK and 17 mutant forms (including G1202R and L1196M) associated with ALK inhibitor resistance.
| Effects with food |
Co-administration with a high-fat meal led to a 13% reduction in Cmax with no effect on AUC relative to fasted conditions. |
| Peak plasma levels |
1 to 4 hours |
| PPB |
91% plasma proteins |
| Cross blood brain barrier? |
Not established |
| Active metabolites |
Yes |
| Feces |
65%; 41% as unchanged drug |
| Urine |
25%; 86% as unchanged drug |
| Half-life |
25 hours |
- Non-small cell lung cancer (NSCLC)
(Includes conditional approvals)
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
The following table lists adverse effects that occurred in ≥2% of patients in a phase III study with advanced ALK-positive NSCLC who received brigatinib 180mg once daily (with an initial 7-day lead-in period at 90mg ) or crizotinib. Severe adverse events from other studies or post-marketing are also included.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Bradycardia (12%) | E | |||
| Hypertension (32%) (13% severe) | E | ||||
| QT interval prolonged (5%) | E | ||||
| Venous thromboembolism (2%) | E | ||||
| Dermatological | Photosensitivity (4%) | E | |||
| Rash, pruritus (40%) (including dry skin) (3% severe) | E | ||||
| Gastrointestinal | Abdominal pain (24%) | E | |||
| Anorexia (9%) | E | ||||
| Constipation (18%) | E | ||||
| Diarrhea (52%) (2% severe) | E | ||||
| Dry mouth (5%) | E | ||||
| Dyspepsia (8%) | E | ||||
| Mucositis (13%) | E | ||||
| Nausea, vomiting (30%) | E | ||||
| General | Edema (18%) | E | |||
| Fatigue (32%) | E | ||||
| Fever (19%) | E | ||||
| Hepatobiliary | ↑ Amylase / lipase (57%) (17% severe) | E D | |||
| ↑ LFTs (71%) (5% severe) | E | ||||
| Other - ↑ Blood LDH, GGT (4%) | E | ||||
| Metabolic / Endocrine | ↑ Cholesterol (3%) | E | |||
| Hyperglycemia (55%) (7% severe) | E | ||||
| Musculoskeletal | Musculoskeletal pain (28%) | E | |||
| ↑CPK (75%) (22% severe) | D | ||||
| Nervous System | Depression (3%) | E | |||
| Dysgeusia (3%) | E | ||||
| Headache (22%) | E | ||||
| Insomnia (8%) | E | ||||
| Peripheral neuropathy (11%) | E | ||||
| Ophthalmic | Visual disorders (7%) | E | |||
| Renal | Creatinine increased (36%) | E | |||
| Respiratory | Cough, dyspnea (35%) | E | |||
| Dysphonia (6%) | E | ||||
| Interstitial lung disease (5%) | I E D | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for brigatinib include ↑CPK, ↑ LFTs, ↑ amylase / lipase, hyperglycemia, diarrhea, rash, pruritus, cough, dyspnea, fatigue, hypertension, nausea and vomiting.
Severe, life-threatening, or fatal adverse pulmonary reactions including interstitial lung disease (ILD)/pneumonitis have been reported. Most pulmonary adverse reactions were observed within the first 7 days of treatment initiation (or re-initiation, following a dose interruption), usually within the first 24-48 hours. The etiology of pulmonary adverse reactions is not known. ILD/pneumonitis occurred with a median onset of 2 days; 2% of patients experienced pneumonitis later in treatment (median onset: 150 days).
Mild to moderate visual disturbances such as blurred vision, photophobia, photopsia, diplopia, and reduced visual acuity have been reported. 2% of patients reported Grade 3 macular edema and cataract.
Elevations of amylase and lipase were reported in patients receiving brigatinib but were not associated with clinical pancreatitis.
New or worsening hyperglycemia have been reported, including grade 3 toxicity. Some patients with diabetes or glucose intolerance (at baseline) required insulin therapy while receiving brigatinib.
Refer to protocol by which patient is being treated.
- Patients must have a documented ALK-positive status based on a validated assay.
- Blood pressure should be controlled prior to initiating brigatinib therapy.
Oral: 90mg Daily for the first 7 days; then if tolerated; increase to 180mg Daily
If therapy is interrupted for ≥14 days due to reasons other than toxicity, resume treatment at 90mg once daily for 7 days before escalating dose to the previously tolerated dose.
If dose is reduced for toxicity, do not subsequently escalate the dose.
See Interactions section for dosing recommendations when administered with CYP3A4 inhibitors/inducers.
Dose Levels
| Dose Level |
Initial Brigatinib Dose (first 7 days) (mg/day) |
Maintenance Brigatinib Dose (mg/day) |
| 0 | 90 | 180 |
| -1 | 60 | 120 |
| -2 | Discontinue | 90 |
| -3 | N/A | 60 |
| -4 | N/A | Discontinue |
| Toxicity | Severity | Action | |
| Interstitial Lung Disease (ILD) /Pneumonitis | Grade 1 |
Hold until recovery to baseline; resume at same dose level. If recurs, discontinue. |
|
| Grade 2 |
Hold until recovery to baseline; resume at 1 dose level ↓. If recurs, discontinue. |
||
| ≥ Grade 3 | Discontinue. | ||
| Hypertension |
Grade 3 |
Hold until recovery to ≤ grade 1; resume at same dose level. |
|
| Grade 4 |
Hold until recovery to ≤grade 1; resume at 1 dose level ↓ or discontinue. If recurs, discontinue. |
||
| Bradycardia (HR <60 bpm) | Symptomatic |
Hold until recovery to asymptomatic or resting heart rate ≥60 bpm; If contributing medication identified and discontinued (or dose-adjusted), resume at same dose. If no contributing medication identified (or cannot be discontinued or dose-adjusted), resume at 1 dose level ↓. |
|
| Life-threatening (urgent intervention indicated) |
Hold until recovery to asymptomatic or resting heart rate ≥60 bpm; If contributing medication identified and discontinued (or dose-adjusted), resume at 1 dose level ↓ If no contributing medication identified, discontinue. If recurs, discontinue. |
||
| Visual Disturbance | Grade 2-3 | Hold until recovery to ≤grade 1 or baseline; resume at 1 dose level ↓. | |
| Grade 4 | Discontinue. | ||
| Creatine Phosphokinase (CPK) Elevation |
≥Grade 3 with ≥grade 2 muscle pain or weakness |
Hold until recovery to ≤grade 1 or baseline; resume at same dose level. If recurs, hold until recovery to ≤grade 1 or baseline; resume at 1 dose level ↓. |
|
| Lipase/Amylase Elevation | Grade 3 | Hold until recovery to ≤ grade 1 or baseline; resume at same dose. | |
| Recurrent Grade 3 or grade 4 | Hold until recovery to ≤ grade 1 or baseline; resume at 1 dose level ↓. | ||
| Hyperglycemia | Blood glucose >13.9 mmol/L | Hold until adequate hyperglycemic control; resume at 1 dose level ↓ or discontinue. | |
| Elevation of hepatic enzymes |
≥Grade 3 AST/ALT with bilirubin ≤2 × ULN | Hold until recovery to ≤3 x ULN or baseline; resume at 1 dose level ↓. | |
| ≥Grade 2 AST/ALT with bilirubin >2 × ULN in the absence of cholestasis or hemolysis | Discontinue. | ||
| Other Toxicities | Grade 3 |
Hold until recovery to baseline; resume at same dose level. |
|
| Grade 4 |
Hold until recovery to baseline; resume at 1 dose level ↓. If recurs, hold until recovery to baseline; resume at 1 dose level ↓ or discontinue. |
||
| Hepatic Impairment | Brigatinib Dose (mg/day) |
| Mild or moderate (Child-Pugh class A or B) | No dose adjustment required |
| Severe (Child-Pugh class C) | Reduce dose by 1 dose level |
| Renal Impairment | Brigatinib Dose (mg/day) |
|
Mild or moderate (CrCl ≥30 mL/min) |
No dose adjustment required |
| Severe (CrCl <30 mL/min) |
For 180mg dose: Reduce by 2 dose levels For 90mg dose: Reduce by 1 dose level |
No dosage adjustment is required. Use brigatinib with caution in elderly patients, especially patients > 85 years of age as there is no available data on patients in this age group. Increased age (≥ 65 years of age) was associated with an increased risk of early pulmonary adverse reactions.
No dose adjustment required. Population pharmacokinetic analyses showed that gender had no clinically meaningful effect on the pharmacokinetics of brigatinib.
No dose adjustment required. Population pharmacokinetic analyses showed that race had no clinically meaningful effect on the pharmacokinetics of brigatinib.
Safety and efficacy in children have not been established.
-
Administer with or without food.
-
Tablets should be swallowed whole; do not crush or chew.
-
Avoid grapefruit, starfruit, Seville oranges, their juices or products during treatment.
-
If a dose is missed or vomiting occurs after taking a dose, an additional dose should not be given; administer the next dose at the regularly scheduled time.
- Store at 15°C to 30°C
- Patients who have a hypersensitivity to this drug or any components of the formulation.
-
Caution in patients with bradycardia (<60 beats per minute), a history of syncope or arrhythmia, sick sinus syndrome, sinoatrial block, atrioventricular (AV) block, ischemic heart disease, congestive heart failure or on medications leading to bradycardia.
-
Patients with a history of ILD or drug-induced pneumonitis were excluded from clinical trial.
-
Brigatinib contains lactose; carefully consider use in patients with lactose intolerance, hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
-
Patients should avoid prolonged sun exposure while taking brigatinib and for at least 5 days after treatment discontinuation. A broad-spectrum UVA/UVB sun screen and lip balm (SPF ≥30) should be used.
-
Caution with driving or using machinery as visual disturbances, dizziness, and fatigue may occur with treatment.
Other Drug Properties:
-
Carcinogenicity:
Unknown
In vitro and in vivo studies demonstrated that brigatinib is aneugenic.
-
Mutagenicity:
No
-
Genotoxicity:
No
-
Embryotoxicity:
Probable
Brigatinib is not recommended for use in pregnancy. Adequate contraception (non-hormonal) should be used during treatment and for at least 4 months in females (and for at least 3 months in males) following the final dose.
Hormonal contraceptives may not be effective during brigatinib treatment (See Interactions section).
-
Excretion into breast milk:
Unknown
Breastfeeding is not recommended during treatment and for 1 week after the last dose.
-
Fertility effects:
Probable
Brigatinib may impair male fertility.
Brigatinib is primarily metabolized by CYP2C8 and CYP3A4. It is also a CYP3A4 inducer. In vitro studies indicate that brigatinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and inhibits P-gp, BCRP, OCT1, MATE1, and MATE2K. Brigatinib induces CYP3A and may also induce CYP2C isoenzymes and P-gp via activation of the pregnane X receptor (PXR).
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, cobicistat, indinavir, saquinavir, telaprevir) | ↑ brigatinib concentration and/or toxicity (Co-administration with itraconazole increased brigatinib Cmax by 21% and AUC by 101%) | ↓ metabolism of brigatinib | Avoid co-administration. If concomitant use cannot be avoided, reduce brigatinib dose from 180mg to 90mg, or from 90mg to 60mg. After discontinuation of strong CYP3A inhibitor, resume brigatinib at dose that was tolerated prior to the initiation of the CYP3A inhibitor. |
| Moderate CYP3A inhibitor (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) | ↑ brigatinib concentration and/or toxicity (↑ brigatinib AUC by ~40% based on PK model) | ↓ metabolism of brigatinib | Avoid co-administration. If concomitant use cannot be avoided, reduce brigatinib dose from 180mg to 120mg, 120mg to 90mg, or from 90mg to 60mg. After discontinuation of CYP3A inhibitor, resume brigatinib at dose that was tolerated prior to the initiation of the CYP3A inhibitor. |
| Strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine, phenobarbital, St. John’s Wort, etc.) | ↓ brigatinib concentration and/or efficacy (Co-administration with rifampin, decreased brigatinib Cmax by 60% and AUC by 80%) | ↑ metabolism of brigatinib | Avoid co-administration |
| Moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, etc.) | ↓ brigatinib concentration and/or efficacy (↓ brigatinib AUC by ~50% based on PK model) | ↑ metabolism of brigatinib | Avoid co-administration with moderate CYP3A inducers. If concomitant use cannot be avoided, increase brigatinib dose as follows: After 7 days at current tolerated dose, increase brigatinib dose in 30mg increments, up to a maximum of 2x the brigatinib dose that was tolerated prior to start of inducer. After discontinuation of the CYP3A inducer, resume brigatinib at the dose that was tolerated prior to the initiation of the CYP3A inducer. |
| CYP3A substrates (e.g. cyclosporine, pimozide, tacrolimus, ergot alkaloids, quetiapine triazolo-benzodiazepines, certain HMG-CoA reductase inhibitors such as simvastatin) | ↓ substrate concentration and/or efficacy | ↑ metabolism of substrate | Caution and monitor with drugs with narrow therapeutic index. |
| Substrates of pregnane X receptor (PXR) inducible enzymes and transporters (e.g., CYP2C, P-gp) | ↓ substrate concentration and/or efficacy | Brigatinib induces PXR inducible enzymes and transporters | Caution and monitor with drugs with narrow therapeutic index. |
| Substrates of P-gp, BCRP, OCT1, MATE1, and MATE2K (e.g., digoxin, dabigatran, colchicine, pravastatin, methotrexate, rosuvastatin, sulfasalazine, metformin) | ↑ substrate concentration and/or toxicity | Brigatinib is an inhibitor of P-gp, BCRP, OCT1, MATE1, and MATE2K in vitro. | Caution and monitor with drugs with narrow therapeutic index. |
| Agents that decrease heart rate (e.g., antiarrhythmics, beta adrenoceptor antagonists, non-dihydropyridine calcium channel blockers, digitalis glycosides, cholinesterase inhibitors, sphingosine-1 phosphate receptor modulators, HIV protease inhibitors, alpha2-adrenoceptor agonists, etc.) | ↑ risk of bradycardia | additive | Avoid to the extent possible. If concomitant use cannot be avoided, monitor heart rate more frequently. |
| Hormonal contraceptives | May ↓ efficacy of hormonal contraceptives | ↑ metabolism of hormonal contraceptives | Caution; Use non-hormonal methods of contraception (see Pregnancy and Lactation section) |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Heart rate and blood pressure |
Baseline, after 2 weeks and at least monthly during treatment; more frequently in patients receiving medications known to cause bradycardia. |
Liver function tests |
Baseline, every 2 weeks for the first 3 months of treatment then as clinically indicated |
Lipase, amylase, CPK, fasting serum glucose |
Baseline, regularly and as clinically indicated |
Clinical toxicity assessment for fatigue, visual disturbances, pulmonary, dermatological, GI and musculoskeletal effects |
At one week (pulmonary) and at each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Exceptional Access Program (EAP Website)
- brigatinib - For the treatment of anaplastic lymphoma kinase-positive locally advanced or metastatic non-small cell lung cancer according to clinical criteria
Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK inhibitor-naive advanced ALK-positive NSCLC: final results of phase 3 ALTA-1L trial. J Thorac Oncol 2021 Dec;16(12):2091-108.
Camidge DR, Kim HR, Ahn MJ. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med 2018 Nov 22;379(21):2027-39.
Kim D, Tiseo M, Ahn M, et al. Brigatinib in patients With crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol 2017; 35:2490-2498.
Prescribing Information: Alunbrig® (brigatinib). Takeda Pharmaceuticals America, Inc. Lexington, MA. February 2022.
Product Monograph: Alunbrig® (brigatinib). Takeda Canada Inc. March 2021.
June 2022 Updated Adverse Effects, Dosage with Toxicity, Special Precautions, Interactions and Clinical Monitoring sections.
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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