Brigatinib

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# Overview
Brigatinib is a kinase inhibitor that is FDA approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) that has progressed on or is intolerant to crizotinib.   Common adverse reactions include nausea, diarrhea, fatigue, cough, and headache.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Brigatinib is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.
- This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
- The recommended dosing regimen for brigatinib is:
- 90 mg orally once daily for the first 7 days;
- If 90 mg is tolerated during the first 7 days, increase the dose to 180 mg orally once daily.
- Administer brigatinib until disease progression or unacceptable toxicity.
- If brigatinib is interrupted for 14 days or longer for reasons other than adverse reactions, resume treatment at 90 mg once daily for 7 days before increasing to the previously tolerated dose.
- Brigatinib may be taken with or without food. Instruct patients to swallow tablets whole. Do not crush or chew tablets.
- If a dose of brigatinib is missed or vomiting occurs after taking a dose, do not administer an additional dose and take the next dose of brigatinib at the scheduled time.
- Brigatinib dose modification levels are summarized in Table 1.
- Once reduced for adverse reactions, do not subsequently increase the dose of brigatinib. Permanently discontinue brigatinib if patients are unable to tolerate the 60 mg once daily dose.
- Recommendations for dose modifications of brigatinib for the management of adverse reactions are provided in Table 2.
- Avoid concomitant use of strong CYP3A inhibitors during treatment with brigatinib. If concomitant use of a strong CYP3A inhibitor cannot be avoided, reduce the brigatinib once daily dose by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg). After discontinuation of a strong CYP3A inhibitor, resume the brigatinib dose that was tolerated prior to initiating the strong CYP3A inhibitor.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding brigatinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding brigatinib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Brigatinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding brigatinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding brigatinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
- None

# Warnings
- Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with brigatinib.
- In Trial ALTA (ALTA), ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily).
- Adverse reactions consistent with possible ILD/pneumonitis occurred early (within 9 days of initiation of brigatinib; median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7%.
- Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly during the first week of initiating brigatinib. Withhold brigatinib in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume brigatinib with dose reduction according to Table 1 after recovery to baseline or permanently discontinue brigatinib. Permanently discontinue brigatinib for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.
- In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received brigatinib and 21% of patients in the 90180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall.
- Control blood pressure prior to treatment with brigatinib. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with brigatinib. Withhold brigatinib for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1 severity, resume brigatinib at a reduced dose. Consider permanent discontinuation of treatment with brigatinib for Grade 4 hypertension or recurrence of Grade 3 hypertension.
- Use caution when administering brigatinib in combination with antihypertensive agents that cause bradycardia.
- Bradycardia can occur with brigatinib. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group.
- Monitor heart rate and blood pressure during treatment with brigatinib. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided.
- For symptomatic bradycardia, withhold brigatinib and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume brigatinib at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of brigatinib following resolution of symptomatic bradycardia. Discontinue brigatinib for life-threatening bradycardia if no contributing concomitant medication is identified.
- In ALTA, adverse reactions leading to visual disturbance including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients receiving brigatinib in the 90 mg group and 10% of patients in the 90180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90180 mg group.
- Advise patients to report any visual symptoms. Withhold brigatinib and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume brigatinib at a reduced dose. Permanently discontinue treatment with brigatinib for Grade 4 visual disturbances.
- In ALTA, creatine phosphokinase (CPK) elevation occurred in 27% of patients receiving brigatinib in the 90 mg group and 48% of patients in the 90 mg180 mg group. The incidence of Grade 3-4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90180 mg group.
- Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% in the 90180 mg group.
- Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during brigatinib treatment. Withhold brigatinib for Grade 3 or 4 CPK elevation. Upon resolution or recovery to Grade 1 or baseline, resume brigatinib at the same dose or at a reduced dose as described in Table 2.
- In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90180 mg group.
- Monitor lipase and amylase during treatment with brigatinib. Withhold brigatinib for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume brigatinib at the same dose or at a reduced dose as described in Table 2.
- In ALTA, 43% of patients who received brigatinib experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving brigatinib.
- Assess fasting serum glucose prior to initiation of brigatinib and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold brigatinib until adequate hyperglycemic control is achieved and consider reducing the dose of brigatinib as described in Table 1 or permanently discontinuing brigatinib.
- Based on its mechanism of action and findings in animals, brigatinib can cause fetal harm when administered to pregnant women. There are no clinical data on the use of brigatinib in pregnant women. Administration of brigatinib to pregnant rats during the period of organogenesis resulted in dose-related skeletal anomalies at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily) as well as increased post implantation loss, malformations, and decreased fetal body weight at doses of 25 mg/kg/day (approximately 1.26 times the human exposure at 180 mg once daily) or higher.
- Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of brigatinib.

# Adverse Reactions

## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety of brigatinib was evaluated in 219 patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who received at least one dose of brigatinib in ALTA after experiencing disease progression on crizotinib. Patients received brigatinib 90 mg once daily continuously (90 mg group) or 90 mg once daily for 7 days followed by 180 mg once daily (90180 mg group). The median duration of treatment was 7.5 months in the 90 mg group and 7.8 months in the 90180 mg group. A total of 150 (68%) patients were exposed to brigatinib for greater than or equal to 6 months and 42 (19%) patients were exposed for greater than or equal to one year.
- The study population characteristics were: median age 54 years (range: 18 to 82), age less than 65 years (77%), female (57%), White (67%), Asian (31%), Stage IV disease (98%), NSCLC adenocarcinoma histology (97%), never or former smoker (95%), ECOG Performance Status (PS) 0 or 1 (93%), and brain metastases at baseline (69%).
- Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).
- In ALTA, 2.8% of patients in the 90 mg group and 8.2% of patients in the 90180 mg group permanently discontinued brigatinib for adverse reactions. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis (0.9% in the 90 mg group and 1.8% in the 90180 mg group) and pneumonia (1.8% in the 90180 mg group only).
- In ALTA, 14% of patients required a dose reduction due to adverse reactions (7.3% in the 90 mg group and 20% in the 90180 mg group). The most common adverse reaction that led to dose reduction was increased creatine phosphokinase for both regimens (1.8% in the 90 mg group and 4.5% in the 90180 mg group).
- Table 3 and Table 4 summarize the common adverse reactions and laboratory abnormalities observed in ALTA.

## Postmarketing Experience
There is limited information regarding Brigatinib Postmarketing Experience in the drug label.

# Drug Interactions
- Drugs That May Increase Brigatinib Plasma Concentrations (Strong CYP3A Inhibitors)
- Drugs That May Decrease Brigatinib Plasma Concentrations (Strong CYP3A Inducers)
- Drugs That May Have Their Plasma Concentrations Altered by Brigatinib (CYP3A Substrates)
- Coadministration of itraconazole, a strong CYP3A inhibitor, increased brigatinib plasma concentrations and may result in increased adverse reactions. Avoid the concomitant use of strong CYP3A inhibitors with brigatinib, including but not limited to certain antivirals (e.g., boceprevir, cobicistat, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir), macrolide antibiotics (e.g., clarithromycin), antifungals (e.g., itraconazole, ketoconazole, posaconazole, voriconazole), and conivaptan. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of brigatinib. If concomitant use of a strong CYP3A inhibitor cannot be avoided, reduce the dose of brigatinib by approximately 50%.
- Coadministration of brigatinib with rifampin, a strong CYP3A inducer, decreased brigatinib plasma concentrations and may result in decreased efficacy. Avoid the concomitant use of strong CYP3A inducers with brigatinib, including but not limited to rifampin, carbamazepine, phenytoin, and St. John's Wort.
- Brigatinib induces CYP3A in vitro and may decrease concentrations of CYP3A substrates. Coadministration of brigatinib with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of CYP3A substrates.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):

### Risk Summary
- Based on its mechanism of action and findings in animals, brigatinib can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of brigatinib in pregnant women. Administration of brigatinib to pregnant rats during the period of organogenesis resulted in dose-related skeletal anomalies at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily) as well as increased post-implantation loss, malformations, and decreased fetal body weight at doses of 25 mg/kg/day (approximately 1.26 times the human exposure at 180 mg once daily) or greater. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.
- In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

### Data (Animal)
- In an embryo-fetal development study in which pregnant rats were administered daily doses of brigatinib during organogenesis, dose-related skeletal (incomplete ossification, small incisors) and visceral anomalies were observed at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily). Malformations observed at 25 mg/kg/day (approximately 1.26 times the human AUC at 180 mg once daily) included anasarca (generalized subcutaneous edema), anophthalmia (absent eyes), forelimb hyperflexion, small, short and/or bent limbs, multiple fused ribs, bent scapulae, omphalocele (intestine protruding into umbilicus), and gastroschisis (intestines protruding through a defect in the abdominal wall) along with visceral findings of moderate bilateral dilatation of the lateral ventricles.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Brigatinib in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Brigatinib during labor and delivery.

### Nursing Mothers
- There are no data regarding the secretion of brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential for adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with brigatinib and for 1 week following the final dose.

### Pediatric Use
- The safety and efficacy of brigatinib in pediatric patients have not been established.

### Geriatic Use
- Clinical studies of brigatinib did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 222 patients in ALTA, 19.4% were 65-74 years and 4.1% were 75 years or older. No clinically relevant differences in safety or efficacy were observed between patients 65 years and younger patients.

### Gender
There is no FDA guidance on the use of Brigatinib with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Brigatinib with respect to specific racial populations.

### Renal Impairment
- No dose adjustment is recommended for patients with mild and moderate renal impairment . The pharmacokinetics and safety of brigatinib in patients with severe renal impairment (CLcr 15 to 29 mL/min estimated by Cockcroft-Gault) have not been studied.

### Hepatic Impairment
- No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin within upper limit of normal  and AST greater than ULN or total bilirubin greater than 1 and up to 1.5 times ULN and any AST). The pharmacokinetics and safety of brigatinib in patients with moderate or severe hepatic impairment have not been studied.

### Females of Reproductive Potential and Males
Contraception (Females)
- Advise females of reproductive potential to use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months after the final dose. Counsel patients to use a non-hormonal method of contraception since brigatinib can render some hormonal contraceptives ineffective.
Infertility (Males)
- Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with brigatinib and for at least 3 months after the final dose.
- Based on findings in male reproductive organs in animals, brigatinib may cause reduced fertility in males.

### Immunocompromised Patients
There is no FDA guidance one the use of Brigatinib in patients who are immunocompromised.

# Administration and Monitoring

### Administration

### Oral
- May be taken with or without food.
- Swallow tablets whole; do not crush or chew.
- Missed dose: If a dose is missed or vomiting occurs after taking a dose, do not administer an additional dose; take the next dose at its scheduled time.

### Monitoring
- Tumor response may indicate efficacy.
- Creatine phosphokinase (CPK) levels: Regularly during treatment.
- Lipase and amylase levels: Regularly during treatment.
- Fasting serum glucose: Prior to initiation and regularly during treatment.
- New or worsening respiratory symptoms (eg, dyspnea, cough): Especially during the first week of treatment.
- Blood pressure: 2 weeks after initiation and at least monthly thereafter during use.
- Heart rate: Regularly throughout treatment, and more frequently in patients requiring concomitant therapy known to cause bradycardia.
- Ophthalmologic evaluation: Upon patient report of new or worsening visual disturbance.

# IV Compatibility
There is limited information regarding the compatibility of Brigatinib and IV administrations.

# Overdosage
There is limited information regarding Brigatinib overdosage.  If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology

## Mechanism of Action
- Brigatinib is a tyrosine kinase inhibitor with in vitro activity at clinically achievable concentrations against multiple kinases including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3 as well as EGFR deletion and point mutations. Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays. Brigatinib also inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice.
- At clinically achievable concentrations ( 500 nM), brigatinib inhibited the in vitro viability of cells expressing EML4-ALK and 17 mutant forms associated with resistance to ALK inhibitors including crizotinib, as well as EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y. Brigatinib exhibited in vivo anti-tumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib. Brigatinib also reduced tumor burden and prolonged survival in mice implanted intracranially with an ALK-driven tumor cell line.

## Structure

## Pharmacodynamics
- Brigatinib exposure-response relationships and the time course of the pharmacodynamic response are unknown.

### Cardiac Electrophysiology
- The QT interval prolongation potential of brigatinib was assessed in 123 patients following once daily brigatinib doses of 30 mg (1/6th of the approved 180 mg dose) to 240 mg (1.3 times the approved 180 mg dose). Brigatinib did not prolong the QT interval to a clinically relevant extent.

## Pharmacokinetics
- The geometric mean (CV%) steady-state maximum concentration (Cmax) of brigatinib at brigatinib doses of 90 mg and 180 mg once daily was 552 (65%) ng/mL and 1452 (60%) ng/mL, respectively, and the corresponding area under the concentration-time curve (AUC0-Tau) was 8165 (57%) ngh/mL and 20276 (56%) ngh/mL. After a single dose and repeat dosing of brigatinib, systemic exposure of brigatinib was dose proportional over the dose range of 60 mg (0.3 times the approved 180 mg dose) to 240 mg (1.3 times the approved 180 mg dose) once daily. The mean accumulation ratio after repeat dosing was 1.9 to 2.4.

### Absorption
- Following administration of single oral doses of brigatinib of 30 to 240 mg, the median time to peak concentration (Tmax) ranged from 1 to 4 hours.
Effect of Food
- Brigatinib Cmax was reduced by 13% with no effect on AUC in healthy subjects administered brigatinib after a high fat meal (approximately 920 calories, 58 grams carbohydrate, 59 grams fat and 40 grams protein) compared to the Cmax and AUC after overnight fasting.

### Distribution
- Brigatinib is 66% bound to human plasma proteins and the binding is not concentration-dependent in vitro. The blood-to-plasma concentration ratio is 0.69. Following oral administration of brigatinib 180 mg once daily, the mean apparent volume of distribution (Vz/F) of brigatinib at steady-state was 153 L.

### Elimination
- Following oral administration of brigatinib 180 mg once daily, the mean apparent oral clearance (CL/F) of brigatinib at steady-state is 12.7 L/h and the mean plasma elimination half-life is 25 hours.
Metabolism
- Brigatinib is primarily metabolized by CYP2C8 and CYP3A4 in vitro. Following oral administration of a single 180 mg dose of radiolabeled brigatinib to healthy subjects, N-demethylation and cysteine conjugation were the two major metabolic pathways. Unchanged brigatinib (92%) and its primary metabolite, AP26123 (3.5%), were the major circulating radioactive components. The steady-state AUC of AP26123 was less than 10% of AUC of brigatinib exposure in patients. The metabolite, AP26123, inhibited ALK with approximately 3-fold lower potency than brigatinib in vitro.
Excretion
- Following oral administration of a single 180 mg dose of radiolabeled brigatinib to healthy subjects, 65% of the administered dose was recovered in feces and 25% of the administered dose was recovered in urine. Unchanged brigatinib represented 41% and 86% of the total radioactivity in feces and urine, respectively.

### Specific Populations
- Age, race, sex, body weight, and albumin concentration have no clinically meaningful effect on the pharmacokinetics of brigatinib.
Hepatic Impairment
- As hepatic elimination is a major route of excretion for brigatinib, hepatic impairment may result in increased plasma brigatinib concentrations. Based on a population pharmacokinetic analysis, brigatinib exposures were similar between 49 subjects with mild hepatic impairment (total bilirubin within upper limit of normal  and AST greater than ULN or total bilirubin greater than 1 and up to 1.5 times ULN and any AST) and 377 subjects with normal hepatic function (total bilirubin and AST within ULN). The pharmacokinetics of brigatinib in patients with moderate (total bilirubin greater than 1.5 and up to 3.0 times ULN and any AST) to severe (total bilirubin greater than 3.0 times ULN and any AST) hepatic impairment has not been studied.
Renal Impairment
Based on a population pharmacokinetic analysis, brigatinib exposures were similar among 125 subjects with mild renal impairment (CLcr 60 to less than 90 mL/min), 34 subjects with moderate renal impairment (CLcr 30 to less than 60 mL/min) and 270 subjects with normal renal function (CLcr greater than or equal to 90 mL/min), suggesting that no dose adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment (CLcr less than 30 mL/min) were not included in clinical trials.

### Drug Interactions
Effects of Other Drugs on Brigatinib
- Strong CYP3A Inhibitors: Coadministration of 200 mg twice daily doses of itraconazole (a strong CYP3A inhibitor) with a single 90 mg dose of brigatinib increased brigatinib Cmax by 21% and AUC0-INF by 101%, relative to a 90 mg dose of brigatinib administered alone.
- Strong CYP2C8 Inhibitors: Coadministration of 600 mg twice daily doses of gemfibrozil (a strong CYP2C8 inhibitor) with a single 90 mg dose of brigatinib decreased brigatinib Cmax by 41% and AUC0-INF by 12%, relative to a 90 mg dose of brigatinib administered alone. The effect of gemfibrozil on the pharmacokinetics of brigatinib is not clinically meaningful and the underlying mechanism for the decreased exposure of brigatinib is unknown.
- Strong CYP3A Inducers: Coadministration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with a single 180 mg dose of brigatinib decreased brigatinib Cmax by 60% and AUC0-INF by 80%, relative to a 180 mg dose of brigatinib administered alone.
- P-gp and BCRP Inhibitors: In vitro studies suggest that brigatinib is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Given that brigatinib exhibits high solubility and high permeability in vitro, P-gp and BCRP inhibitors are unlikely to increase plasma concentrations of brigatinib.
- Other Transporters: Brigatinib is not a substrate of organic anion transporting polypeptide (OATP1B1, OATP1B3), organic anion transporter (OAT1, OAT3), organic cation transporter (OCT1, OCT2), multidrug and toxin extrusion protein (MATE1, MATE2K), or bile salt export pump (BSEP).
Effects of Brigatinib on Other Drugs
- Transporter Substrates: Brigatinib is an inhibitor of P-gp, BCRP, OCT1, MATE1, and MATE2K in vitro. Therefore, brigatinib may have the potential to increase concentrations of coadministered substrates of these transporters. Brigatinib at clinically relevant concentrations did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, OCT2 or BSEP.
- CYP Substrates: Brigatinib and its primary metabolite, AP26123, did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5 at clinically relevant concentrations.
- Brigatinib, at clinically relevant plasma concentrations, induced CYP3A via activation of the pregnane X receptor (PXR). Brigatinib may also induce CYP2C enzymes via the same mechanism at clinically relevant concentrations.

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity studies have not been performed with brigatinib.
- Treatment with brigatinib resulted in chromosomal damage in an in vivo mammalian erythrocyte micronucleus in the rat, but was not mutagenic in the Ames or in vitro mammalian chromosome aberration tests.
- Dedicated animal fertility studies were not conducted with brigatinib. Testicular toxicity was observed in repeat-dose animal studies at doses resulting in exposure as low as 0.2 times the exposure in patients at the 180 mg dose. In rats, findings included lower weight of testes, seminal vesicles and prostate gland, and testicular tubular degeneration; these effects were not reversible during the 2-month recovery period. In monkeys, findings included reduced size of testes along with microscopic evidence of hypospermatogenesis; these effects were reversible during the recovery period.

# Clinical Studies
- The efficacy of brigatinib was demonstrated in a two-arm, open-label, multicenter trial (ALTA, NCT02094573) in adult patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who had progressed on crizotinib. The study required patients to have a documented ALK rearrangement based on an FDA-approved test or a different test with adequate archival tissue to confirm ALK arrangement by the Vysis ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit test. Key eligibility criteria included an ECOG Performance Status of 0-2 and progression on crizotinib. Neurologically stable patients with central nervous system (CNS) metastases were permitted to enroll. Patients with a history of interstitial lung disease or drug-related pneumonitis or who had received crizotinib within 3 days of the first dose of brigatinib were excluded. The major efficacy outcome measure was confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by an Independent Review Committee (IRC). Additional efficacy outcome measures included Investigator-assessed ORR, duration of response (DOR), intracranial ORR, and intracranial DOR.
- A total of 222 patients were randomized to receive brigatinib either 90 mg once daily (90 mg arm; n=112) or 180 mg once daily following a 7-day lead-in at 90 mg once daily (90180 mg arm; n=110). Randomization was stratified by brain metastases (present versus absent) and best prior response to crizotinib (complete or partial response versus any other response/unevaluable).
- Baseline demographic characteristics of the overall study population were: median age 54 years (range 18 to 82, 23% 65 and over), 67% White and 31% Asian, 57% female, 36% ECOG PS 0 and 57% ECOG PS 1, and 95% never or former smokers. The disease characteristics of the overall study population were: Stage IV disease in 98%, adenocarcinoma histology in 97%, prior systemic chemotherapy in 74%, metastatic disease to the brain in 69% (61% had received prior radiation to the brain), bone metastases in 39%, and liver metastases in 26% of patients. Sixty-four percent of patients had an objective response to prior crizotinib.
- The median duration of follow-up was 8 months (range: 0.1-20.2). Efficacy results from ALTA are summarized in Table 5.
- IRC assessment of intracranial ORR and intracranial DOR according to RECIST v1.1 in the subgroup of 44 patients with measurable brain metastases (10 mm in longest diameter) at baseline are summarized in Table 6. Duration of intracranial response was measured from date of first intracranial response until intracranial disease progression (new lesions, intracranial target lesion diameter growth 20% from nadir, or unequivocal progression of intracranial non-target lesions) or death.
- Among the 23 patients who exhibited an intracranial response, 78% of patients in the 90 mg arm and 68% of patients in the 90180 mg arm maintained a response for at least 4 months.

# How Supplied
- 30 mg tablets: round, white to off-white film-coated tablet with "U3" debossed on one side and plain on the other side; available in:
- Bottles of 21 tablets (NDC 76189-113-21)
- Bottles of 180 tablets (NDC 76189-113-18)
- 90 mg tablets: oval, white to off-white film-coated tablet with "U7" debossed on one side and plain on the other side; available in:
- Bottles of 7 tablets (NDC 76189-119-07)
- Bottles of 30 tablets (NDC 76189-119-30)

## Storage
- Store at controlled room temperature 20C to 25C (68F to 77F); excursion permitted between 15C to 30C (59F to 86F).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information

### Interstitial Lung Disease (ILD)/Pneumonitis
- Inform patients of the symptoms and risks of serious pulmonary adverse reactions such as ILD/pneumonitis. Advise patients to immediately report any new or worsening respiratory symptoms

### Hypertension
- Advise patients of risks of hypertension and to promptly report signs or symptoms of hypertension.

### Bradycardia
- Advise patients to report any symptoms of bradycardia and to inform their healthcare provider about the use of heart and blood pressure medications.

### Visual Disturbance
- Advise patients to inform their healthcare provider of any new or worsening vision symptoms.

### Creatine Phosphokinase (CPK) Elevation
- Inform patients of the signs and symptoms of creatinine phosphokinase (CPK) elevation and the need for monitoring during treatment. Advise patients to inform their healthcare provider of any new or worsening symptoms of unexplained muscle pain, tenderness, or weakness.

### Pancreatic Enzyme Elevation
- Inform patients of the signs and symptoms of pancreatitis and the need to monitor for amylase and lipase elevations during treatment.

### Hyperglycemia
- Inform patients of the risks of new or worsening hyperglycemia and the need to periodically monitor glucose levels. Advise patients with diabetes mellitus or glucose intolerance that anti-hyperglycemic medications may need to be adjusted during treatment with brigatinib.

### Females and Males of Reproductive Potential
Embryo-Fetal Toxicity
- Advise females and males of reproductive potential that brigatinib can cause fetal harm.
- Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy and to use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months after the final dose.
- Advise males with female partners of reproductive potential to use effective contraception during treatment with brigatinib and for at least 3 months after the final dose.
Lactation
- Advise females not to breastfeed during treatment with brigatinib and for at least 1 week following the final dose.
Infertility
- Advise males of reproductive potential of the potential for reduced fertility from brigatinib.

### Drug Interactions
- Advise patients to inform their health care provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid grapefruit or grapefruit juice while taking brigatinib.

### Dosing and Administration
- Instruct patients to start with 90 mg of brigatinib once daily for the first 7 days and if tolerated, increase the dose to 180 mg once daily. Advise patients to take brigatinib with or without food.

### Missed Dose
- Advise patients that if a dose of brigatinib is missed or if the patient vomits after taking a dose of brigatinib, not to take an extra dose, but to take the next dose at the regular time.

# Precautions with Alcohol
Alcohol-Brigatinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
- Alunbrig

# Look-Alike Drug Names
There is limited information regarding Brigatinib Look-Alike Drug Names in the drug label.

# Drug Shortage Status
Drug Shortage

# Price